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Sample records for mutation frequency due

  1. Selection-driven accumulation of suppressor mutants in bacillus subtilis: the apparent high mutation frequency of the cryptic gudB gene and the rapid clonal expansion of gudB(+) suppressors are due to growth under selection.

    PubMed

    Gunka, Katrin; Stannek, Lorena; Care, Rachel A; Commichau, Fabian M

    2013-01-01

    Soil bacteria like Bacillus subtilis can cope with many growth conditions by adjusting gene expression and metabolic pathways. Alternatively, bacteria can spontaneously accumulate beneficial mutations or shape their genomes in response to stress. Recently, it has been observed that a B. subtilis mutant lacking the catabolically active glutamate dehydrogenase (GDH), RocG, mutates the cryptic gudB(CR) gene at a high frequency. The suppressor mutants express the active GDH GudB, which can fully replace the function of RocG. Interestingly, the cryptic gudB(CR) allele is stably inherited as long as the bacteria synthesize the functional GDH RocG. Competition experiments revealed that the presence of the cryptic gudB(CR) allele provides the bacteria with a selective growth advantage when glutamate is scarce. Moreover, the lack of exogenous glutamate is the driving force for the selection of mutants that have inactivated the active gudB gene. In contrast, two functional GDHs are beneficial for the cells when glutamate was available. Thus, the amount of GDH activity strongly affects fitness of the bacteria depending on the availability of exogenous glutamate. At a first glance the high mutation frequency of the cryptic gudB(CR) allele might be attributed to stress-induced adaptive mutagenesis. However, other loci on the chromosome that could be potentially mutated during growth under the selective pressure that is exerted on a GDH-deficient mutant remained unaffected. Moreover, we show that a GDH-proficient B. subtilis strain has a strong selective growth advantage in a glutamate-dependent manner. Thus, the emergence and rapid clonal expansion of the active gudB allele can be in fact explained by spontaneous mutation and growth under selection without an increase of the mutation rate. Moreover, this study shows that the selective pressure that is exerted on a maladapted bacterium strongly affects the apparent mutation frequency of mutational hot spots.

  2. Inherited thrombocytopenia due to GATA-1 mutations.

    PubMed

    Millikan, Patrick D; Balamohan, Sanjeev M; Raskind, Wendy H; Kacena, Melissa A

    2011-09-01

    The GATA family of transcription factors, including the founding member, GATA-1, have an important role in gene regulation. GATA-1 is integral to successful hematopoiesis. A wide variety of mutations in GATA-1 affect its function, as well as its interaction with its cofactors (especially Friend of GATA) and the genes upon which GATA-1 acts. Here we review the known mutations, focusing on the specific alterations within the amino acid sequence, the resulting effect on hematopoietic development, and the clinical manifestations that result. Attention is also paid to the relationship between Trisomy 21, also known as Down syndrome, and the phenomenon of a truncated GATA-1, named GATA-1s. The evidence for specific interaction between GATA-1 and chromosome 21, which may explain the correlation between these two mutations, is briefly reviewed.

  3. Cancer risk in space due to radiation assessed by determining cell lethality and mutation frequencies of prokaryotes and a plasmid during the Second International Microgravity Laboratory (IML-2) Space Shuttle experiment.

    PubMed

    Harada, K; Obiya, Y; Nakano, T; Kawashima, M; Miki, T; Kobayashi, Y; Watanabe, H; Okaichi, K; Ohnishi, T; Mukai, C; Nagaoka, S

    1997-01-01

    We participated in a space experiment conducted during the 2nd International Microgravity Laboratory Mission (IML-2) project. The aim of our study was to investigate the effects of space radiation, i.e., high-LET (linear energy transfer) cosmic radiation, on living organisms in the 'Realtime Radiation Monitoring Device (RRMD)'. The biological samples, dried E. coli DNA repair-deficient mutant cells and shuttle vector plasmid pZl89 DNA, were prepared and placed in a biospecimen box sandwiched between 'Harzlas' plastic radiation detectors. This box was then loaded into the RRMD sensor unit in the Space Shuttle 'Columbia' and an identical box was left in the NASA John F. Kennedy Space Center (KSC) as a control. 'Columbia' (flight No. STS-65) was launched from KSC in Florida, USA on July 8, 1994. The mission duration was 14.75 days and after 'Columbia' returned to earth, we studied (i) the lethal and mutagenic effects of high-LET cosmic radiation on E. coli mutants and (ii) the relationship between high-LET cosmic radiation and the mutation frequency of pZ189 DNA. There were virtually no differences between the cell viabilities of the space and control samples of Escherichia coli KMBL3835 (wild-type), KY383 (lexA-), KY385 (recA-) and KY386 (uvrA-), nor between the mutation frequency ratios of the space and control E. coli mutant samples. Furthermore, the survival and mutation frequency of the supF gene of pZ189 DNA space samples did not differ from those of the control samples. We concluded there was no cancer risk during this Space Shuttle flight.

  4. Normosmic Congenital Hypogonadotropic Hypogonadism Due to TAC3/TACR3 Mutations: Characterization of Neuroendocrine Phenotypes and Novel Mutations

    PubMed Central

    Voican, Adela; Amazit, Larbi; Trabado, Séverine; Fagart, Jérôme; Meduri, Geri; Brailly-Tabard, Sylvie; Chanson, Philippe; Lecomte, Pierre; Guiochon-Mantel, Anne; Young, Jacques

    2011-01-01

    Context TAC3/TACR3 mutations have been reported in normosmic congenital hypogonadotropic hypogonadism (nCHH) (OMIM #146110). In the absence of animal models, studies of human neuroendocrine phenotypes associated with neurokinin B and NK3R receptor dysfunction can help to decipher the pathophysiology of this signaling pathway. Objective To evaluate the prevalence of TAC3/TACR3 mutations, characterize novel TACR3 mutations and to analyze neuroendocrine profiles in nCHH caused by deleterious TAC3/TACR3 biallelic mutations. Results From a cohort of 352 CHH, we selected 173 nCHH patients and identified nine patients carrying TAC3 or TACR3 variants (5.2%). We describe here 7 of these TACR3 variants (1 frameshift and 2 nonsense deleterious mutations and 4 missense variants) found in 5 subjects. Modeling and functional studies of the latter demonstrated the deleterious consequence of one missense mutation (Tyr267Asn) probably caused by the misfolding of the mutated NK3R protein. We found a statistically significant (p<0.0001) higher mean FSH/LH ratio in 11 nCHH patients with TAC3/TACR3 biallelic mutations than in 47 nCHH patients with either biallelic mutations in KISS1R, GNRHR, or with no identified mutations and than in 50 Kallmann patients with mutations in KAL1, FGFR1 or PROK2/PROKR2. Three patients with TAC3/TACR3 biallelic mutations had an apulsatile LH profile but low-frequency alpha-subunit pulses. Pulsatile GnRH administration increased alpha-subunit pulsatile frequency and reduced the FSH/LH ratio. Conclusion The gonadotropin axis dysfunction associated with nCHH due to TAC3/TACR3 mutations is related to a low GnRH pulsatile frequency leading to a low frequency of alpha-subunit pulses and to an elevated FSH/LH ratio. This ratio might be useful for pre-screening nCHH patients for TAC3/TACR3 mutations. PMID:22031817

  5. Accelerating Mutational Load Is Not Due to Synergistic Epistasis or Mutator Alleles in Mutation Accumulation Lines of Yeast.

    PubMed

    Jasmin, Jean-Nicolas; Lenormand, Thomas

    2016-02-01

    Much of our knowledge about the fitness effects of new mutations has been gained from mutation accumulation (MA) experiments. Yet the fitness effect of single mutations is rarely measured in MA experiments. This raises several issues, notably for inferring epistasis for fitness. The acceleration of fitness decline in MA lines has been taken as evidence for synergistic epistasis, but establishing the role of epistasis requires measuring the fitness of genotypes carrying known numbers of mutations. Otherwise, accelerating fitness loss could be explained by increased genetic mutation rates. Here we segregated mutations accumulated over 4800 generations in haploid and diploid MA lines of the yeast Saccharomyces cerevisiae. We found no correspondence between an accelerated fitness decline and synergistic epistasis among deleterious mutations in haploid lines. Pairs of mutations showed no overall epistasis. Furthermore, several lines of evidence indicate that genetic mutation rates did not increase in the MA lines. Crucially, segregant fitness analyses revealed that MA accelerated in both haploid and diploid lines, even though the fitness of diploid lines was nearly constant during the MA experiment. This suggests that the accelerated fitness decline in haploids was caused by cryptic environmental factors that increased mutation rates in all lines during the last third of the lines' transfers. In addition, we provide new estimates of deleterious mutation rates, including lethal mutations, and highlight that nearly all the mutational load we observed was due to one or two mutations having a large effect on fitness.

  6. Mutated tumor alleles are expressed according to their DNA frequency.

    PubMed

    Castle, John C; Loewer, Martin; Boegel, Sebastian; Tadmor, Arbel D; Boisguerin, Valesca; de Graaf, Jos; Paret, Claudia; Diken, Mustafa; Kreiter, Sebastian; Türeci, Özlem; Sahin, Ugur

    2014-04-22

    The transcription of tumor mutations from DNA into RNA has implications for biology, epigenetics and clinical practice. It is not clear if mutations are in general transcribed and, if so, at what proportion to the wild-type allele. Here, we examined the correlation between DNA mutation allele frequency and RNA mutation allele frequency. We sequenced the exome and transcriptome of tumor cell lines with large copy number variations, identified heterozygous single nucleotide mutations and absolute DNA copy number, and determined the corresponding DNA and RNA mutation allele fraction. We found that 99% of the DNA mutations in expressed genes are expressed as RNA. Moreover, we found a high correlation between the DNA and RNA mutation allele frequency. Exceptions are mutations that cause premature termination codons and therefore activate nonsense-mediated decay. Beyond this, we did not find evidence of any wide-scale mechanism, such as allele-specific epigenetic silencing, preferentially promoting mutated or wild-type alleles. In conclusion, our data strongly suggest that genes are equally transcribed from all alleles, mutated and wild-type, and thus transcribed in proportion to their DNA allele frequency.

  7. Comparison of somatic mutation frequency among immunoglobulin genes.

    PubMed

    Motoyama, N; Miwa, T; Suzuki, Y; Okada, H; Azuma, T

    1994-02-01

    We analyzed the frequency of somatic mutation in immunoglobulin genes from hybridomas that secrete anti-(4-hydroxy-3-nitrophenyl)acetyl (NP) monoclonal antibodies. A high frequency of mutation (3.3-4.4%) was observed in both the rearranged VH186.2 and V lambda 1 genes, indicating that somatic mutation occurs with similar frequency in these genes in spite of the absence of an intron enhancer in lambda 1 chain genes. In contrast to the high frequency in J-C introns, only two nucleotide substitutions occurred at positions -462 and -555 in the 5' noncoding region in one of the lambda 1-chain genes and in none of the other three so far studied. Since a similar low frequency of somatic mutation was observed in the 5' noncoding region of inactive lambda 2-chain genes rendered inactive because of incorrect rearrangement, this region may not be a target or alternatively, may be protected from the mutator system. We observed a low frequency of nucleotide substitution in unrearranged V lambda 1 genes (approximately 1/15 that of rearranged genes). Together with previous results (Azuma T., N. Motoyama, L. Fields, and D. Loh, 1993. Int. Immunol. 5:121), these findings suggest that the 5' noncoding region, which contains the promoter element, provides a signal for the somatic mutator system and that rearrangement, which brings the promoter into close proximity to the enhancer element, should increase mutation efficiency.

  8. Estimating Exceptionally Rare Germline and Somatic Mutation Frequencies via Next Generation Sequencing

    PubMed Central

    Yoon, Song-Ro; Arnheim, Norman; Calabrese, Peter

    2016-01-01

    We used targeted next generation deep-sequencing (Safe Sequencing System) to measure ultra-rare de novo mutation frequencies in the human male germline by attaching a unique identifier code to each target DNA molecule. Segments from three different human genes (FGFR3, MECP2 and PTPN11) were studied. Regardless of the gene segment, the particular testis donor or the 73 different testis pieces used, the frequencies for any one of the six different mutation types were consistent. Averaging over the C>T/G>A and G>T/C>A mutation types the background mutation frequency was 2.6x10-5 per base pair, while for the four other mutation types the average background frequency was lower at 1.5x10-6 per base pair. These rates far exceed the well documented human genome average frequency per base pair (~10−8) suggesting a non-biological explanation for our data. By computational modeling and a new experimental procedure to distinguish between pre-mutagenic lesion base mismatches and a fully mutated base pair in the original DNA molecule, we argue that most of the base-dependent variation in background frequency is due to a mixture of deamination and oxidation during the first two PCR cycles. Finally, we looked at a previously studied disease mutation in the PTPN11 gene and could easily distinguish true mutations from the SSS background. We also discuss the limits and possibilities of this and other methods to measure exceptionally rare mutation frequencies, and we present calculations for other scientists seeking to design their own such experiments. PMID:27341568

  9. Atypical Progeroid Syndrome due to Heterozygous Missense LMNA Mutations

    PubMed Central

    Garg, Abhimanyu; Subramanyam, Lalitha; Agarwal, Anil K.; Simha, Vinaya; Levine, Benjamin; D'Apice, Maria Rosaria; Novelli, Giuseppe; Crow, Yanick

    2009-01-01

    Context: Hutchinson-Gilford progeria syndrome (HGPS) and mandibuloacral dysplasia are well-recognized allelic autosomal dominant and recessive progeroid disorders, respectively, due to mutations in lamin A/C (LMNA) gene. Heterozygous LMNA mutations have also been reported in a small number of patients with a less well-characterized atypical progeroid syndrome (APS). Objective: The objective of the study was to investigate the underlying genetic and molecular basis of the phenotype of patients presenting with APS. Results: We report 11 patients with APS from nine families, many with novel heterozygous missense LMNA mutations, such as, P4R, E111K, D136H, E159K, and C588R. These and previously reported patients now reveal a spectrum of clinical features including progeroid manifestations such as short stature, beaked nose, premature graying, partial alopecia, high-pitched voice, skin atrophy over the hands and feet, partial and generalized lipodystrophy with metabolic complications, and skeletal anomalies such as mandibular hypoplasia and mild acroosteolysis. Skin fibroblasts from these patients when assessed for lamin A/C expression using epifluorescence microscopy revealed variable nuclear morphological abnormalities similar to those observed in patients with HGPS. However, these nuclear abnormalities in APS patients could not be rescued with 48 h treatment with farnesyl transferase inhibitors, geranylgeranyl transferase inhibitors or trichostatin-A, a histone deacetylase inhibitor. Immunoblots of cell lysates from fibroblasts did not reveal prelamin A accumulation in any of these patients. Conclusions: APS patients have a few overlapping but some distinct clinical features as compared with HGPS and mandibuloacral dysplasia. The pathogenesis of clinical manifestations in APS patients seems not to be related to accumulation of mutant farnesylated prelamin A. PMID:19875478

  10. Allele frequencies at microsatellite loci: The stepwise mutation model revisited

    SciTech Connect

    Valdes, A.M.; Slatkin, M. ); Freimer, N.B. )

    1993-03-01

    The authors summarize available data on the frequencies of alleles at microsatellite loci in human populations and compare observed distributions of allele frequencies to those generated by a simulation of the stepwise mutation model. They show that observed frequency distributions at 108 loci are consistent with the results of the model under the assumption that mutations cause an increase or decrease in repeat number by one and under the condition that the product Nu, where N is the effective population size and u is the mutation rate, is larger than one. It is also shown that the variance of the distribution of allele sizes is a useful estimator of Nu and performs much better than previously suggested estimators for the stepwise mutation model. In the data, there is no correlation between the mean and variance in allele size at a locus or between the number of alleles and mean allele size, which suggests that the mutation rate at these loci is independent of allele size. 39 refs., 6 figs., 4 tabs.

  11. Comments on Landau damping due to synchrotron frequency spread

    SciTech Connect

    Ng, K.Y.; /Fermilab

    2005-01-01

    An inductive/space-charge impedance shifts the synchrotron frequency downwards above/below transition, but it is often said that the coherent synchrotron frequency of the bunch is not shifted in the rigid-dipole mode. On the other hand, the incoherent synchrotron frequency due to the sinusoidal rf always spreads in the downward direction. This spread will therefore not be able to cover the coherent synchrotron frequency, implying that there will not be any Landau damping no matter how large the frequency spread is. By studying the dispersion relation, it is shown that the above argument is incorrect, and there will be Landau damping if there is sufficient frequency spread. The main reason is that the coherent frequency of the rigid-dipole mode will no longer remain unshifted in the presence of a synchrotron frequency spread.

  12. Determination and Therapeutic Exploitation of Ebola Virus Spontaneous Mutation Frequency

    PubMed Central

    Alfson, Kendra J.; Worwa, Gabriella; Carrion, Ricardo

    2015-01-01

    ABSTRACT Ebola virus (EBOV) is an RNA virus that can cause hemorrhagic fever with high fatality rates, and there are no approved vaccines or therapies. Typically, RNA viruses have high spontaneous mutation rates, which permit rapid adaptation to selection pressures and have other important biological consequences. However, it is unknown if filoviruses exhibit high mutation frequencies. Ultradeep sequencing and a recombinant EBOV that carries the gene encoding green fluorescent protein were used to determine the spontaneous mutation frequency of EBOV. The effects of the guanosine analogue ribavirin during EBOV infections were also assessed. Ultradeep sequencing revealed that the mutation frequency for EBOV was high and similar to those of other RNA viruses. Interestingly, significant genetic diversity was not observed in viable viruses, implying that changes were not well tolerated. We hypothesized that this could be exploited therapeutically. In vitro, the presence of ribavirin increased the error rate, and the 50% inhibitory concentration (IC50) was 27 μM. In a mouse model of ribavirin therapy given pre-EBOV exposure, ribavirin treatment corresponded with a significant delay in time to death and up to 75% survival. In mouse and monkey models of therapy given post-EBOV exposure, ribavirin treatment also delayed the time to death and increased survival. These results demonstrate that EBOV has a spontaneous mutation frequency similar to those of other RNA viruses. These data also suggest a potential for therapeutic use of ribavirin for human EBOV infections. IMPORTANCE Ebola virus (EBOV) causes a severe hemorrhagic disease with high case fatality rates; there are no approved vaccines or therapies. We determined the spontaneous mutation frequency of EBOV, which is relevant to understanding the potential for the virus to adapt. The frequency was similar to those of other RNA viruses. Significant genetic diversity was not observed in viable viruses, implying that

  13. Frequency and Complexity of De Novo Structural Mutation in Autism

    PubMed Central

    Brandler, William M.; Antaki, Danny; Gujral, Madhusudan; Noor, Amina; Rosanio, Gabriel; Chapman, Timothy R.; Barrera, Daniel J.; Lin, Guan Ning; Malhotra, Dheeraj; Watts, Amanda C.; Wong, Lawrence C.; Estabillo, Jasper A.; Gadomski, Therese E.; Hong, Oanh; Fajardo, Karin V. Fuentes; Bhandari, Abhishek; Owen, Renius; Baughn, Michael; Yuan, Jeffrey; Solomon, Terry; Moyzis, Alexandra G.; Maile, Michelle S.; Sanders, Stephan J.; Reiner, Gail E.; Vaux, Keith K.; Strom, Charles M.; Zhang, Kang; Muotri, Alysson R.; Akshoomoff, Natacha; Leal, Suzanne M.; Pierce, Karen; Courchesne, Eric; Iakoucheva, Lilia M.; Corsello, Christina; Sebat, Jonathan

    2016-01-01

    Genetic studies of autism spectrum disorder (ASD) have established that de novo duplications and deletions contribute to risk. However, ascertainment of structural variants (SVs) has been restricted by the coarse resolution of current approaches. By applying a custom pipeline for SV discovery, genotyping, and de novo assembly to genome sequencing of 235 subjects (71 affected individuals, 26 healthy siblings, and their parents), we compiled an atlas of 29,719 SV loci (5,213/genome), comprising 11 different classes. We found a high diversity of de novo mutations, the majority of which were undetectable by previous methods. In addition, we observed complex mutation clusters where combinations of de novo SVs, nucleotide substitutions, and indels occurred as a single event. We estimate a high rate of structural mutation in humans (20%) and propose that genetic risk for ASD is attributable to an elevated frequency of gene-disrupting de novo SVs, but not an elevated rate of genome rearrangement. PMID:27018473

  14. Pre-thymic somatic mutation leads to high mutant frequency at hypoxanthine-guanine phosphoribosyltransferase gene

    SciTech Connect

    Jett, J.

    1994-12-01

    While characterizing the background mutation spectrum of the Hypoxathine-guanine phosphoribosyltransferase (HPRT) gene in a healthy population, an outlier with a high mutant frequency of thioguanine resistant lymphocytes was found. When studied at the age of 46, this individual had been smoking 60 cigarettes per day for 38 years. His mutant frequency was calculated at 3.6 and 4.2x10{sup {minus}4} for two sampling periods eight months apart. Sequencing analysis of the HPRT gene in his mutant thioguanine resistant T lymphocytes was done to find whether the cells had a high rate of mutation, or if the mutation was due to a single occurrence of mutation and, if so, when in the T lymphocyte development the mutation occurred. By T-cell receptor analysis it has been found that out of 35 thioguanine resistant clones there was no dominant gamma T cell receptor gene rearrangement. During my appointment in the Science & Engineering Research Semester, I found that 34 of those clones have the same base substitution of G{yields}T at cDNA position 197. Due to the consistent mutant frequency from both sampling periods and the varying T cell receptors, the high mutant frequency cannot be due to recent proliferation of a mature mutant T lymphocyte. From the TCR and DNA sequence analysis we conclude that the G{yields}T mutation must have occurred in a T lymphocyte precursor before thymic differentiation so that the thioguanine resistant clones share the same base substitution but not the same gamma T cell receptor gene.

  15. HIV-1 pol mutation frequency by subtype and treatment experience

    PubMed Central

    Rhee, Soo-Yon; Kantor, Rami; Katzenstein, David A.; Camacho, Ricardo; Morris, Lynn; Sirivichayakul, Sunee; Jorgensen, Louise; Brigido, Luis F.; Schapiro, Jonathan M.; Shafer, Robert W.

    2008-01-01

    Objective HIVseq was developed in 2000 to make published data on the frequency of HIV-1 group M protease and reverse transcriptase (RT) mutations available in real time to laboratories and researchers sequencing these genes. Because most published protease and RT sequences belonged to subtype B, the initial version of HIVseq was based on this subtype. As additional non-B sequences from persons with well-characterized antiretroviral treatment histories have become available, the program has been extended to subtypes A, C, D, F, G, CRF01, and CRF02. Methods The latest frequency of each protease and RT mutation according to subtype and drug-class exposure was calculated using published sequences in the Stanford HIV RT and Protease Sequence Database. Each mutation was hyperlinked to published reports of viruses containing the mutation. Results As of September 2005, the mean number of protease sequences per non-B subtype was 534 from protease inhibitor-naive persons and 133 from protease inhibitor-treated persons, representing 13.2% and 2.3%, respectively, of the data available for subtype B. The mean number of RT sequences per non-B subtype was 373 from RT inhibitor-naive persons and 288 from RT inhibitor-treated persons, representing 17.9% and 3.8%, respectively, of the data available for subtype B. Conclusions HIVseq allows users to examine protease and RT mutations within the context of previously published sequences of these genes. The publication of additional non-B protease and RT sequences from persons with well-characterized treatment histories, however, will be required to perform the same types of analysis possible with the much larger number of subtype B sequences. PMID:16514293

  16. PSORS2 is due to mutations in CARD14.

    PubMed

    Jordan, Catherine T; Cao, Li; Roberson, Elisha D O; Pierson, Katherine C; Yang, Chi-Fan; Joyce, Cailin E; Ryan, Caitriona; Duan, Shenghui; Helms, Cynthia A; Liu, Yin; Chen, Yongqing; McBride, Alison A; Hwu, Wuh-Liang; Wu, Jer-Yuarn; Chen, Yuan-Tsong; Menter, Alan; Goldbach-Mansky, Raphaela; Lowes, Michelle A; Bowcock, Anne M

    2012-05-01

    Psoriasis is a common, immune-mediated genetic disorder of the skin and is associated with arthritis in approximately 30% of cases. Previously, we localized PSORS2 (psoriasis susceptibility locus 2) to chromosomal region 17q25.3-qter after a genome-wide linkage scan in a family of European ancestry with multiple cases of psoriasis and psoriatic arthritis. Linkage to PSORS2 was also observed in a Taiwanese family with multiple psoriasis-affected members. In caspase recruitment domain family, member 14 (CARD14), we identified unique gain-of-function mutations that segregated with psoriasis by using genomic capture and DNA sequencing. The mutations c.349G>A (p.Gly117Ser) (in the family of European descent) and c.349+5G>A (in the Taiwanese family) altered splicing between CARD14 exons 3 and 4. A de novo CARD14 mutation, c.413A>C (p.Glu138Ala), was detected in a child with sporadic, early-onset, generalized pustular psoriasis. CARD14 activates nuclear factor kappa B (NF-kB), and compared with wild-type CARD14, the p.Gly117Ser and p.Glu138Ala substitutions were shown to lead to enhanced NF-kB activation and upregulation of a subset of psoriasis-associated genes in keratinocytes. These genes included chemokine (C-C motif) ligand 20 (CCL20) and interleukin 8 (IL8). CARD14 is localized mainly in the basal and suprabasal layers of healthy skin epidermis, whereas in lesional psoriatic skin, it is reduced in the basal layer and more diffusely upregulated in the suprabasal layers of the epidermis. We propose that, after a triggering event that can include epidermal injury, rare gain-of-function mutations in CARD14 initiate a process that includes inflammatory cell recruitment by keratinocytes. This perpetuates a vicious cycle of epidermal inflammation and regeneration, a cycle which is the hallmark of psoriasis.

  17. Virus mutation frequencies can be greatly underestimated by monoclonal antibody neutralization of virions.

    PubMed Central

    Holland, J J; de la Torre, J C; Steinhauer, D A; Clarke, D; Duarte, E; Domingo, E

    1989-01-01

    Monoclonal antibody-resistant mutants have been widely used to estimate virus mutation frequencies. We demonstrate that standard virion neutralization inevitably underestimates monoclonal antibody-resistant mutant genome frequencies of vesicular stomatitis virus, due to phenotypic masking-mixing when wild-type (wt) virions are present in thousandsfold greater numbers. We show that incorporation of antibody into the plaque overlay medium (after virus penetration at 37 degrees C) can provide accurate estimates of genome frequencies of neutral monoclonal antibody-resistant mutant viruses in wt clones. By using this method, we have observed two adjacent G----A base transition frequencies in the I3 epitope to be of the order of 10(-4) in a wt glycine codon. This appears to be slightly lower than the frequencies observed at other sites for total (viable and nonviable) virus genomes when using a direct sequence approach. Images PMID:2479770

  18. Development of ciprofloxacin resistance due to chromosomal mutations induced by 2-nitrofluorene.

    PubMed

    Birosová, Lucia; Mikulásová, Mária

    2005-12-01

    In this paper we investigated the ability of 2-nitrofluorene to induce mutations leading to antibiotic resistance in quinolone-sensitive strain Salmonella typhimurium. After preincubation of bacteria with 2-nitrofluorene, the frequency of mutation to ciprofloxacin resistance was 57 fold higher than in the case of spontaneous mutability. Some of resultant resistant colonies showed a great increase of ciprofloxacin MIC. PMID:16601798

  19. Models of Frequency-Dependent Selection with Mutation from Parental Alleles

    PubMed Central

    Trotter, Meredith V.; Spencer, Hamish G.

    2013-01-01

    Frequency-dependent selection (FDS) remains a common heuristic explanation for the maintenance of genetic variation in natural populations. The pairwise-interaction model (PIM) is a well-studied general model of frequency-dependent selection, which assumes that a genotype’s fitness is a function of within-population intergenotypic interactions. Previous theoretical work indicated that this type of model is able to sustain large numbers of alleles at a single locus when it incorporates recurrent mutation. These studies, however, have ignored the impact of the distribution of fitness effects of new mutations on the dynamics and end results of polymorphism construction. We suggest that a natural way to model mutation would be to assume mutant fitness is related to the fitness of the parental allele, i.e., the existing allele from which the mutant arose. Here we examine the numbers and distributions of fitnesses and alleles produced by construction under the PIM with mutation from parental alleles and the impacts on such measures due to different methods of generating mutant fitnesses. We find that, in comparison with previous results, generating mutants from existing alleles lowers the average number of alleles likely to be observed in a system subject to FDS, but produces polymorphisms that are highly stable and have realistic allele-frequency distributions. PMID:23852384

  20. Detecting ultralow-frequency mutations by Duplex Sequencing

    PubMed Central

    Kennedy, Scott R; Schmitt, Michael W; Fox, Edward J; Kohrn, Brendan F; Salk, Jesse J; Ahn, Eun Hyun; Prindle, Marc J; Kuong, Kawai J; Shen, Jiang-Cheng; Risques, Rosa-Ana; Loeb, Lawrence A

    2014-01-01

    Duplex Sequencing (DS) is a next-generation sequencing methodology capable of detecting a single mutation among >1 × 107 wild-type nucleotides, thereby enabling the study of heterogeneous populations and very-low-frequency genetic alterations. DS can be applied to any double-stranded DNA sample, but it is ideal for small genomic regions of <1 Mb in size. The method relies on the ligation of sequencing adapters harboring random yet complementary double-stranded nucleotide sequences to the sample DNA of interest. Individually labeled strands are then PCR-amplified, creating sequence ‘families’ that share a common tag sequence derived from the two original complementary strands. Mutations are scored only if the variant is present in the PCR families arising from both of the two DNA strands. Here we provide a detailed protocol for efficient DS adapter synthesis, library preparation and target enrichment, as well as an overview of the data analysis workflow. The protocol typically takes 1–3 d. PMID:25299156

  1. The impact of random frequency-dependent mutations on the average population fitness

    PubMed Central

    2012-01-01

    Background In addition to selection, the process of evolution is accompanied by stochastic effects, such as changing environmental conditions, genetic drift and mutations. Commonly it is believed that without genetic drift, advantageous mutations quickly fixate in a halpoid population due to strong selection and lead to a continuous increase of the average fitness. This conclusion is based on the assumption of constant fitness. However, for frequency dependent fitness, where the fitness of an individual depends on the interactions with other individuals in the population, this does not hold. Results We propose a mathematical model that allows to understand the consequences of random frequency dependent mutations on the dynamics of an infinite large population. The frequencies of different types change according to the replicator equations and the fitness of a mutant is random and frequency dependent. To capture the interactions of different types, we employ a payoff matrix of variable size and thus are able to accommodate an arbitrary number of mutations. We assume that at most one mutant type arises at a time. The payoff entries to describe the mutant type are random variables obeying a probability distribution which is related to the fitness of the parent type. Conclusions We show that a random mutant can decrease the average fitness under frequency dependent selection, based on analytical results for two types and simulations for n types. Interestingly, in the case of at most two types the probabilities to increase or decrease the average fitness are independent of the concrete probability density function. Instead, they only depend on the probability that the payoff entries of the mutant are larger than the payoff entries of the parent type. PMID:22935138

  2. Navajo microvillous inclusion disease is due to a mutation in MYO5B.

    PubMed

    Erickson, Robert P; Larson-Thomé, Katherine; Valenzuela, Robert K; Whitaker, Stacia E; Shub, Mitchell D

    2008-12-15

    Microvillous Inclusion Disease (MID) is a rare, autosomal recessive gastrointestinal disease of increased frequency among the Navajos. Previous work has shown a deficiency of RAB8 in one Japanese patient, while homozygous mutations in MYO5B were found in 7 of 10 mostly Middle Eastern families. We have identified a shared homozygous mutation in MYO5B in seven affected Navajos with the expected heterozygosity in five parents. We have developed a simple restriction enzyme based assay that allows for rapid screening for this mutation. PMID:19006234

  3. Mutation frequency and specificity with age in liver, bladder and brain of lacI transgenic mice.

    PubMed Central

    Stuart, G R; Oda, Y; de Boer, J G; Glickman, B W

    2000-01-01

    Mutation frequency and specificity were determined as a function of age in nuclear DNA from liver, bladder, and brain of Big Blue lacI transgenic mice aged 1.5-25 months. Mutations accumulated with age in liver and accumulated more rapidly in bladder. In the brain a small initial increase in mutation frequency was observed in young animals; however, no further increase was observed in adult mice. To investigate the origin of mutations, the mutational spectra for each tissue and age were determined. DNA sequence analysis of mutant lacI transgenes revealed no significant changes in mutational specificity in any tissue at any age. The spectra of mutations found in aging animals were identical to those in younger animals, suggesting that they originated from a common set of DNA lesions manifested during DNA replication. The data also indicated that there were no significant age-related mutational changes due to oxidative damage, or errors resulting from either changes in the fidelity of DNA polymerase or the efficiency of DNA repair. Hence, no evidence was found to support hypotheses that predict that oxidative damage or accumulation of errors in nuclear DNA contributes significantly to the aging process, at least in these three somatic tissues. PMID:10757770

  4. The frequency of point mutations in mitochondrial DNA is elevated in the Alzheimer's brain.

    PubMed

    Chang, S W; Zhang, D; Chung, H D; Zassenhaus, H P

    2000-06-24

    Using a PCR-based strategy, we found that point mutation frequencies in mitochondrial DNA (mtDNA) were 2- to 3-fold higher in the parietal gyrus, hippocampus, and cerebellum from subjects with Alzheimer's disease (AD) compared to normal controls. In contrast, levels of a commonly studied deletion mutation, mtDNA(4977), were not elevated in AD. The frequency of point mutations did not vary significantly among the three brain areas, whereas the frequency of mtDNA(4977) was 15- to 25-fold lower in the cerebellum in comparison to the cortex; this regional variation was seen in both the normal and Alzheimer's brain. In blood mtDNA, point mutation frequencies were not elevated in AD patients. The elevated frequency of point mutations in all three brain regions is consistent with the idea that increased oxidant stress is associated with AD.

  5. Frequency of TERT promoter mutations in human cancers.

    PubMed

    Vinagre, João; Almeida, Ana; Pópulo, Helena; Batista, Rui; Lyra, Joana; Pinto, Vasco; Coelho, Ricardo; Celestino, Ricardo; Prazeres, Hugo; Lima, Luis; Melo, Miguel; da Rocha, Adriana Gaspar; Preto, Ana; Castro, Patrícia; Castro, Ligia; Pardal, Fernando; Lopes, José Manuel; Santos, Lúcio Lara; Reis, Rui Manuel; Cameselle-Teijeiro, José; Sobrinho-Simões, Manuel; Lima, Jorge; Máximo, Valdemar; Soares, Paula

    2013-01-01

    Reactivation of telomerase has been implicated in human tumorigenesis, but the underlying mechanisms remain poorly understood. Here we report the presence of recurrent somatic mutations in the TERT promoter in cancers of the central nervous system (43%), bladder (59%), thyroid (follicular cell-derived, 10%) and skin (melanoma, 29%). In thyroid cancers, the presence of TERT promoter mutations (when occurring together with BRAF mutations) is significantly associated with higher TERT mRNA expression, and in glioblastoma we find a trend for increased telomerase expression in cases harbouring TERT promoter mutations. Both in thyroid cancers and glioblastoma, TERT promoter mutations are significantly associated with older age of the patients. Our results show that TERT promoter mutations are relatively frequent in specific types of human cancers, where they lead to enhanced expression of telomerase. PMID:23887589

  6. Patterns of missplicing due to somatic U2AF1 mutations in myeloid neoplasms

    PubMed Central

    Przychodzen, Bartlomiej; Jerez, Andres; Guinta, Kathryn; Sekeres, Mikkael A.; Padgett, Richard; Maciejewski, Jaroslaw P.

    2013-01-01

    Recently, recurrent mutations of spliceosomal genes were frequently identified in myeloid malignancies, as well as other types of cancers. One of these spliceosomal genes, U2AF1, was affected by canonical somatic mutations in aggressive type of myeloid malignancies. We hypothesized that U2AF1 mutations causes defects of splicing (missplicing) in specific genes and that such misspliced genes might be important in leukemogenesis. We analyzed RNA deep sequencing to compare splicing patterns of 201 837 exons between the cases with U2AF1 mutations (n = 6) and wild type (n = 14). We identified different alternative splicing patterns in 35 genes comparing cells with mutant and wild-type U2AF1. U2AF1 mutations are associated with abnormal splicing of genes involved in functionally important pathways, such as cell cycle progression and RNA processing. In addition, many of these genes are somatically mutated or deleted in various cancers. Of note is that the alternative splicing patterns associated with U2AF1 mutations were associated with specific sequence signals at the affected splice sites. These novel observations support the hypothesis that U2AF1 mutations play a significant role in myeloid leukemogenesis due to selective missplicing of tumor-associated genes. PMID:23775717

  7. Echinocandin failure case due to a previously unreported FKS1 mutation in Candida krusei.

    PubMed

    Jensen, Rasmus Hare; Justesen, Ulrik Stenz; Rewes, Annika; Perlin, David S; Arendrup, Maiken Cavling

    2014-06-01

    Echinocandins are the preferred therapy for invasive infections due to Candida krusei. We present here a case of clinical failure involving C. krusei with a characteristic FKS1 hot spot mutation not previously reported in C. krusei that was isolated after 14 days of treatment. Anidulafungin MICs were elevated by ≥ 5 dilution steps above the clinical breakpoint but by only 1 step for a Candida albicans isolate harboring the corresponding mutation, suggesting a notable species-specific difference in the MIC increase conferred by this mutation. PMID:24687511

  8. Lethal Keratitis, Ichthyosis, and Deafness Syndrome Due to the A88V Connexin 26 Mutation.

    PubMed

    Esmer, Carmen; Salas-Alanis, Julio C; Fajardo-Ramirez, Oscar R; Ramírez, Brenda; Hua, Rong; Choate, Keith

    2016-01-01

    Keratitis-ichthyosis-deafness syndrome is a well-characterized disease that has been related to mutations in the GJB6 gene. Clinical features such as erythrokeratoderma, palmoplantar keratoderma, alopecia, and progressive vascularizing keratitis, among others, are well known in this entity. In this report we describe a newborn female patient diagnosed with keratitis-ichthyosis-deafness syndrome with a lethal outcome due to sepsis. The patient harbored the mutation A88V that has been previously reported in lethal cases.

  9. Lethal Keratitis, Ichthyosis, and Deafness Syndrome Due to the A88V Connexin 26 Mutation.

    PubMed

    Esmer, Carmen; Salas-Alanis, Julio C; Fajardo-Ramirez, Oscar R; Ramírez, Brenda; Hua, Rong; Choate, Keith

    2016-01-01

    Keratitis-ichthyosis-deafness syndrome is a well-characterized disease that has been related to mutations in the GJB6 gene. Clinical features such as erythrokeratoderma, palmoplantar keratoderma, alopecia, and progressive vascularizing keratitis, among others, are well known in this entity. In this report we describe a newborn female patient diagnosed with keratitis-ichthyosis-deafness syndrome with a lethal outcome due to sepsis. The patient harbored the mutation A88V that has been previously reported in lethal cases. PMID:27409001

  10. Frequency of MED12 mutations in phyllodes tumors: Inverse correlation with histologic grade.

    PubMed

    Yoon, Nara; Bae, Go Eun; Kang, So Young; Choi, Mi Sun; Hwang, Hye Won; Kim, Seok Won; Lee, Jeong Eon; Nam, Seok Jin; Gong, Gyungyub; Lee, Hee Jin; Bae, Young Kyung; Lee, Ahwon; Cho, Eun Yoon

    2016-06-01

    Phyllodes tumor (PT) is a rare breast biphasic tumor with a potential risk of recurrence and metastasis. In this study, the frequency of MED12 mutations in 176 PTs (49 benign, 49 borderline, and 78 malignant) was determined and the prognostic effect of these mutations in malignant type PT was evaluated. Analysis of MED12 mutations was performed by Sanger sequencing targeting the hotspot mutation region (exon 2) of MED12. Immunohistochemistry was also applied for evaluation of MED12 protein expression on tissue microarray blocks for 133 PTs including 50 benign, 50 borderline, and 33 malignant cases. A notable difference in the frequency of MED12 mutations was found according to histologic grade (71.4% of benign PTs, 51% of borderline PTs, 26.9% of malignant PTs; P < 0.001). MED12 protein expression was not correlated with MED12 mutation status. Patients with malignant PTs that harbored MED12 mutations demonstrated improved disease-free survival (DFS) compared with those without MED12 mutation (P = 0.07). MED12 mutation was a common molecular alteration in PT and the frequency of MED12 mutation decreased with increasing histologic grade. In malignant PT, MED12 exon 2 mutations showed improved DFS but without significance. © 2016 Wiley Periodicals, Inc.

  11. Frequency of MED12 mutations in phyllodes tumors: Inverse correlation with histologic grade.

    PubMed

    Yoon, Nara; Bae, Go Eun; Kang, So Young; Choi, Mi Sun; Hwang, Hye Won; Kim, Seok Won; Lee, Jeong Eon; Nam, Seok Jin; Gong, Gyungyub; Lee, Hee Jin; Bae, Young Kyung; Lee, Ahwon; Cho, Eun Yoon

    2016-06-01

    Phyllodes tumor (PT) is a rare breast biphasic tumor with a potential risk of recurrence and metastasis. In this study, the frequency of MED12 mutations in 176 PTs (49 benign, 49 borderline, and 78 malignant) was determined and the prognostic effect of these mutations in malignant type PT was evaluated. Analysis of MED12 mutations was performed by Sanger sequencing targeting the hotspot mutation region (exon 2) of MED12. Immunohistochemistry was also applied for evaluation of MED12 protein expression on tissue microarray blocks for 133 PTs including 50 benign, 50 borderline, and 33 malignant cases. A notable difference in the frequency of MED12 mutations was found according to histologic grade (71.4% of benign PTs, 51% of borderline PTs, 26.9% of malignant PTs; P < 0.001). MED12 protein expression was not correlated with MED12 mutation status. Patients with malignant PTs that harbored MED12 mutations demonstrated improved disease-free survival (DFS) compared with those without MED12 mutation (P = 0.07). MED12 mutation was a common molecular alteration in PT and the frequency of MED12 mutation decreased with increasing histologic grade. In malignant PT, MED12 exon 2 mutations showed improved DFS but without significance. © 2016 Wiley Periodicals, Inc. PMID:26856273

  12. Lipoid congenital adrenal hyperplasia due to STAR mutations in a Caucasian patient

    PubMed Central

    Kaur, Jasmeet; Casas, Luis

    2016-01-01

    Summary Lipoid congenital adrenal hyperplasia (lipoid CAH), the most severe form of CAH, is most commonly caused by mutations in steroidogenic acute regulatory protein (STAR), which is required for the movement of cholesterol from the outer to the inner mitochondrial membranes to synthesize pregnenolone. This study was performed to evaluate whether the salt-losing crisis and the adrenal inactivity experienced by a Scandinavian infant is due to a de novo STAR mutation. The study was conducted at the University of North Dakota, the Mercer University School of Medicine and the Memorial University Medical Center to identify the cause of this disease. The patient was admitted to a pediatric endocrinologist at the Sanford Health Center for salt-losing crisis and possible adrenal failure. Lipoid CAH is an autosomal recessive disease, we identified two de novo heterozygous mutations (STAR c.444C>A (STAR p.N148K) and STAR c.557C>T (STAR p.R193X)) in the STAR gene, causing lipoid CAH. New onset lipoid CAH can occur through de novo mutations and is not restricted to any specific region of the world. This Scandinavian family was of Norwegian descent and had lipoid CAH due to a mutation in S TAR exons 4 and 5. Overexpression of the STAR p.N148K mutant in nonsteroidogenic COS-1 cells supplemented with an electron transport system showed activity similar to the background level, which was ∼10% of that observed with wild-type (WT) STAR. Protein-folding analysis showed that the finger printing of the STAR p.N148K mutant is also different from the WT protein. Inherited STAR mutations may be more prevalent in some geographical areas but not necessarily restricted to those regions. Learning points STAR mutations cause lipoid CAH.This is a pure population from a caucasian family.Mutation ablated STAR activity.The mutation resulted in loosely folded conformation of STAR. PMID:27047663

  13. Low frequency of p57KIP2 mutation in Beckwith-Wiedemann syndrome.

    PubMed Central

    Lee, M P; DeBaun, M; Randhawa, G; Reichard, B A; Elledge, S J; Feinberg, A P

    1997-01-01

    Beckwith-Wiedemann syndrome (BWS) is an autosomal dominant disorder of increased prenatal growth and predisposition to embryonal cancers such as Wilms tumor. BWS is thought to involve one or more imprinted genes, since some patients show paternal uniparental disomy, and others show balanced germ-line chromosomal rearrangements involving the maternal chromosome. We previously mapped BWS, by genetic linkage analysis, to 11p15.5, which we and others also found to contain several imprinted genes; these include the gene for insulin-like growth factor II (IGF2) and H19, which show abnormal imprint-specific expression and/or methylation in 20% of BWS patients, and p57KIP2, a cyclin-dependent kinase inhibitor, which we found showed biallelic expression in one of nine BWS patients studied. In addition, p57KIP2 was recently reported to show mutations in two of nine BWS patients. We have now analyzed the entire coding sequence and intron-exon boundaries of p57KIP2 in 40 unrelated BWS patients. Of these patients, only two (5%) showed mutations, both involving frameshifts in the second exon. In one case, the mutation was transmitted to the proband's mother, who was also affected, from the maternal grandfather, suggesting that p57KIP2 is not imprinted in at least some affected tissues at a critical stage of development and that haploinsufficiency due to mutation of either parental allele may cause at least some features of BWS. The low frequency of p57KIP2 mutations, as well as our recent discovery of disruption of the K(v)LQT1 gene in patients with chromosomal rearrangements, suggest that BWS can involve disruption of multiple independent 11p15.5 genes. Images Figure 2 Figure 3 Figure 4 PMID:9311734

  14. Sporadic Hirschsprung`s disease due to a novel nonsense mutation in the RET protooncogene

    SciTech Connect

    Carlson, K.M.; Donis-Keller, H.; Langer, J.C.

    1994-09-01

    Hirschsprung`s disease (HSCR, aganglionic megacolon) is characterized by a lack of ganglion cells along variable lengths of the hindgut. This is most likely due to a failure of the progenitor cells (that are destined to become the ganglion cells of the submucosal and myenteric plexuses) to complete their distal migration in the colon. Recently, mutations in the RET protoocogene have been reported in association with HSCR. We report a novel nonsense mutation resulting in a severely truncated protein. Germline DNA from a panel of 6 HSCR patients was analyzed by SSCP for 20 exons of RET. Eight exons were also directly sequenced. We identified a novel mutation within RET exon 2. The mutation (TAC{sub 36}{yields}TAG{sub 36}), which occurs at nucleotide position 108, involves the replacement of tyrosine with a stop codon and results in a truncated 35 amino acid protein. This mutation is the most 5{prime} nonsense mutation reported thus far. Interestingly, the patient has no prior family history of HSCR and was also diagnosed with multiple developmental anomalies including dysplastic kidney. Recent gene targeting studies with mouse models have shown that RET is essential for normal renal development. However, a parallel phenotype has not been seen in other reported HSCR patients with RET mutations. The observations reported here provide evidence that RET plays a role in human renal development. Ongoing studies will determine the extent of RET involvement in sporadic cases of HSCR.

  15. Permanent neonatal diabetes due to a novel insulin signal peptide mutation

    PubMed Central

    Hussain, Suhaimi; Mohd Ali, Johari; Jalaludin, Muhammad Yazid; Harun, Fatimah

    2013-01-01

    We report a rare case of permanent neonatal diabetes (PND) due to insulin (INS) gene mutation in a 51-month-old girl who presented with hyperglycemia in the neonatal period. Mutational analysis of KCNJ11 and INS was performed and this detected a novel heterozygous c.38T>G (p.Leu13Arg) INS de novo mutation. The non-conservative change substitutes the highly conserved L13 residue within the hydrophobic core region of the preproinsulin signal peptide. Given the frequent tendency of heterozygous INS mutations to exhibit dominant negative disease pathogenesis, it is likely that the mutant preproinsulin perturbed the non-mutant counterpart progression and processing within the β-cells, and this resulted to a permanent form of congenital diabetes. PMID:23350652

  16. Permanent neonatal diabetes due to a novel insulin signal peptide mutation.

    PubMed

    Hussain, Suhaimi; Mohd Ali, Johari; Jalaludin, Muhammad Yazid; Harun, Fatimah

    2013-06-01

    We report a rare case of permanent neonatal diabetes (PND) due to insulin (INS) gene mutation in a 51-month-old girl who presented with hyperglycemia in the neonatal period. Mutational analysis of KCNJ11 and INS was performed and this detected a novel heterozygous c.38T>G (p.Leu13Arg) INS de novo mutation. The non-conservative change substitutes the highly conserved L(13) residue within the hydrophobic core region of the preproinsulin signal peptide. Given the frequent tendency of heterozygous INS mutations to exhibit dominant negative disease pathogenesis, it is likely that the mutant preproinsulin perturbed the non-mutant counterpart progression and processing within the β-cells, and this resulted to a permanent form of congenital diabetes.

  17. Unravelling 5-oxoprolinuria (pyroglutamic aciduria) due to bi-allelic OPLAH mutations: 20 new mutations in 14 families.

    PubMed

    Sass, Jörn Oliver; Gemperle-Britschgi, Corinne; Tarailo-Graovac, Maja; Patel, Nisha; Walter, Melanie; Jordanova, Albena; Alfadhel, Majid; Barić, Ivo; Çoker, Mahmut; Damli-Huber, Aynur; Faqeih, Eissa Ali; García Segarra, Nuria; Geraghty, Michael T; Jåtun, Bjørn Magne; Kalkan Uçar, Sema; Kriewitz, Merten; Rauchenzauner, Markus; Bilić, Karmen; Tournev, Ivailo; Till, Claudia; Sayson, Bryan; Beumer, Daniel; Ye, Cynthia Xin; Zhang, Lin-Hua; Vallance, Hilary; Alkuraya, Fowzan S; van Karnebeek, Clara D M

    2016-09-01

    Primary 5-oxoprolinuria (pyroglutamic aciduria) is caused by a genetic defect in the γ-glutamyl cycle, affecting either glutathione synthetase or 5-oxoprolinase. While several dozens of patients with glutathione synthetase deficiency have been reported, with hemolytic anemia representing the clinical key feature, 5-oxoprolinase deficiency due to OPLAH mutations is less frequent and so far has not attracted much attention. This has prompted us to investigate the clinical phenotype as well as the underlying genotype in patients from 14 families of various ethnic backgrounds who underwent diagnostic mutation analysis following the detection of 5-oxoprolinuria. In all patients with 5-oxoprolinuria studied, bi-allelic mutations in OPLAH were indicated. An autosomal recessive mode of inheritance for 5-oxoprolinase deficiency is further supported by the identification of a single mutation in all 9/14 parent sample sets investigated (except for the father of one patient whose result suggests homozygosity), and the absence of 5-oxoprolinuria in all tested heterozygotes. It is remarkable, that all 20 mutations identified were novel and private to the respective families. Clinical features were highly variable and in several sib pairs, did not segregate with 5-oxoprolinuria. Although a pathogenic role of 5-oxoprolinase deficiency remains possible, this is not supported by our findings. Additional patient ascertainment and long-term follow-up is needed to establish the benign nature of this inborn error of metabolism. It is important that all symptomatic patients with persistently elevated levels of 5-oxoproline and no obvious explanation are investigated for the genetic etiology.

  18. Unravelling 5-oxoprolinuria (pyroglutamic aciduria) due to bi-allelic OPLAH mutations: 20 new mutations in 14 families.

    PubMed

    Sass, Jörn Oliver; Gemperle-Britschgi, Corinne; Tarailo-Graovac, Maja; Patel, Nisha; Walter, Melanie; Jordanova, Albena; Alfadhel, Majid; Barić, Ivo; Çoker, Mahmut; Damli-Huber, Aynur; Faqeih, Eissa Ali; García Segarra, Nuria; Geraghty, Michael T; Jåtun, Bjørn Magne; Kalkan Uçar, Sema; Kriewitz, Merten; Rauchenzauner, Markus; Bilić, Karmen; Tournev, Ivailo; Till, Claudia; Sayson, Bryan; Beumer, Daniel; Ye, Cynthia Xin; Zhang, Lin-Hua; Vallance, Hilary; Alkuraya, Fowzan S; van Karnebeek, Clara D M

    2016-09-01

    Primary 5-oxoprolinuria (pyroglutamic aciduria) is caused by a genetic defect in the γ-glutamyl cycle, affecting either glutathione synthetase or 5-oxoprolinase. While several dozens of patients with glutathione synthetase deficiency have been reported, with hemolytic anemia representing the clinical key feature, 5-oxoprolinase deficiency due to OPLAH mutations is less frequent and so far has not attracted much attention. This has prompted us to investigate the clinical phenotype as well as the underlying genotype in patients from 14 families of various ethnic backgrounds who underwent diagnostic mutation analysis following the detection of 5-oxoprolinuria. In all patients with 5-oxoprolinuria studied, bi-allelic mutations in OPLAH were indicated. An autosomal recessive mode of inheritance for 5-oxoprolinase deficiency is further supported by the identification of a single mutation in all 9/14 parent sample sets investigated (except for the father of one patient whose result suggests homozygosity), and the absence of 5-oxoprolinuria in all tested heterozygotes. It is remarkable, that all 20 mutations identified were novel and private to the respective families. Clinical features were highly variable and in several sib pairs, did not segregate with 5-oxoprolinuria. Although a pathogenic role of 5-oxoprolinase deficiency remains possible, this is not supported by our findings. Additional patient ascertainment and long-term follow-up is needed to establish the benign nature of this inborn error of metabolism. It is important that all symptomatic patients with persistently elevated levels of 5-oxoproline and no obvious explanation are investigated for the genetic etiology. PMID:27477828

  19. Low frequency of recurrent BRCA1 and BRCA2 mutations in Spain.

    PubMed

    Llort, Gemma; Muñoz, Carmen Yagüe; Tuser, Mercè Peris; Guillermo, Ignacio Blanco; Lluch, José Ramón Germà; Bale, Allen E; Franco, Mayra Alvarez

    2002-03-01

    BRCA1 and BRCA2 mutations underlie a substantial proportion of all hereditary breast cancer. The mutational spectrum in these genes is very broad, with hundreds of different BRCA mutations reported worldwide. However, high frequency founder mutations make up a substantial fraction of all mutations in some ethnic groups. We directly sequenced BRCA1 and BRCA2 in 35 Spanish breast/ovarian cancer families and found 13 mutations of which 3 had been reported previously in Spain. The ten novel mutations are: IVS5+1 G>A, 1491delA, Leu1086Ter, and Gln895Ter in BRCA1; Glu49Ter, 5373delGTAT, 5947delCTCT, 6672delTA, 8281insA, and Pro3039Leu (which also involves a splice site) in BRCA2. Our data, in combination with previous reports, indicate that 14 mutations have been seen recurrently in Spanish families. Analyzing these 14 mutations in 42 previously untested breast/ovarian cancer families revealed only two families testing positive, one for BRCA1 185delAG and one for BRCA2 9254delATCAT. While several mutations have been found recurrently in Spain, none appear to be high frequency founder mutations based on studies of breast and ovarian cancer families.

  20. Osteoporosis-Pseudoglioma in a Mauritanian Child due to a Novel Mutation in LRP5

    PubMed Central

    Biha, Noura; Ghaber, S. M.; Hacen, M. M.; Collet, Corinne

    2016-01-01

    Osteoporosis-pseudoglioma (OPPG) syndrome is a very rare autosomal recessive disorder, caused by mutations in the low-density lipoprotein receptor-related protein 5 (LRP5) gene. It manifests by severe juvenile osteoporosis with congenital or infancy-onset visual loss. We describe a case of OPPG due to novel mutation in LRP5 gene, occurring in a female Mauritanian child. This 10-year-old female child was born blind, and after then multiple fragility fractures appeared. PCR amplification and sequencing revealed a novel homozygous nonsense mutation in exon 10 of the LRP5 gene (c.2270G>A; pTrP757⁎); this mutation leads to the production of a truncated protein containing 757 amino acids instead of 1615, located in the third β-propeller domain of the LRP5 protein. Both parents were heterozygous for the mutation. This is the first case of the OPPG described in black Africans, which broadens the spectrum of LRP5 gene mutations in OPPG. PMID:26904320

  1. [Mortality due to accidents in pediatrics. Their causes and frequency].

    PubMed

    Carol Murillo, J; Arnau Figuerras, J; Salvador Vilalta, X

    1992-06-01

    The aim of the study was to ascertain the magnitude, causes and frequency of fatal accidents in Spain in children aged O to 14 years. The information was provided by the Instituto Nacional de Estadística. The latest data published for the five years 1982 to 1986 inclusive are studied and the causes of death by accident evaluated.

  2. Frequency of mutations in mismatch repair genes in a population-based study of women with ovarian cancer

    PubMed Central

    Pal, T; Akbari, M R; Sun, P; Lee, J-H; Fulp, J; Thompson, Z; Coppola, D; Nicosia, S; Sellers, T A; McLaughlin, J; Risch, H A; Rosen, B; Shaw, P; Schildkraut, J; Narod, S A

    2012-01-01

    Background: Mutations in genes for hereditary non-polyposis colorectal cancer (HNPCC) in ovarian cancer patients remains poorly defined. We sought to estimate the frequency and characteristics of HNPCC gene mutations in a population-based sample of women with epithelial ovarian cancer. Methods: The analysis included 1893 women with epithelial ovarian cancer ascertained from three population-based studies. Full-germline DNA sequencing of the coding regions was performed on three HNPCC genes, MLH1, MSH2 and MSH6. Collection of demographic, clinical and family history information was attempted in all women. Results: Nine clearly pathogenic mutations were identified, including five in MSH6, two each in MLH1 and MSH2. In addition, 28 unique predicted pathogenic missense variants were identified in 55 patients. Pathogenic mutation carriers had an earlier mean age at diagnosis of ovarian cancer, overrepresentation of cancers with non-serous histologies and a higher number of relatives with HNPCC-related cancers. Conclusions: Our findings suggest that fewer than 1% of women with ovarian cancer harbour a germline mutation in the HNPCC genes, with overrepresentation of MSH6 mutations. This represents a lower-range estimate due to the large number of predicted pathogenic variants in which pathogenicity could not definitively be determined. Identification of mismatch repair gene mutations has the potential to impact screening and treatment decisions in these women. PMID:23047549

  3. Terminal osseous dysplasia with pigmentary defects (TODPD) due to a recurrent filamin A (FLNA) mutation

    PubMed Central

    Brunetti-Pierri, Nicola; Torrado, Maria; Fernandez, Maria del Carmen; Tello, Ana Maria; Arberas, Claudia L; Cardinale, Antonella; Piccolo, Pasquale; Bacino, Carlos A

    2014-01-01

    Terminal osseous dysplasia with pigmentary defects (TODPD) is an X-linked dominant syndrome with distal limb anomalies, pigmentary skin defects, digital fibromas, and generalized bone involvement due to a recurrent mutation in the filamin A (FLNA) gene. We here report the mutation c.5217G>A in FLNA in three families with TODPD and we found possible germline and somatic mosaicism in two out of the three families. The occurrence of somatic and germline mosaicism for TODPD indicates that caution should be taken in counseling recurrence risks for these conditions upon presentation of an isolated case. PMID:25614868

  4. Terminal osseous dysplasia with pigmentary defects (TODPD) due to a recurrent filamin A (FLNA) mutation.

    PubMed

    Brunetti-Pierri, Nicola; Torrado, Maria; Fernandez, Maria Del Carmen; Tello, Ana Maria; Arberas, Claudia L; Cardinale, Antonella; Piccolo, Pasquale; Bacino, Carlos A

    2014-11-01

    Terminal osseous dysplasia with pigmentary defects (TODPD) is an X-linked dominant syndrome with distal limb anomalies, pigmentary skin defects, digital fibromas, and generalized bone involvement due to a recurrent mutation in the filamin A (FLNA) gene. We here report the mutation c.5217G>A in FLNA in three families with TODPD and we found possible germline and somatic mosaicism in two out of the three families. The occurrence of somatic and germline mosaicism for TODPD indicates that caution should be taken in counseling recurrence risks for these conditions upon presentation of an isolated case.

  5. The effects of extremely low frequency magnetic fields on mutation induction in mice.

    PubMed

    Wilson, James W; Haines, Jackie; Sienkiewicz, Zenon; Dubrova, Yuri E

    2015-03-01

    The growing human exposure to extremely low frequency (ELF) magnetic fields has raised a considerable concern regarding their genotoxic effects. The aim of this study was to evaluate the in vivo effects of ELF magnetic fields irradiation on mutation induction in the germline and somatic tissues of male mice. Seven week old BALB/c×CBA/Ca F1 hybrid males were exposed to 10, 100 or 300μT of 50Hz magnetic fields for 2 or 15h. Using single-molecule PCR, the frequency of mutation at the mouse Expanded Simple Tandem Repeat (ESTR) locus Ms6-hm was established in sperm and blood samples of exposed and matched sham-treated males. ESTR mutation frequency was also established in sperm and blood samples taken from male mice exposed to 1Gy of acute X-rays. The frequency of ESTR mutation in DNA samples extracted from blood of mice exposed to magnetic fields did not significantly differ from that in sham-treated controls. However, there was a marginally significant increase in mutation frequency in sperm but this was not dose-dependent. In contrast, acute exposure X-rays led to significant increases in mutation frequency in sperm and blood of exposed males. The results of our study suggest that, within the range of doses analyzed here, the in vivo mutagenic effects of ELF magnetic fields are likely to be minor if not negligible.

  6. Molecular principles behind pyrazinamide resistance due to mutations in panD gene in Mycobacterium tuberculosis.

    PubMed

    Pandey, Bharati; Grover, Sonam; Tyagi, Chetna; Goyal, Sukriti; Jamal, Salma; Singh, Aditi; Kaur, Jagdeep; Grover, Abhinav

    2016-04-25

    The latest resurrection of drug resistance poses serious threat to the treatment and control of the disease. Mutations have been detected in panD gene in the Mycobacterium tuberculosis (Mtb) strains. Mutation of histidine to arginine at residue 21 (H21R) and isoleucine to valine at residue 29 (I49V) in the non-active site of panD gene has led to PZA resistance. This study will help in reconnoitering the mechanism of pyrazinamide (PZA) resistance caused due to double mutation identified in the panD gene of M. tuberculosis clinical isolates. It is known that panD gene encodes aspartate decarboxylase essential for β-alanine synthesis that makes it a potential therapeutic drug target for tuberculosis treatment. The knowledge about the molecular mechanism conferring drug resistance in M. tuberculosis is scarce, which is a significant challenge in designing successful therapeutic drug. In this study, structural and dynamic repercussions of H21R-I49V double mutation in panD complexed with PZA have been corroborated through docking and molecular dynamics based simulation. The double mutant (DM) shows low docking score and thus, low binding affinity for PZA as compared to the native protein. It was observed that the mutant protein exhibits more structural fluctuation at the ligand binding site in comparison to the native type. Furthermore, the flexibility and compactness analyses indicate that the double mutation influence interaction of PZA with the protein. The hydrogen-bond interaction patterns further supported our results. The covariance and PCA analysis elucidated that the double mutation affects the collective motion of residues in phase space. The results have been presented with an explanation for the induced drug resistance conferred by the H21R-I49V double mutation in panD gene and gain valuable insight to facilitate the advent of efficient therapeutics for combating resistance against PZA. PMID:26784657

  7. Molecular principles behind pyrazinamide resistance due to mutations in panD gene in Mycobacterium tuberculosis.

    PubMed

    Pandey, Bharati; Grover, Sonam; Tyagi, Chetna; Goyal, Sukriti; Jamal, Salma; Singh, Aditi; Kaur, Jagdeep; Grover, Abhinav

    2016-04-25

    The latest resurrection of drug resistance poses serious threat to the treatment and control of the disease. Mutations have been detected in panD gene in the Mycobacterium tuberculosis (Mtb) strains. Mutation of histidine to arginine at residue 21 (H21R) and isoleucine to valine at residue 29 (I49V) in the non-active site of panD gene has led to PZA resistance. This study will help in reconnoitering the mechanism of pyrazinamide (PZA) resistance caused due to double mutation identified in the panD gene of M. tuberculosis clinical isolates. It is known that panD gene encodes aspartate decarboxylase essential for β-alanine synthesis that makes it a potential therapeutic drug target for tuberculosis treatment. The knowledge about the molecular mechanism conferring drug resistance in M. tuberculosis is scarce, which is a significant challenge in designing successful therapeutic drug. In this study, structural and dynamic repercussions of H21R-I49V double mutation in panD complexed with PZA have been corroborated through docking and molecular dynamics based simulation. The double mutant (DM) shows low docking score and thus, low binding affinity for PZA as compared to the native protein. It was observed that the mutant protein exhibits more structural fluctuation at the ligand binding site in comparison to the native type. Furthermore, the flexibility and compactness analyses indicate that the double mutation influence interaction of PZA with the protein. The hydrogen-bond interaction patterns further supported our results. The covariance and PCA analysis elucidated that the double mutation affects the collective motion of residues in phase space. The results have been presented with an explanation for the induced drug resistance conferred by the H21R-I49V double mutation in panD gene and gain valuable insight to facilitate the advent of efficient therapeutics for combating resistance against PZA.

  8. A high frequency of distinct ATM gene mutations in ataxia-telangiectasia

    SciTech Connect

    Wright, J.; Teraoka, S.; Concannon, P.

    1996-10-01

    The clinical features of the autosomal recessive disorder ataxia-telangiectasia (AT) include a progressive cerebellar ataxia, hypersensitivity to ionizing radiation, and an increased susceptibility to malignancies. Epidemiological studies have suggested that AT heterozygotes may also be at increased risk for malignancy, possibly as a consequence of radiation exposure. A gene mutated in AT patients (ATM) has recently been isolated, making mutation screening in both patients and the general population possible. Because of the relatively large size of the ATM gene, the design of screening programs will depend on the types and distribution of mutations in the general population. In this report, we describe 30 mutations identified in a panel of unrelated AT patients and controls. Twenty-five of the 30 were distinct, and most patients were compound heterozygotes. The most frequently detected mutation was found in three different families and had previously been reported in five others. This corresponds to a frequency of 8% of all reported ATM mutations. Twenty-two of the alterations observed would be predicted to lead to protein truncation at sites scattered throughout the molecule. Two fibroblast cell lines, which displayed normal responses to ionizing radiation, also proved to be heterozygous for truncation mutations of ATM. These observations suggest that the carrier frequency of ATM mutations may be sufficiently high to make population screening practical. However, such screening may need to be done prospectively, that is, by searching for new mutations rather than by screening for just those already identified in AT families. 33 refs., 1 fig., 1 tab.

  9. High Frequency QPOs due to Black Hole Spin

    NASA Technical Reports Server (NTRS)

    Kazanas, Demos; Fukumura, K.

    2009-01-01

    We present detailed computations of photon orbits emitted by flares at the innermost stable circular orbit (ISCO) of accretion disks around rotating black holes. We show that for sufficiently large spin parameter, i.e. a > 0.94 M, flare a sufficient number of photons arrive at an observer after multiple orbits around the black hole, to produce an "photon echo" of constant lag, i.e. independent of the relative phase between the black hole and the observer, of T approximates 14 M. This constant time delay, then, leads to a power spectrum with a QPO at a frequency nu approximates 1/14M, even for a totally random ensemble of such flares. Observation of such a QPO will provide incontrovertible evidence for the high spin of the black hole and a very accurate, independent, measurement of its mass.

  10. [Mutation frequencies in HIV-1 subtype-A genome in regions containing efficient RNAi targets].

    PubMed

    Kravatsky, Y V; Chechetkin, V R; Fedoseeva, D M; Gorbacheva, M A; Kretova, O V; Tchurikov, N A

    2016-01-01

    The development of gene-therapy technology using RNAi for AIDS/HIV-1 treatment is a prospective alternative to traditional anti-retroviral therapy. RNAi targets could be selected in HIV-1 transcripts and in CCR5 mRNA. Previously, we experimentally selected a number of efficient siRNAs that target HIV-1 RNAs. The viral genome mutates frequently, and RNAi strength is very sensitive, even for a single mismatches. That is why it is important to study nucleotide sequences of targets in clinical isolates of HIV-1. In the present study, we analyzed mutations in 6 of about 300-bp regions containing RNAi targets from HIV-1 subtype A isolates in Russia. Estimates of the mean frequencies of mutations in the targets were obtained and the frequencies of mutations in the different codon positions were compared. The frequencies of mutations in the vicinity of the targets and directly within the targets were also compared and have been shown to be approximately the same. The frequencies of indels in the chosen regions have been assessed. Their frequencies have proved to be two to three orders of magnitude less compared to that for mutations. PMID:27414786

  11. Frequency and Distribution of Tuberculosis Resistance-Associated Mutations between Mumbai, Moldova, and Eastern Cape.

    PubMed

    Georghiou, S B; Seifert, M; Catanzaro, D; Garfein, R S; Valafar, F; Crudu, V; Rodrigues, C; Victor, T C; Catanzaro, A; Rodwell, T C

    2016-07-01

    Molecular diagnostic assays, with their ability to rapidly detect resistance-associated mutations in bacterial genes, are promising technologies to control the spread of drug-resistant tuberculosis (DR-TB). Sequencing assays provide detailed information for specific gene regions and can help diagnostic assay developers prioritize mutations for inclusion in their assays. We performed pyrosequencing of seven Mycobacterium tuberculosis gene regions (katG, inhA, ahpC, rpoB, gyrA, rrs, and eis) for 1,128 clinical specimens from India, Moldova, and South Africa. We determined the frequencies of each mutation among drug-resistant and -susceptible specimens based on phenotypic drug susceptibility testing results and examined mutation distributions by country. The most common mutation among isoniazid-resistant (INH(r)) specimens was the katG 315ACC mutation (87%). However, in the Eastern Cape, INH(r) specimens had a lower frequency of katG mutations (44%) and higher frequencies of inhA (47%) and ahpC (10%) promoter mutations. The most common mutation among rifampin-resistant (RIF(r)) specimens was the rpoB 531TTG mutation (80%). The mutation was common in RIF(r) specimens in Mumbai (83%) and Moldova (84%) but not the Eastern Cape (17%), where the 516GTC mutation appeared more frequently (57%). The most common mutation among fluoroquinolone-resistant specimens was the gyrA 94GGC mutation (44%). The rrs 1401G mutation was found in 84%, 84%, and 50% of amikacin-resistant, capreomycin-resistant, and kanamycin (KAN)-resistant (KAN(r)) specimens, respectively. The eis promoter mutation -12T was found in 26% of KAN(r) and 4% of KAN-susceptible (KAN(s)) specimens. Inclusion of the ahpC and eis promoter gene regions was critical for optimal test sensitivity for the detection of INH resistance in the Eastern Cape and KAN resistance in Moldova. (This study has been registered at ClinicalTrials.gov under registration number NCT02170441.).

  12. Unusual presentation of phosphoglycerate mutase deficiency due to two different mutations in PGAM-M gene.

    PubMed

    Tonin, Paola; Bruno, Claudio; Cassandrini, Denise; Savio, Chiara; Tavazzi, Eleonora; Tomelleri, Giuliano; Piccolo, Giovanni

    2009-11-01

    Phosphoglycerate mutase (PGAM) deficiency causes a rare metabolic myopathy characterized by exercise-related myalgia and myoglobinuria. This disorder was described in 13 patients and five different mutations in the PGAM-M gene were identified. We report on a new patient with an unusual clinical presentation. As a youth, he participated in different sports without complaining of muscular symptoms, but at 44 years of age, after a brief, intense effort, he experienced lightheadedness without fainting. Serum CK was elevated and the ischemic exercise test showed a pathological lactate response. Muscle biopsy showed only mild abnormalities, but biochemical study revealed a defect of PGAM and genetic analysis showed two different mutations in the PGAM-M gene. Our case expands the clinical spectrum of PGAM deficiency and suggests that the frequency of this metabolic myopathy may be underestimated. PMID:19783439

  13. Hidden association of Cowden syndrome, PTEN mutation and meningioma frequency

    PubMed Central

    Yakubov, Eduard; Ghoochani, Ali; Buslei, Rolf; Buchfelder, Michael; Eyüpoglu, Ilker Y.; Savaskan, Nicolai

    2016-01-01

    Cowden syndrome (CS) is clinically presented by multiple hamartomas, often with mucocutaneous lesions, goiter, breast cancer and gastrointestinal polyps. CS is a genetic disorder of autosomal dominant inheritance and is one distinct syndrome of the phosphatase and tensin homolog on chromosome 10 (PTEN) hamartoma tumor spectrum. Noteworthy, PTEN germline mutations are related to a wide range of brain tumors. We performed a systematic analysis and review of the medical literature for Cowden syndrome and meningioma and additionally present the case of a 29-year- old CS patient diagnosed with multiple meningiomas. We found strong evidence for high incidence of brain tumors in CS patients. In particular meningiomas and gangliocytomas/Lhermitte-Duclos disease were often associated with 8% and 9% respectively in CS patients. Since aberrations in chromosome 10q are associated with meningiomas, it is likely that the underlying mutations in CS drive to a certain extent neoplastic meningioma growth. We propose to include meningiomas and brain tumors in the major criteria spectrum of CS-related disorders. This could warrant early diagnosis of brain lesions and close therapy, as well as better monitoring of patients with CS. PMID:27489861

  14. Neb: a zebrafish model of nemaline myopathy due to nebulin mutation.

    PubMed

    Telfer, William R; Nelson, Darcee D; Waugh, Trent; Brooks, Susan V; Dowling, James J

    2012-05-01

    Nemaline myopathy is one of the most common and severe non-dystrophic muscle diseases of childhood. Patients typically present in infancy with hypotonia, weakness, delayed motor development, and bulbar and respiratory difficulties. Mutations in six different genes are associated with nemaline myopathy, with nebulin mutations being the most common. No treatments or disease-modifying therapies have been identified for this disease. One of the major barriers to treatment development is the lack of models amenable to rapid and coordinated testing of potential therapeutic strategies. To overcome this barrier, we have characterized the first zebrafish model of nemaline myopathy. This model, termed neb, harbors a recessive mutation in the nebulin gene that results in decreased Nebulin protein levels, a severe motor phenotype and premature lethality. In addition to impaired motor function, neb zebrafish exhibit many of the features associated with human nemaline myopathy. These include impaired force generation, altered thin filament length and the presence of specific histopathological changes, including the formation of nemaline bodies. In summary, neb zebrafish mirror the genetic, clinical and pathological aspects of nemaline myopathy due to NEB mutation, and thus are an excellent model for future therapy development for this devastating disorder. PMID:22159874

  15. TBK1 mutation frequencies in French frontotemporal dementia and amyotrophic lateral sclerosis cohorts.

    PubMed

    Le Ber, Isabelle; De Septenville, Anne; Millecamps, Stéphanie; Camuzat, Agnès; Caroppo, Paola; Couratier, Philippe; Blanc, Frédéric; Lacomblez, Lucette; Sellal, François; Fleury, Marie-Céline; Meininger, Vincent; Cazeneuve, Cécile; Clot, Fabienne; Flabeau, Olivier; LeGuern, Eric; Brice, Alexis

    2015-11-01

    TANK1-binding kinase 1 (TBK1) has been recently identified as a new amyotrophic lateral sclerosis (ALS) gene. Loss-of-function (LoF) mutations in TBK1 could be responsible for 0.4%-4% of ALS. Considering the strong genetic overlap existing between frontotemporal dementia (FTD) and ALS, we have evaluated the frequencies of TBK1 mutations in a cohort of French FTD and of ALS patients. We identified 5 LoF mutations, in 4 FTD-ALS and 1 ALS patients. We also identified 5 heterozygous missense variants, predicted to be deleterious, in 1 isolated FTD, 1 FTD-ALS, and 3 ALS cases. Our results demonstrate that TBK1 loss-of-function mutations are more frequent in patients with FTD-ALS (10.8%) than in isolated ALS. TBK1 should thus also be sequenced, after exclusion of C9orf72 mutation, in patients presenting FTD, particularly in cases secondarily associated with ALS.

  16. Cholesteryl Ester Storage Disease (CESD) due to novel mutations in the LIPA gene.

    PubMed

    Pisciotta, Livia; Fresa, Raffaele; Bellocchio, Antonella; Pino, Elisabetta; Guido, Virgilia; Cantafora, Alfredo; Di Rocco, Maja; Calandra, Sebastiano; Bertolini, Stefano

    2009-06-01

    Cholesteryl Ester Storage Disease (CESD) is a rare recessive disorder due to mutations in LIPA gene encoding the lysosomal acidic lipase (LAL). CESD patients have liver disease associated with mixed hyperlipidemia and low plasma levels of high-density lipoproteins (HDL). The aim of this study was the molecular characterization of three patients with CESD. LAL activity was measured in blood leukocytes. In two patients (twin sisters) the clinical diagnosis of CESD was made at 9 years of age, following the fortuitous discovery of elevated serum liver enzymes in apparently healthy children. They had mixed hyperlipidemia, hepatosplenomegaly, reduced LAL activity (approximately 5% of control) and heteroalleic mutations in LIPA gene coding sequence: (i) the common c.894 G>A mutation and (ii) a novel nonsense mutation c.652 C>T (p.R218X). The other patient was an 80 year-old female who for several years had been treated with simvastatin because of severe hyperlipidemia associated with low plasma HDL. In this patient the sequence of major candidate genes for monogenic hypercholesterolemia and hypoalphalipoproteinemia was negative. She was found to be a compound heterozygote for two LIPA gene mutations resulting in 5% LAL activity: (i) c.894 G>A and (ii) a novel complex insertion/deletion leading to a premature termination codon at position 82. These findings suggest that, in view of the variable severity of its phenotypic expression, CESD may sometimes be difficult to diagnose, but it should be considered in patients with severe type IIb hyperlipidemia associated with low HDL, mildly elevated serum liver enzymes and hepatomegaly. PMID:19307143

  17. 5-hydroxymethylcytosine marks regions with reduced mutation frequency in human DNA

    PubMed Central

    Tomkova, Marketa; McClellan, Michael; Kriaucionis, Skirmantas; Schuster-Boeckler, Benjamin

    2016-01-01

    CpG dinucleotides are the main mutational hot-spot in most cancers. The characteristic elevated C>T mutation rate in CpG sites has been related to 5-methylcytosine (5mC), an epigenetically modified base which resides in CpGs and plays a role in transcription silencing. In brain nearly a third of 5mCs have recently been found to exist in the form of 5-hydroxymethylcytosine (5hmC), yet the effect of 5hmC on mutational processes is still poorly understood. Here we show that 5hmC is associated with an up to 53% decrease in the frequency of C>T mutations in a CpG context compared to 5mC. Tissue specific 5hmC patterns in brain, kidney and blood correlate with lower regional CpG>T mutation frequency in cancers originating in the respective tissues. Together our data reveal global and opposing effects of the two most common cytosine modifications on the frequency of cancer causing somatic mutations in different cell types. DOI: http://dx.doi.org/10.7554/eLife.17082.001 PMID:27183007

  18. Insulin resistance uncoupled from dyslipidemia due to C-terminal PIK3R1 mutations

    PubMed Central

    Huang-Doran, Isabel; Tomlinson, Patsy; Payne, Felicity; Gast, Alexandra; Sleigh, Alison; Bottomley, William; Harris, Julie; Daly, Allan; Rocha, Nuno; Rudge, Simon; Clark, Jonathan; Kwok, Albert; Romeo, Stefano; McCann, Emma; Müksch, Barbara; Dattani, Mehul; Zucchini, Stefano; Wakelam, Michael; Foukas, Lazaros C.; Savage, David B.; Murphy, Rinki; O’Rahilly, Stephen; Semple, Robert K.

    2016-01-01

    Obesity-related insulin resistance is associated with fatty liver, dyslipidemia, and low plasma adiponectin. Insulin resistance due to insulin receptor (INSR) dysfunction is associated with none of these, but when due to dysfunction of the downstream kinase AKT2 phenocopies obesity-related insulin resistance. We report 5 patients with SHORT syndrome and C-terminal mutations in PIK3R1, encoding the p85α/p55α/p50α subunits of PI3K, which act between INSR and AKT in insulin signaling. Four of 5 patients had extreme insulin resistance without dyslipidemia or hepatic steatosis. In 3 of these 4, plasma adiponectin was preserved, as in insulin receptor dysfunction. The fourth patient and her healthy mother had low plasma adiponectin associated with a potentially novel mutation, p.Asp231Ala, in adiponectin itself. Cells studied from one patient with the p.Tyr657X PIK3R1 mutation expressed abundant truncated PIK3R1 products and showed severely reduced insulin-stimulated association of mutant but not WT p85α with IRS1, but normal downstream signaling. In 3T3-L1 preadipocytes, mutant p85α overexpression attenuated insulin-induced AKT phosphorylation and adipocyte differentiation. Thus, PIK3R1 C-terminal mutations impair insulin signaling only in some cellular contexts and produce a subphenotype of insulin resistance resembling INSR dysfunction but unlike AKT2 dysfunction, implicating PI3K in the pathogenesis of key components of the metabolic syndrome. PMID:27766312

  19. Familial Hemophagocytic Lymphohistiocytosis due to Mutation of UNC13D Gene.

    PubMed

    Giri, Prabhas Prasun; Biswas, Nirmoy; Chakravarty, Swati

    2016-06-01

    Hemophagocytic lymphohistiocytosis (HLH) are basically a heterogenous group of clinical syndromes, characterised by activation and non-malignant proliferation of benign histiocytes i.e. lymphocytes and macrophages, leading to a cytokine storm that accounts for the fever, organomegaly and multi-organ dysfunction. Two types of HLH are described, either due to known genetic defect (familial HLH/FHL) or due to some acquired cause either infection or rheumatological diseases. Here we present a case of a 3 months old baby, admitted with fever, hepatosplenomegaly and cytopenia and ultimately was diagnosed to be a case of Familial HLH type 3 due to defect in UNC13D gene as a result of compound heterozygous for two nonsense mutation resulting in the Munc13-4 protein defect. PMID:27408432

  20. The observed human sperm mutation frequency cannot explain the achondroplasia paternal age effect.

    PubMed

    Tiemann-Boege, Irene; Navidi, William; Grewal, Raji; Cohn, Dan; Eskenazi, Brenda; Wyrobek, Andrew J; Arnheim, Norman

    2002-11-12

    The lifelong spermatogonial stem cell divisions unique to male germ cell production are thought to contribute to a higher mutation frequency in males. The fact that certain de novo human genetic conditions (e.g., achondroplasia) increase in incidence with the age of the father is consistent with this idea. Although it is assumed that the paternal age effect is the result of an increasing frequency of mutant sperm as a man grows older, no direct molecular measurement of the germ-line mutation frequency has been made to confirm this hypothesis. Using sperm DNA from donors of different ages, we determined the frequency of the nucleotide substitution in the fibroblast growth factor receptor 3 (FGFR3) gene that causes achondroplasia. Surprisingly, the magnitude of the increase in mutation frequency with age appears insufficient to explain why older fathers have a greater chance of having a child with this condition. A number of alternatives may explain this discrepancy, including selection for sperm that carry the mutation or an age-dependent increase in premutagenic lesions that remain unrepaired in sperm and are inefficiently detected by the PCR assay. PMID:12397172

  1. Autoimmune manifestations in SCID due to IL7R mutations: Omenn syndrome and cytopenias.

    PubMed

    Zago, Claudia Augusta; Jacob, Cristina Miuki Abe; de Albuquerque Diniz, Edna Maria; Lovisolo, Silvana Maria; Zerbini, Maria Claudia Nogueira; Dorna, Mayra; Watanabe, Letícia; Fernandes, Juliana Folloni; Rocha, Vanderson; Oliveira, João Bosco; Carneiro-Sampaio, Magda

    2014-07-01

    B+NK+SCID (severe combined immunodeficiency) due to IL7Rα deficiency represents approximately 10% of American SCID cases. To better understand the spectrum of autoimmune disorders associated with IL7Rα deficiency, we describe two unrelated IL7Rα-deficient female SCID infants whose clinical picture was dominated by autoimmune manifestations: one with intrauterine Omenn syndrome (OS) and another with persistent thrombocytopenic purpura since 4months of age. The OS baby harbored a homozygous p.C118Y mutation in IL7R. She presented dense eosinophilic infiltrates in several organs, including pancarditis, which may have contributed to her death (on the 2nd day of life). B cells were observed in lymph nodes, spleen, bone marrow and thymus. The second patient harbored compound heterozygous p.C118Y and p.I121NfsX8 mutations. She underwent a successful unrelated cord blood transplant. In conclusion, early OS can be observed in patients with IL7R mutations, and autoimmune cytopenias could also complicate the clinical course of SCID babies with this type of defect.

  2. High frequency of additional gene mutations in acute myeloid leukemia with MLL partial tandem duplication: DNMT3A mutation is associated with poor prognosis.

    PubMed

    Kao, Hsiao-Wen; Liang, D Cherng; Kuo, Ming-Chung; Wu, Jin-Hou; Dunn, Po; Wang, Po-Nan; Lin, Tung-Liang; Shih, Yu-Shu; Liang, Sung-Tzu; Lin, Tung-Huei; Lai, Chen-Yu; Lin, Chun-Hui; Shih, Lee-Yung

    2015-10-20

    The mutational profiles of acute myeloid leukemia (AML) with partial tandem duplication of mixed-lineage leukemia gene (MLL-PTD) have not been comprehensively studied. We studied 19 gene mutations for 98 patients with MLL-PTD AML to determine the mutation frequency and clinical correlations. MLL-PTD was screened by reverse-transcriptase PCR and confirmed by real-time quantitative PCR. The mutational analyses were performed with PCR-based assays followed by direct sequencing. Gene mutations of signaling pathways occurred in 63.3% of patients, with FLT3-ITD (44.9%) and FLT3-TKD (13.3%) being the most frequent. 66% of patients had gene mutations involving epigenetic regulation, and DNMT3A (32.7%), IDH2 (18.4%), TET2 (18.4%), and IDH1 (10.2%) mutations were most common. Genes of transcription pathways and tumor suppressors accounted for 23.5% and 10.2% of patients. RUNX1 mutation occurred in 23.5% of patients, while none had NPM1 or double CEBPA mutation. 90.8% of MLL-PTD AML patients had at least one additional gene mutation. Of 55 MLL-PTD AML patients who received standard chemotherapy, age older than 50 years and DNMT3A mutation were associated with inferior outcome. In conclusion, gene mutations involving DNA methylation and activated signaling pathway were common co-existed gene mutations. DNMT3A mutation was a poor prognostic factor in MLL-PTD AML.

  3. Frequency shifts in a rubidium frequency standard due to coupling to another standard

    NASA Technical Reports Server (NTRS)

    Jaduszliwer, Bernardo; Cook, R. A.; Frueholz, R. P.

    1990-01-01

    Highly reliable timing system, such as used on board satellites, may incorporate a hot standby atomic clock besides the active one. RF couplings between them may affect the performance of the active clock. The effect of such couplings between two rubidium atomic clocks was investigated, and it was found that they will add an oscillatory term to the Allan Variance of the active clock, degrading its frequency stability, and that under certain circumstances they may also shift the active clock's operating frequency. These two effects are discussed in detail, and the level of isolation required to render them negligible is established.

  4. Intra- and Interdomain Effects Due to Mutation of Calcium-binding Sites in Calmodulin*

    PubMed Central

    Xiong, Liang-Wen; Kleerekoper, Quinn K.; Wang, Xu; Putkey, John A.

    2010-01-01

    The IQ-motif protein PEP-19, binds to the C-domain of calmodulin (CaM) with significantly different kon and koff rates in the presence and absence of Ca2+, which could play a role in defining the levels of free CaM during Ca2+ transients. The initial goal of the current study was to determine whether Ca2+ binding to sites III or IV in the C-domain of CaM was responsible for affecting the kinetics of binding PEP-19. EF-hand Ca2+-binding sites were selectively inactivated by the common strategy of changing Asp to Ala at the X-coordination position. Although Ca2+ binding to both sites III and IV appeared necessary for native-like interactions with PEP-19, the data also indicated that the mutations caused undesirable structural alterations as evidenced by significant changes in amide chemical shifts for apoCaM. Mutations in the C-domain also affected chemical shifts in the unmodified N-domain, and altered the Ca2+ binding properties of the N-domain. Conversion of Asp93 to Ala caused the greatest structural perturbations, possibly due to the loss of stabilizing hydrogen bonds between the side chain of Asp93 and backbone amides in apo loop III. Thus, although these mutations inhibit binding of Ca2+, the mutated CaM may not be able to support potentially important native-like activity of the apoprotein. This should be taken into account when designing CaM mutants for expression in cell culture. PMID:20048169

  5. A biophysical model for estimating the frequency of radiation-induced mutations resulting from chromosomal translocations

    NASA Astrophysics Data System (ADS)

    Wu, Honglu; Durante, Marco

    Gene mutations can be induced by radiation as a result of chromosomal translocations. A biophysical model is developed to estimate the frequency of this type of mutation induced by low-LET radiation. Mutations resulting from translocations are assumed to be formed by misrejoining of two DNA double strand breaks (DSB), one within the gene and one on a different chromosome. The chromosome containing the gene is assumed to occupy a spherical territory and does not overlap spatially with other chromosomes. Misrejoining between two DSB can occur only if the two DSB are closer than an interaction distance at the time of their induction. Applying the model to mutations of the hprt gene induced in G0 human lymphocyte cells by low-LET radiation, it is calculated that mutations resulting from translocations account for about 14% of the total mutations. The value of the interaction distance is determined to be 0.6 μm by comparing with the observed frequency of translocations in the X-chromosome.

  6. Somatic mutation frequencies in the stamen hairs of Tradescantia grown in soil samples from the Bikini Island.

    PubMed

    Ichikawa, S; Ishii, C

    1991-02-01

    Somatic pink mutation frequencies in the stamen hairs of Tradescantia BNL 02 clone grown for 76 days in two soil samples taken from the Bikini Island (where a hydrogen bomb explosion test had been conducted in 1954) were investigated. A significantly high mutation frequency (2.58 +/- 0.17 pink mutant events per 10(3) hairs or 1.34 +/- 0.09 pink mutant events per 10(4) hair-cell divisions) was observed for the plant grown in one of the two Bikini soil samples, as compared to the control plants (1.70 +/- 0.14 or 0.88 +/- 0.07, respectively) grown in the field soil of Saitama University. The soil sample which caused the significant increase in mutation frequency contained 6,880 +/- 330 mBq/g 137Cs, 62.5 +/- 4.4 mBq/g 60Co, and some other nuclides; a 150 microR/hr exposure rate being measured on the surface of the soil sample. The effective cumulative external exposures measured for the inflorescences of the plant grown in this soil sample averaged at most 60.8 mR, being too small to explain the significant elevation in mutation frequency observed. On the other hand, internal exposure due to uptake of radioactive nuclides was estimated to be 125 mrad (1.25 mGy) as an accumulated effective dose, mainly based on a gamma-spectrometrical analysis. However, it seemed highly likely that this value of internal exposure was a considerable underestimate, and the internal exposure was considered to be more significant than the external exposure. PMID:2064800

  7. Somatic mutation frequencies in the stamen hairs of Tradescantia grown in soil samples from the Bikini Island.

    PubMed

    Ichikawa, S; Ishii, C

    1991-02-01

    Somatic pink mutation frequencies in the stamen hairs of Tradescantia BNL 02 clone grown for 76 days in two soil samples taken from the Bikini Island (where a hydrogen bomb explosion test had been conducted in 1954) were investigated. A significantly high mutation frequency (2.58 +/- 0.17 pink mutant events per 10(3) hairs or 1.34 +/- 0.09 pink mutant events per 10(4) hair-cell divisions) was observed for the plant grown in one of the two Bikini soil samples, as compared to the control plants (1.70 +/- 0.14 or 0.88 +/- 0.07, respectively) grown in the field soil of Saitama University. The soil sample which caused the significant increase in mutation frequency contained 6,880 +/- 330 mBq/g 137Cs, 62.5 +/- 4.4 mBq/g 60Co, and some other nuclides; a 150 microR/hr exposure rate being measured on the surface of the soil sample. The effective cumulative external exposures measured for the inflorescences of the plant grown in this soil sample averaged at most 60.8 mR, being too small to explain the significant elevation in mutation frequency observed. On the other hand, internal exposure due to uptake of radioactive nuclides was estimated to be 125 mrad (1.25 mGy) as an accumulated effective dose, mainly based on a gamma-spectrometrical analysis. However, it seemed highly likely that this value of internal exposure was a considerable underestimate, and the internal exposure was considered to be more significant than the external exposure.

  8. Ethyl methanesulfonate induces mutations in Caenorhabditis elegans embryos at a high frequency.

    PubMed

    Hartman, Phil S; Barry, James; Finstad, Whitney; Khan, Numan; Tanaka, Masayuki; Yasuda, Kayo; Ishii, Naoaki

    2014-01-01

    Mutagenesis protocols typically call for exposure of late-stage larvae or adults to a mutagen with the intention of inducing mutations in a robust germ line. Instead, ca. 16,000 CB665 [unc-58(e665)] one- to four-cell embryos of the nematode Caenorhabditis elegans were hand selected and exposed to ethyl methanesulfonate (EMS) for 50min. Twenty-one reversion mutants were recovered, of which 17 were intragenic suppressors of the e665 mutation. The mutation frequency was 6.5-fold higher than when CB665 adults were similarly mutagenized, which was predicted given that cell-cycle checkpoints are muted in C. elegans embryos. The mutation spectrum was similar to that obtained after standard EMS mutagenesis. PMID:25847271

  9. Mutation and Recombination Frequencies Reveal a Biological Contrast within Strains of Cucumber Mosaic Virus

    PubMed Central

    Pita, Justin S.; Morris, Viktoriya

    2015-01-01

    ABSTRACT Recent in planta studies have shown that strains Fny and LS of Cucumber mosaic virus (CMV) display differential genetic diversities, Fny and LS having higher and lower mutation frequencies, respectively (J. S. Pita and M. J. Roossinck, J Virol 87:790–797, 2012 http://dx.doi.org/10.1128/JVI.01891-12). In this article, we show that these virus strains have differential recombination frequencies as well. However, the high-diversity Fny strain is a low-recombination virus, whereas the very-low-diversity LS strain is instead a high-recombination virus. Unlike the mutation frequency that was determined by both RNAs 1 and 2, the control elements of recombination frequency reside predominantly within RNA 2, specifically within the 2a gene. IMPORTANCE Recombination is an important mechanism in virus evolution that can lead to increased or decreased variation and is a major player in virus speciation events that can lead to emerging viruses. Although viral genomes show very frequent evidence of recombination, details of the mechanism involved in these events are still poorly understood. We show here that the reciprocal effects of high mutation frequency and low recombination frequency (and vice versa) involve the RNA-dependent RNA polymerase of the virus, and we speculate that these evolutionary events are related to differences in processivity for two strains of the same virus. PMID:25903331

  10. Leber Congenital Amaurosis due to RPE65 Mutations and its Treatment with Gene Therapy

    PubMed Central

    Cideciyan, Artur V.

    2010-01-01

    Leber congenital amaurosis (LCA) is a rare hereditary retinal degeneration caused by mutations in more than a dozen genes. RPE65, one of these mutated genes, is highly expressed in the retinal pigment epithelium where it encodes the retinoid isomerase enzyme essential for the production of chromophore which forms the visual pigment in rod and cone photoreceptors of the retina. Congenital loss of chromophore production due to RPE65-deficiency together with progressive photoreceptor degeneration cause severe and progressive loss of vision. RPE65-associated LCA recently gained recognition outside of specialty ophthalmic circles due to early success achieved by three clinical trials of gene therapy using recombinant adeno-associated virus (AAV) vectors. The trials were built on multitude of basic, pre-clinical and clinical research defining the pathophysiology of the disease in human subjects and animal models, and demonstrating the proof-of-concept of gene (augmentation) therapy. Substantial gains in visual function of clinical trial participants provided evidence for physiologically relevant biological activity resulting from a newly introduced gene. This article reviews the current knowledge on retinal degeneration and visual dysfunction in animal models and human patients with RPE65 disease, and examines the consequences of gene therapy in terms of improvement of vision reported. PMID:20399883

  11. Familial adult onset hyperinsulinism due to an activating glucokinase mutation: Implications for pharmacological glucokinase activation

    PubMed Central

    Challis, Benjamin G.; Harris, Julie; Sleigh, Alison; Isaac, Iona; Orme, Steve M.; Seevaratnam, Nandini; Dhatariya, Ketan; Simpson, Helen L.; Semple, Robert K.

    2016-01-01

    Context Glucokinase (GCK) phosphorylates and thereby “traps” glucose in cells, thus serving as a gatekeeper for cellular glucose metabolism, particularly in hepatocytes and pancreatic beta cells. In humans, activating GCK mutations cause familial hyperinsulinaemic hypoglycaemia (GCK-HH), leading to keen interest in the potential of small molecule glucokinase activators (GKAs) as treatments for diabetes mellitus. Many such agents have been developed, however observation of side effects including hypertriglyceridaemia and hepatic steatosis have delayed their clinical development. Objective To describe the clinical presentation and metabolic profiles of affected family members in a kindred with familial hyperinsulinism of adult presentation due to a known activating mutation in GCK. Design Clinical, biochemical and metabolic assessment, and GCK sequencing in affected family members. Results In the 60 year-old female proband, hyperinsulinaemic hypoglycaemia (blood glucose 2.1mmol/mol, insulin 18pmol/l) was confirmed following 34 hours of fasting, however abdominal computed tomography (CT), pancreatic MRI, endoscopic ultrasound, octreotide scintigraphy and selective arterial calcium stimulation failed to localise an insulinoma. A prolonged OGTT revealed fasting hypoglycaemia that was exacerbated after glucose challenge, consistent with dysregulated glucose-stimulated insulin release. A heterozygous activating mutation, p.Val389Leu, in the glucokinase gene (GCK) was found in the proband and four other family members. Of these, two had been investigated elsewhere for recurrent hypoglycaemia in adulthood, while the other two adult relatives were asymptomatic despite profound hypoglycaemia. All three of the available family members with the p.Val389Leu mutation had normal serum lipid profiles, normal rates of fasting hepatic de novo lipogenesis and had hepatic triglyceride levels commensurate with their degree of adiposity. Conclusion Activating GCK mutations may

  12. Carrier Frequency of CYP1B1 Mutations in the United States (An American Ophthalmological Society Thesis)

    PubMed Central

    Wiggs, Janey L.; Langgurth, Anne M.; Allen, Keri F.

    2014-01-01

    Purpose: CYP1B1 mutations cause autosomal recessive congenital glaucoma. Disease risk assessment for families with CYP1B1 mutations requires knowledge of the population mutation carrier frequency. The purpose of this study is to determine the CYP1B1 mutation carrier frequency in clinically normal individuals residing in the United States. Because CYP1B1 mutations can exhibit variable expressivity, we hypothesize that the mutation carrier frequency is higher than expected. Methods: Two hundred fifty individuals without glaucoma or a family history of glaucoma were enrolled. CYP1B1 mutations were identified by DNA sequencing, and pathogenicity was estimated by PolyPhen-2 or a previous report of disease causality. Results: Based on the disease frequency (1 in 10,000) and prevalence of CYP1B1-related congenital glaucoma (15% to 20%), the frequency of CYP1B1-related congenital glaucoma in the United States is approximately 1 in 50,000. Assuming Hardy-Weinberg equilibrium, the expected CYP1B1 mutation carrier frequency would be 1 in 112, or 0.89%. Among the 250 study participants, 11 (4.4%) are carriers of a single pathogenic mutation, representing a carrier frequency of 1 in 22, which is 5.1 times the expected frequency. A higher-than-expected carrier frequency (1 in 33, 3.0%) was also observed in 4300 white individuals sequenced by the National Heart Lung and Blood Institute Exome Sequencing Project. Conclusions: Our results show that the CYP1B1 mutation carrier frequency in the US population is between 1 in 22 and 1 in 33, which is 5.1 to 3.4 times the expected frequency. These results suggest that more individuals than expected are carriers of a deleterious CYP1B1 mutation, and that the prevalence of CYP1B1-related disease may be higher than expected. PMID:25646030

  13. Protein-induced hyperinsulinaemic hypoglycaemia due to a homozygous HADH mutation in three siblings of a Saudi family.

    PubMed

    Babiker, Omer; Flanagan, Sarah E; Ellard, Sian; Al Girim, Hesham; Hussain, Khalid; Senniappan, Senthil

    2015-09-01

    Hyperinsulinaemic hypoglycaemia (HH) is caused by mutations in the key genes involved in regulation of insulin secretion from the pancreatic β-cells and mutations in ABCC8 and KCNJ11 are the most common causes of HH. Mutations in HADH (which encodes the enzyme 3-hydroxyacyl-CoA dehydrogenase) are a rare cause of HH. We report three siblings (21, 9, and 7 years old) from a consanguineous Saudi family with HH due to a homozygous mutation in HADH. All three siblings presented with HH in the 1st year of life. HH responded well to medical therapy (diazoxide/octreotide) although the 1st sibling suffered neurological damage. The protein load test revealed protein sensitivity in the 21-year-old proband, the oldest reported patient with HH secondary to a HADH mutation. Genetic analysis revealed a homozygous HADH splicing mutation (c.133-1G>A) in all three siblings. HADH mutations can present in later infancy or childhood with severe HH that is usually diazoxide responsive. Severe neurological complications such as epilepsy and developmental delay can be associated with HADH mutations. This is the 1st report of HH due to HADH mutation in an adult suggesting that HH could persist into adulthood possibly becoming milder over the years.

  14. Frequencies, Laboratory Features, and Granulocyte Activation in Chinese Patients with CALR-Mutated Myeloproliferative Neoplasms

    PubMed Central

    Tian, Ruiyuan; Chang, Jianmei; Li, Jianlan; Tan, Yanhong; Xu, Zhifang; Ren, Fanggang; Zhao, Junxia; Pan, Jie; Zhang, Na; Wang, Xiaojuan; He, Jianxia; Yang, Wanfang; Wang, Hongwei

    2015-01-01

    Somatic mutations in the CALR gene have been recently identified as acquired alterations in myeloproliferative neoplasms (MPNs). In this study, we evaluated mutation frequencies, laboratory features, and granulocyte activation in Chinese patients with MPNs. A combination of qualitative allele-specific polymerase chain reaction and Sanger sequencing was used to detect three driver mutations (i.e., CALR, JAK2V617F, and MPL). CALR mutations were identified in 8.4% of cases with essential thrombocythemia (ET) and 5.3% of cases with primary myelofibrosis (PMF). Moreover, 25% of polycythemia vera, 29.5% of ET, and 48.1% of PMF were negative for all three mutations (JAK2V617F, MPL, and CALR). Compared with those patients with JAK2V617F mutation, CALR-mutated ET patients displayed unique hematological phenotypes, including higher platelet counts, and lower leukocyte counts and hemoglobin levels. Significant differences were not found between Chinese PMF patients with mutants CALR and JAK2V617F in terms of laboratory features. Interestingly, patients with CALR mutations showed markedly decreased levels of leukocyte alkaline phosphatase (LAP) expression, whereas those with JAK2V617F mutation presented with elevated levels. Overall, a lower mutant rate of CALR gene and a higher triple-negative rate were identified in the cohort of Chinese patients with MPNs. This result indicates that an undiscovered mutant gene may have a significant role in these patients. Moreover, these pathological features further imply that the disease biology varies considerably between mutants CALR and JAK2V617F. PMID:26375990

  15. Infertility due to congenital absence of vas deferens in mainly caused by variable exon 9 skipping of the CFTR gene in heterozygous males for cystic fibrosis mutations

    SciTech Connect

    Chillon, M.; Casals, T.; Nunes, V.

    1994-09-01

    About 65% or the individuals with congenital bilateral absence of the vas deferens (CBAVD) have mutations in at least one of the CFTR alleles. We have studied the phenotypic effects of the CFTR gene intron 8 polyT tract 5T allele in 90 CBAVD subjects and in parents of CF patients. This group was compared with normal individuals, and with fathers and mothers of CF patients. Allele 5T was significantly associated with CBAVD (19.6%) when compared to the general population (5.2%) ({chi}{sup 2} = 33.3%; p<<0.0001). It was represented poorly in fathers of CF patients (1.3%). Mutations were identified in one (60%) or both CFTR alleles (8.9%) of CBAVD patients. Heterozygosity for the 5T allele was strongly associated with heterozygosity for CF mutations ({chi}{sup 2} = 10.9; p<0.0004). The strong correlation between allele 5T and CBAVD, together with the low frequency of this allele in fathers of CF patients, demonstrates that variable {Delta}exon 9 produces infertility in males if associated with a CF mutation on the other chromosome. The 30% of CBAVD cases with only one CFTR mutation and without a 5T-allele may be due to other molecular mechanisms involving CFTR, distinct from {Delta}exon 9. Since there is a relatively high proportion of CBAVD without CF mutations (25%), other gene(s), distinct from CFTR, may have a role in the CBAVD phenotype.

  16. Low frequency of filaggrin null mutations in Croatia and their relation with allergic diseases.

    PubMed

    Sabolić Pipinić, I; Varnai, V M; Turk, R; Breljak, D; Kezić, S; Macan, J

    2013-06-01

    Filaggrin gene (FLG) null mutations are considered associated with atopic dermatitis. This study was conducted to determine the prevalence of FLG null mutations R501X, 2282del4, R2447X and S3247X in the Croatian population and their role in the occurrence of allergic diseases including atopic dermatitis, allergic rhinitis, asthma and allergic contact dermatitis (ACD). Study enrolled 440 freshmen with defined allergic diseases by means of both present symptoms in International Study of Asthma and Allergies in Childhood questionnaire (relevant respiratory and/or skin symptoms) and markers of allergic sensitization (positive skin prick and/or patch test). FLG null mutations were successfully genotyped in 423 students of which 11 (2.6%) were carriers of FLG null mutation: 1/423 (0.2%) was heterozygous for R501X and 10/423 (2.4%) were heterozygous for 2282del4. No carriers of R2447X and S3247X mutations were identified. In wild-type FLG carriers (412 subjects), atopic dermatitis was present in 45 (11%), allergic rhinitis in 70 (17%) and allergic asthma in 29 (7%) students. Twenty-five of 393 (7%) patch-tested wild-type FLG carriers had ACD. Among 11 FLG null mutation carriers, four had one or more allergic diseases, and five had reported skin symptoms without defined allergic sensitization (positive skin prick test and/or patch test). FLG null mutations were not confirmed as a predictor of analysed allergic diseases, but were confirmed as an independent predictor of skin symptoms (OR 17.19, 95% CI 3.41-86.6, P < 0.001). Our results in general indicate a low frequency of FLG null mutations in the studied Croatian population supporting a theory of a latitude-dependent distribution of FGL null mutations in Europe, with a decreasing north-south gradient of R501X and 2282del4 mutation frequency. The relation between FLG null mutations and skin disorders was confirmed.

  17. Frequency of Calreticulin (CALR) Mutation and Its Clinical Prognostic Significance in Essential Thrombocythemia and Primary Myelofibrosis: A Meta-analysis.

    PubMed

    Kong, Hao; Liu, Yancheng; Luo, Sai; Li, Qiaoqiao; Wang, Qinglu

    2016-01-01

    Objective As the calreticulin (CALR) mutation frequency is significantly associated with essential thrombocythemia (ET) and primary myelofibrosis (PMF), this mutation may be an important biomarker in patients with ET and PMF. Methods We performed a literature search until April 2015 and obtained 21 relevant studies. The outcome was pooled as the effect size by using the Stata software program. Results The CALR mutation frequencies in patients with ET and PMF were 19% and 22%, respectively. The CALR mutation ratio in Asian patients with ET was 23% and higher than that in European-American patients (16%). Moreover, the mutation ratio in Asian patients with PMF was lower (21%) than that in European-American patients (23%). A slight trend toward fibrotic transformation was found in ET with CALR mutations, whereas leukemic transformation was not significant in patients with ET or PMF with CALR mutations. Conclusion CALR mutations significantly influence the incident of ET as demonstrated by the meta-analysis. PMID:27477402

  18. C282Y and H63D Mutation Frequencies in a Population from Central Spain

    PubMed Central

    Alvarez, S.; Mesa, M. S.; Bandrés, F.; Arroyo, E.

    2001-01-01

    Objectives: To determine the frequency of hereditary hemochromatosis gene mutations, C282Y and H63D, from 125 autochthonous blood donors originating from a Central region of Spain, to provide epidemiological data about HFE gene in the Iberian Peninsula. Methods: DNA extracted from blood samples was analyzed by PCR-RFLP. Restriction enzimes were Snab I and Bcl I for C282Y and H63D, respectively. Results were visualized with Ethidium Bromide staining after gel electrophoresis. Results and discussion: C282Y frequency was 0.02 and that of H63D was 0.16. Result for C282Y mutation falls within the range of variation of the Mediterranean populations. H63D frequency agrees with those reported for other European populations. In both cases frequencies obtained are the lowest of compared Spanish data. Conclusions: This study is useful to compare expected versus presented C282Y and H63D frequencies in Spanish populations and to contribute to the knowledge of Spanish variability, rarely analyzed until now for HFE gene mutations. PMID:11673657

  19. High frequency of PTEN mutations in nevi and melanomas from xeroderma pigmentosum patients.

    PubMed

    Masaki, Taro; Wang, Yun; DiGiovanna, John J; Khan, Sikandar G; Raffeld, Mark; Beltaifa, Senda; Hornyak, Thomas J; Darling, Thomas N; Lee, Chyi-Chia R; Kraemer, Kenneth H

    2014-05-01

    We examined nevi and melanomas in 10 xeroderma pigmentosum (XP) patients with defective DNA repair. The lesions had a lentiginous appearance with markedly increased numbers of melanocytes. Using laser capture microdissection, we performed DNA sequencing of 18 benign and atypical nevi and 75 melanomas (melanoma in situ and invasive melanomas). The nevi had a similar high frequency of PTEN mutations as melanomas [61% (11/18) versus 53% (39/73)]. Both had a very high proportion of UV-type mutations (occurring at adjacent pyrimidines) [91% (10/11) versus 92% (36/39)]. In contrast to melanomas in the general population, the frequency of BRAF mutations (11%, 7/61), NRAS mutations (21%, 13/62), and KIT mutations (21%, 6/28) in XP melanomas was lower than for PTEN. Phospho-S6 immunostaining indicated activation of the mTOR pathway in the atypical nevi and melanomas. Thus, the clinical and histological appearances and the molecular pathology of these UV-related XP nevi and melanomas were different from nevi and melanomas in the general population. PMID:24483290

  20. The phenotype of the musculocontractural type of Ehlers-Danlos syndrome due to CHST14 mutations.

    PubMed

    Janecke, Andreas R; Li, Ben; Boehm, Manfred; Krabichler, Birgit; Rohrbach, Marianne; Müller, Thomas; Fuchs, Irene; Golas, Gretchen; Katagiri, Yasuhiro; Ziegler, Shira G; Gahl, William A; Wilnai, Yael; Zoppi, Nicoletta; Geller, Herbert M; Giunta, Cecilia; Slavotinek, Anne; Steinmann, Beat

    2016-01-01

    The musculocontractural type of Ehlers-Danlos syndrome (MC-EDS) has been recently recognized as a clinical entity. MC-EDS represents a differential diagnosis within the congenital neuromuscular and connective tissue disorders spectrum. Thirty-one and three patients have been reported with MC-EDS so far with bi-allelic mutations identified in CHST14 and DSE, respectively, encoding two enzymes necessary for dermatan sulfate (DS) biosynthesis. We report seven additional patients with MC-EDS from four unrelated families, including the follow-up of a sib-pair originally reported with the kyphoscoliotic type of EDS in 1975. Brachycephaly, a characteristic facial appearance, an asthenic build, hyperextensible and bruisable skin, tapering fingers, instability of large joints, and recurrent formation of large subcutaneous hematomas are always present. Three of seven patients had mildly elevated serum creatine kinase. The oldest patient was blind due to retinal detachment at 45 years and died at 59 years from intracranial bleeding; her affected brother died at 28 years from fulminant endocarditis. All patients in this series harbored homozygous, predicted loss-of-function CHST14 mutations. Indeed, DS was not detectable in fibroblasts from two unrelated patients with homozygous mutations. Patient fibroblasts produced higher amounts of chondroitin sulfate, showed intracellular retention of collagen types I and III, and lacked decorin and thrombospondin fibrils compared with control. A great proportion of collagen fibrils were not integrated into fibers, and fiber bundles were dispersed into the ground substance in one patient, all of which is likely to contribute to the clinical phenotype. This report should increase awareness for MC-EDS.

  1. The phenotype of the musculocontractural type of Ehlers-Danlos syndrome due to CHST14 mutations.

    PubMed

    Janecke, Andreas R; Li, Ben; Boehm, Manfred; Krabichler, Birgit; Rohrbach, Marianne; Müller, Thomas; Fuchs, Irene; Golas, Gretchen; Katagiri, Yasuhiro; Ziegler, Shira G; Gahl, William A; Wilnai, Yael; Zoppi, Nicoletta; Geller, Herbert M; Giunta, Cecilia; Slavotinek, Anne; Steinmann, Beat

    2016-01-01

    The musculocontractural type of Ehlers-Danlos syndrome (MC-EDS) has been recently recognized as a clinical entity. MC-EDS represents a differential diagnosis within the congenital neuromuscular and connective tissue disorders spectrum. Thirty-one and three patients have been reported with MC-EDS so far with bi-allelic mutations identified in CHST14 and DSE, respectively, encoding two enzymes necessary for dermatan sulfate (DS) biosynthesis. We report seven additional patients with MC-EDS from four unrelated families, including the follow-up of a sib-pair originally reported with the kyphoscoliotic type of EDS in 1975. Brachycephaly, a characteristic facial appearance, an asthenic build, hyperextensible and bruisable skin, tapering fingers, instability of large joints, and recurrent formation of large subcutaneous hematomas are always present. Three of seven patients had mildly elevated serum creatine kinase. The oldest patient was blind due to retinal detachment at 45 years and died at 59 years from intracranial bleeding; her affected brother died at 28 years from fulminant endocarditis. All patients in this series harbored homozygous, predicted loss-of-function CHST14 mutations. Indeed, DS was not detectable in fibroblasts from two unrelated patients with homozygous mutations. Patient fibroblasts produced higher amounts of chondroitin sulfate, showed intracellular retention of collagen types I and III, and lacked decorin and thrombospondin fibrils compared with control. A great proportion of collagen fibrils were not integrated into fibers, and fiber bundles were dispersed into the ground substance in one patient, all of which is likely to contribute to the clinical phenotype. This report should increase awareness for MC-EDS. PMID:26373698

  2. Prevalence of common MEFV mutations and carrier frequencies in a large cohort of Iranian populations.

    PubMed

    Beheshtian, Maryam; Izadi, Nasim; Kriegshauser, Gernot; Kahrizi, Kimia; Mehr, Elham Parsi; Rostami, Maryam; Hosseini, Masoumeh; Azad, Maryam; Montajabiniat, Mona; Kariminejad, Ariana; Nemeth, Stefan; Oberkanins, Christian; Najmabadi, Hossein

    2016-09-01

    Familial Mediterranean fever (FMF) is a hereditary autoinflammatory disorder caused by mutations in the MEFV gene. The disease is especially common among Armenian, Turkish, Jewish and Middle East Arab populations. To identify the frequency and the spectrum of common MEFV mutations in different Iranian populations, we investigated a cohort of 208 unselected asymptomatic individuals and 743 FMF patients. Nine hundred and fifty-one samples were analysed for the presence of 12 MEFV mutations by PCR and reverse-hybridization (FMF StripAssay, ViennaLab, Vienna, Austria). Confirmatory dideoxy sequencing of all MEFV gene exons was performed for 39 patients. Fifty-seven (27.4%) healthy individual carried mutant MEFV alleles. Three hundred and ninety-one (52.6%) FMF patients were found positive for either one (172/743; 23.1%), two or three MEFV mutations. Using dideoxy sequencing, three novel variants, A66P, R202W and H300Q, could be identified. Our analysis revealed an allele frequency and carrier rate of 15.6 and 27.4%, respectively, among healthy Iranians. Still moderate compared to neighbouring Armenia, but higher than in Turkey or Iraq, these data suggest that FMF is remarkably common among Iranian populations. E148Q was most frequent in the group of healthy individuals, whereas M694V was the most common mutation among FMF patients, thereby corroborating previous studies on MEFV mutational spectra in the Middle East. Accordingly, MEFV mutations are frequent in healthy Iranian individuals across different ethnic groups. Based on this finding, the awareness for FMF and the implementation of augmented carrier screening programmes considering the multiethnic nature of the Iranian population should be promoted. PMID:27659338

  3. ARCN1 Mutations Cause a Recognizable Craniofacial Syndrome Due to COPI-Mediated Transport Defects.

    PubMed

    Izumi, Kosuke; Brett, Maggie; Nishi, Eriko; Drunat, Séverine; Tan, Ee-Shien; Fujiki, Katsunori; Lebon, Sophie; Cham, Breana; Masuda, Koji; Arakawa, Michiko; Jacquinet, Adeline; Yamazumi, Yusuke; Chen, Shu-Ting; Verloes, Alain; Okada, Yuki; Katou, Yuki; Nakamura, Tomohiko; Akiyama, Tetsu; Gressens, Pierre; Foo, Roger; Passemard, Sandrine; Tan, Ene-Choo; El Ghouzzi, Vincent; Shirahige, Katsuhiko

    2016-08-01

    Cellular homeostasis is maintained by the highly organized cooperation of intracellular trafficking systems, including COPI, COPII, and clathrin complexes. COPI is a coatomer protein complex responsible for intracellular protein transport between the endoplasmic reticulum and the Golgi apparatus. The importance of such intracellular transport mechanisms is underscored by the various disorders, including skeletal disorders such as cranio-lenticulo-sutural dysplasia and osteogenesis imperfect, caused by mutations in the COPII coatomer complex. In this article, we report a clinically recognizable craniofacial disorder characterized by facial dysmorphisms, severe micrognathia, rhizomelic shortening, microcephalic dwarfism, and mild developmental delay due to loss-of-function heterozygous mutations in ARCN1, which encodes the coatomer subunit delta of COPI. ARCN1 mutant cell lines were revealed to have endoplasmic reticulum stress, suggesting the involvement of ER stress response in the pathogenesis of this disorder. Given that ARCN1 deficiency causes defective type I collagen transport, reduction of collagen secretion represents the likely mechanism underlying the skeletal phenotype that characterizes this condition. Our findings demonstrate the importance of COPI-mediated transport in human development, including skeletogenesis and brain growth. PMID:27476655

  4. [A girl with hereditary myotonia due to an exceptional sodium channel mutation].

    PubMed

    van den Bergen, J C; Verbruggen, K T; Ginjaar, H B; Kerstjens-Frederikse, W S

    2006-11-11

    A 22-month-old girl had cramps and stiffness of her muscles. After medical history, physical examination and an EMG, a short differential diagnosis based on the symptoms of myotonia was made. Initially, the symptoms were incorrectly assumed to be due to Becker's myotonia, an autosomal recessive condition caused by a mutation in the chloride channel. Molecular analysis did not show a defect in the chloride channel, but instead a defect in the sodium channel of the muscle fibre. Since defects in the sodium channel are responsible for several myotonic diseases, further analysis was necessary. Based on knowledge of the structure and mechanism of the sodium channel and study of literature on cases involving the identical mutation, the diagnosis 'potassium-aggravated myotonia' (PAM) was made. Re-evaluation of the patient showed that her symptoms fitted the diagnosis 'myotonia permanens', the severest form of PAM. She was treated with mexiletine. In myotonia several features can give direction to the diagnosis, including sensitivity to temperature and exercise, and family history. However, it is often necessary to use molecular analysis to be able to diagnose the disease correctly, make a prognosis and predict the risk of recurrence as well as to formulate a treatment plan. PMID:17137100

  5. Hereditary desmoid disease due to a frameshift mutation at codon 1924 of the APC gene.

    PubMed Central

    Eccles, D. M.; van der Luijt, R.; Breukel, C.; Bullman, H.; Bunyan, D.; Fisher, A.; Barber, J.; du Boulay, C.; Primrose, J.; Burn, J.; Fodde, R.

    1996-01-01

    Desmoid tumors are slowly growing fibrous tumors highly resistant to therapy and often fatal. Here, we report hereditary desmoid disease (HDD), a novel autosomal dominant trait with 100% penetrance affecting a three-generation kindred. Desmoid tumors are usually a complication of familial adenomatous polyposis, a predisposition to the early development of premalignant adenomatous polyps in the colorectum due to chain-terminating mutations of the APC gene. In general, one or more members in approximately 10% of the FAP families manifest desmoid tumors. Affected individuals from the HDD kindred are characterized by multifocal fibromatosis of the paraspinal muscles, breast, occiput, arms, lower ribs, abdominal wall, and mesentery. Osteomas, epidermal cysts, and other congenital features were also observed. We show that HDD segregates with an unusual germ-line chain-terminating mutation at the 3' end of the APC gene (codon 1924) with somatic loss of the wild-type allele leading to tumor development. Images Figure 2 Figure 3 Figure 4 Figure 5 PMID:8940264

  6. The tRNA-Tyr gene family of Saccharomyces cerevisiae: agents of phenotypic variation and position effects on mutation frequency.

    PubMed Central

    Ito-Harashima, Sayoko; Hartzog, Phillip E; Sinha, Himanshu; McCusker, John H

    2002-01-01

    Extensive phenotypic diversity or variation exists in clonal populations of microorganisms and is thought to play a role in adaptation to novel environments. This phenotypic variation or instability, which occurs by multiple mechanisms, may be a form of cellular differentiation and a stochastic means for modulating gene expression. This work dissects a case of phenotypic variation in a clinically derived Saccharomyces cerevisiae strain involving a cox15 ochre mutation, which acts as a reporter. The ochre mutation reverts to sense at a low frequency while tRNA-Tyr ochre suppressors (SUP-o) arise at a very high frequency to produce this phenotypic variation. The SUP-o mutations are highly pleiotropic. In addition, although all SUP-o mutations within the eight-member tRNA-Tyr gene family suppress the ochre mutation reporter, there are considerable phenotypic differences among the different SUP-o mutants. Finally, and of particular interest, there is a strong position effect on mutation frequency within the eight-member tRNA-Tyr gene family, with one locus, SUP6, mutating at a much higher than average frequency and two other loci, SUP2 and SUP8, mutating at much lower than average frequencies. Mechanisms for the position effect on mutation frequency are evaluated. PMID:12196388

  7. Abnormal cerebellar development and axonal decussation due to mutations in AHI1 in Joubert syndrome.

    PubMed

    Ferland, Russell J; Eyaid, Wafaa; Collura, Randall V; Tully, Laura D; Hill, R Sean; Al-Nouri, Doha; Al-Rumayyan, Ahmed; Topcu, Meral; Gascon, Generoso; Bodell, Adria; Shugart, Yin Yao; Ruvolo, Maryellen; Walsh, Christopher A

    2004-09-01

    Joubert syndrome is a congenital brain malformation of the cerebellar vermis and brainstem with abnormalities of axonal decussation (crossing in the brain) affecting the corticospinal tract and superior cerebellar peduncles. Individuals with Joubert syndrome have motor and behavioral abnormalities, including an inability to walk due to severe clumsiness and 'mirror' movements, and cognitive and behavioral disturbances. Here we identified a locus associated with Joubert syndrome, JBTS3, on chromosome 6q23.2-q23.3 and found three deleterious mutations in AHI1, the first gene to be associated with Joubert syndrome. AHI1 is most highly expressed in brain, particularly in neurons that give rise to the crossing axons of the corticospinal tract and superior cerebellar peduncles. Comparative genetic analysis of AHI1 indicates that it has undergone positive evolutionary selection along the human lineage. Therefore, changes in AHI1 may have been important in the evolution of human-specific motor behaviors.

  8. Genetics and phenomics of hypothyroidism and goiter due to iodotyrosine deiodinase (DEHAL1) gene mutations.

    PubMed

    Moreno, José C; Visser, Theo J

    2010-06-30

    Iodotyrosine deiodinase is a thyroidal enzyme that deiodinates mono- and di-iodotyrosines (MIT, DIT) and recycles iodine, a scarce element in the environment, for the efficient synthesis of thyroid hormone. Failure of this enzyme leads to hypothyroidism, goiter and mental retardation, a clinical phenotype yet described in the 1950s, whose diagnostic hallmark is the elevation of iodotyrosines in serum and urine. DEHAL1, the gene responsible for this activity, was recently isolated and the molecular basis for the iodotyrosine deiodinase deficiency (ITDD) unraveled. The current clinical picture of mutations in DEHAL1 mostly recapitulates the "classical" phenotype of ITDD, including the psychomotor deficits. This is probably due to the lack of expression of the disease at the beginning of life, which causes ITDD being undetected in current screening programs for congenital hypothyroidism. This worrying feature calls for efforts to improve the preclinical detection of iodotyrosine deiodinase deficiency in the neonatal time. PMID:20298747

  9. Cytoplasmic Mislocalization of POU3F4 Due to Novel Mutations Leads to Deafness in Humans and Mice

    PubMed Central

    Parzefall, Thomas; Shivatzki, Shaked; Lenz, Danielle R.; Rathkolb, Birgit; Ushakov, Kathy; Karfunkel, Daphne; Shapira, Yisgav; Wolf, Michael; Mohr, Manuela; Wolf, Eckhard; Sabrautzki, Sibylle; De Angelis, Martin Hrabé; Frydman, Moshe; Brownstein, Zippora; Avraham, Karen B.

    2013-01-01

    POU3F4 is a POU domain transcription factor that is required for hearing. In the ear, POU3F4 is essential for mesenchymal remodeling of the bony labyrinth and is the causative gene for DFNX2 human non-syndromic deafness. Ear abnormalities underlie this form of deafness, characterized previously in multiple spontaneous, radiation-induced and transgenic mouse mutants. Here we report three novel mutations in the POU3F4 gene that result in profound hearing loss in both humans and mice. A p.Gln79* mutation was identified in a child from an Israeli family, revealed by massively parallel sequencing (MPS). This strategy demonstrates the strength of MPS for diagnosis with only one affected individual. A second mutation, p.Ile285Argfs*43, was identified by Sanger sequencing. A p.Cys300* mutation was found in an ENU-induced mutant mouse, schwindel (sdl), by positional cloning. The mutation leads to a predicted truncated protein, similar to the human mutations, providing a relevant mouse model. The p.Ile285Argfs*43 and p.Cys300* mutations lead to a shift of Pou3f4 nuclear localization to the cytoplasm, demonstrated in cellular localization studies and in the inner ears of the mutant mice. The discovery of these mutations facilitates a deeper comprehension of the molecular basis of inner ear defects due to mutations in the POU3F4 transcription factor. PMID:23606368

  10. Heavy smokers have higher bcl-2 mutation frequency and risk for lymphoma than non-smokers

    SciTech Connect

    Liu, Y.; Cortopassi, G.A.; Bell, D.A.

    1994-09-01

    Early detection of cells carrying somatic mutations at oncogenic loci could prove useful for identifying individuals at high risk for cancer and permit intervention prior to the onset of clinically recognizable disease. We have determined the frequency of rare t(14;18)(q32;q21) translocations at the bcl-2 proto-oncogene locus in the peripheral blood of 85 smokers and 35 nonsmokers using a sensitive nested PCR assay. The identical translocation occurs in 85% of follicular lymphoma tumors, and about 50% of all non-Hodgkin`s Lymphoma. Smokers with the highest exposure had a 3.6-fold higher mutation frequency relative to the nonsmokers. Logistic regression analysis showed that of the variables tested (age, race, sex, current smoking, years of smoking, and pack-years), the cumulative smoking measure (pack-years) was the best predictor of t(14;18) frequency (p=0.004). These observations are consistent with two recent epidemiological studies showing 2.3-fold and 3.8-fold increased risk for Non-Hodgkins lymphoma among heavy smokers. The results support the hypothesis that smokers have an increased burden of lymphocytes bearing bcl-2 mutations which raises their individual risk for future lymphoid tumors. We speculate that the increased frequency of oncogenic translocations in smokers may result either from the mutagenic or antigenic activity of cigarette smoke.

  11. Recessive axonal Charcot-Marie-Tooth disease due to compound heterozygous mitofusin 2 mutations

    PubMed Central

    Polke, J.M.; Laurá, M.; Pareyson, D.; Taroni, F.; Milani, M.; Bergamin, G.; Gibbons, V.S.; Houlden, H.; Chamley, S.C.; Blake, J.; DeVile, C.; Sandford, R.; Sweeney, M.G.; Davis, M.B.

    2011-01-01

    Objective: Mutations in mitofusin 2 (MFN2) are the most common cause of axonal Charcot-Marie-Tooth disease (CMT2). Over 50 mutations have been reported, mainly causing autosomal dominant disease, though families with homozygous or compound heterozygous mutations have been described. We present 3 families with early-onset CMT2 associated with compound heterozygous MFN2 mutations. Transcriptional analysis was performed to investigate the effects of the mutations. Methods: Patients were examined clinically and electrophysiologically; parents were also examined where available. Genetic investigations included MFN2 DNA sequencing and dosage analysis by multiplex ligation-dependent probe amplification. MFN2 mRNA transcripts from blood lymphocytes were analyzed in 2 families. Results: Compound heterozygosity for MFN2 mutations was associated with early-onset CMT2 of varying severity between pedigrees. Parents, where examined, were unaffected and were heterozygous for the expected mutations. Four novel mutations were detected (one missense, one nonsense, an intragenic deletion of exons 7 + 8, and a 3–base pair deletion), as well as 2 previously reported missense mutations. Transcriptional analysis demonstrated aberrant splicing of the exonic deletion and indicated nonsense-mediated decay of mutant alleles with premature truncating mutations. Conclusions: Our findings confirm that MFN2 mutations can cause early-onset CMT2 with apparent recessive inheritance. Novel genetic findings include an intragenic MFN2 deletion and nonsense-mediated decay. Carrier parents were asymptomatic, suggesting that MFN2 null alleles can be nonpathogenic unless coinherited with another mutation. PMID:21715711

  12. Characterization of the factor VIII defect in 147 patients with sporadic hemophilia A: family studies indicate a mutation type-dependent sex ratio of mutation frequencies.

    PubMed Central

    Becker, J.; Schwaab, R.; Möller-Taube, A.; Schwaab, U.; Schmidt, W.; Brackmann, H. H.; Grimm, T.; Olek, K.; Oldenburg, J.

    1996-01-01

    The clinical manifestation of hemophilia A is caused by a wide range of different mutations. In this study the factor VIII genes of 147 severe hemophilia A patients--all exclusively from sporadic families--were screened for mutations by use of the complete panel of modern DNA techniques. The pathogenous defect could be characterized in 126 patients (85.7 percent). Fifty-five patients (37.4 percent) showed a F8A-gene inversion, 47 (32.0 percent) a point mutation, 14 (9.5 percent) a small deletion, 8 (5.4 percent) a large deletion, and 2 (1.4 percent) a small insertion. Further, four (2.7 percent) mutations were localized but could not be sequenced yet. No mutation could be identified in 17 patients (11.6 percent). Sixteen (10.9 percent) of the identified mutations occurred in the B domain. Four of these were located in an adenosine nucleotide stretch at codon 1192, indicating a mutation hotspot. Somatic mosaicisms were detected in 3 (3.9 percent) of 76 patients, mothers, comprising 3 of 16 de novo mutations in the patients mothers. Investigation of family relatives allowed detection of a de novo mutation in 16 of 76 two-generation and 28 of 34 three-generation families. On the basis of these data, the male:female ratio of mutation frequencies (k) was estimated as k = 3.6. By use of the quotients of mutation origin in maternal grandfather to patients mother or to maternal grandmother, k was directly estimated as k = 15 and k = 7.5, respectively. Considering each mutation type separately, we revealed a mutation type-specific sex ratio of mutation frequencies. Point mutations showed a 5-to-10-fold-higher and inversions a >10-fold-higher mutation rate in male germ cells, whereas deletions showed a >5-fold-higher mutation rate in female germ cells. Consequently, and in accordance with the data of other diseases like Duchenne muscular dystrophy, our results indicate that at least for X-chromosomal disorders the male:female mutation rate of a disease is determined by its

  13. Characterization of the factor VIII defect in 147 patients with sporadic hemophilia A: Family studies indicate a mutation type-dependent sex ratio of mutation frequencies

    SciTech Connect

    Becker, J.; Schmidt, W.; Olek, K.

    1996-04-01

    The clinical manifestation of hemophilia A is caused by a wide range of different mutations. In this study the factor VIII genes of 147 severe hemophilia A patients-all exclusively from sporadic families-were screened for mutations by use of the complete panel of modern DNA techniques. The pathogenous defect could be characterized in 126 patients (85.7%). Fifty-five patients (37.4%) showed a F8A-gene inversion, 47 (32.0%) a point mutation, 14 (9.5%) a small deletion, 8 (5.4%) a large deletion, and 2 (1.4%) a small insertion. Further, four (2.7%) mutations were localized but could not be sequenced yet. No mutation could be identified in 17 patients (11.6%). Sixteen (10.9%) of the P identified mutations occurred in the B domain. Four of these were located in an adenosine nucleotide stretch at codon 1192, indicating a mutation hotspot. Somatic mosaicisms were detected in 3 (3.9%) of 76 patients` mothers, comprising 3 of 16 de novo mutations in the patients` mothers. Investigation of family relatives allowed detection of a de novo mutation in 16 of 76 two-generation and 28 of 34 three-generation families. On the basis of these data, the male:female ratio of mutation frequencies (k) was estimated as k = 3.6. By use of the quotients of mutation origin in maternal grandfather to patient`s mother or to maternal grandmother, k was directly estimated as k = 15 and k = 7.5, respectively. Considering each mutation type separately, we revealed a mutation type-specific sex ratio of mutation frequencies. Point mutations showed a 5-to-10-fold-higher and inversions a >10-fold- higher mutation rate in male germ cells, whereas deletions showed a >5-fold-higher mutation rate in female germ cells. Consequently, and in accordance with the data of other diseases like Duchenne muscular dystrophy, our results indicate that at least for X-chromosomal disorders the male:female mutation rate of a disease is determined by its proportion of the different mutation types. 68 refs., 1 fig., 5 tabs.

  14. Ethnic heterogeneity and cystic fibrosis transmembrane regulator (CFTR) mutation frequencies in Chicago-area CF families

    SciTech Connect

    Ober, C.; Lester, L.A.; Mott, C.; Billstrand, C.; Lemke, A.; Ven, K. van der ); Marcus, S.; Kraut, J.; Booth, C. ); Lloyd-Still, J. )

    1992-12-01

    The identification of a common mutation, [Delta]F508, in the CFTR gene allowed, for the first time, the detection of cystic fibrosis (CF) carriers in the general population. Further genetic studies revealed >100 additional disease-causing mutations in this gene, few of which occur on >1% of CF chromosomes in any ethnic group. Prior to establishing counseling guidelines and carrier risk assessments, the authors sought to establish the frequencies of the CFTR mutations that are present in CF families living in the Chicago are, a region notable for its ethnic heterogeneity. Their sample included 283 unrelated CF carriers, with the following ethnic composition: 78% non-Ashkenazi Caucasians, 5% Ashkenazi, 9% African-American, 3% Mexican, 0.3% Native American, and 5% mixed ancestry. When a panel of 10 mutations ([Delta]F508, [Delta]I507, G542X, G551D, R553X, S549N, R1162X, W1282X, N1303K, and 1717-1G[r arrow]A) was used, detection rates ranged from 75% in non-Ashkenazi Caucasians to 40% in African-Americans. These data suggest that the goal of screening for 90%-95% of CF mutations may be unrealistic in this and other, similar US populations. 22 refs., 1 tab.

  15. Analysis of the T354P mutation of the sodium/iodide cotransporter gene in children with congenital hypothyroidism due to dyshormonogenesis

    PubMed Central

    Miranzadeh-Mahabadi, Hajar; Emadi-Baygi, Modjtaba; Nikpour, Parvaneh; Mostofizade, Neda; Hovsepian, Silva; Hashemipour, Mahin

    2016-01-01

    Background: Congenital hypothyroidism (CH) due to the thyroid dyshormonogenesis is more prevalent in Iran in comparison to other countries. Sodium iodide symporter (NIS) is one of the plasma membrane glycoproteins that is located on the basolateral side of thyroid follicular cells and mediates active I− trapping into these cells. Playing a prominent role in thyroid hormone synthesis, NIS gene mutations can be a cause of permanent CH with the etiology of dyshormonogenesis. The aim of this study was to investigate the occurrence of T354P mutation of the NIS gene, in a group of children affected with permanent CH in Isfahan. Materials and Methods: Thirty-five patients with the etiology of dyshormonogenesis, and 35 healthy children, collected between 2002 and 2011 in Isfahan Endocrine and Metabolism Research Center, were examined for T354P mutation of the NIS gene by direct polymerase chain reaction-sequencing method. Results: No T354P mutation was detected in any of the studied children. Conclusions: More subjects with confirmed iodide transport defects should be screened for detecting the frequency of different reported NIS gene mutations in our population. PMID:27169104

  16. DNA-PKcs mutations in dogs and horses: allele frequency and association with neoplasia.

    PubMed

    Ding, Qi; Bramble, Lori; Yuzbasiyan-Gurkan, Vilma; Bell, Thomas; Meek, Katheryn

    2002-01-23

    Previously, spontaneous genetic immunodeficiencies in mice, Arabian foals, and recently in Jack Russell terriers have been ascribed to defects in DNA-PKcs (catalytic subunit of the DNA dependent protein kinase) expression. In severe combined immunodeficiency (SCID) foals, a 5 bp deletion at codon 9480 results in a frameshift and a 967 amino acid deletion from the C terminus (including the entire PI3 kinase domain) and an unstable mutant protein. In SCID mice, a single base pair mutation results in a premature stop codon and deletion of 83 amino acids; as in SCID foals, the mutant protein is unstable. Here, we define the mutation within the canine DNA-PKcs gene that results in SCID. In this case, a point mutation results in a stop codon at nucleotide 10,828 and premature termination at a position 517 amino acids before the normal C terminus resulting in a functionally null allele. Thus, this is the third documentation of a spontaneous germline mutation in the C terminus of DNA-PKcs. Emerging data implicate DNA repair factors as potential tumor suppressors. Here, we have ascertained the carrier frequency of the defective DNA-PKcs genes in Arabian horses and in Jack Russell terriers. Our data indicate (in good agreement with a previous report) that the carrier frequency of the equine SCID allele is approximately 8%; in contrast, the carrier frequency of the canine SCID allele is less than 1.1%. We also assessed the frequency of the equine SCID allele in a series of 295 tumors from Arabian horses. We find a statistically significant correlation between the development of a virally induced tumor (sarcoid) and heterozygosity for the equine SCID allele. These data provide further support for an emerging consensus: that DNA-PK may normally act as a tumor suppressor through its caretaker role in maintaining chromosomal stability. PMID:11867233

  17. Fundamental Limit of 1/f Frequency Noise in Semiconductor Lasers Due to Mechanical Thermal Noise

    NASA Technical Reports Server (NTRS)

    Numata, K.; Camp, J.

    2011-01-01

    So-called 1/f noise has power spectral density inversely proportional to frequency, and is observed in many physical processes. Single longitudinal-mode semiconductor lasers, used in variety of interferometric sensing applications, as well as coherent communications, exhibit 1/f frequency noise at low frequency (typically below 100kHz). Here we evaluate mechanical thermal noise due to mechanical dissipation in semiconductor laser components and give a plausible explanation for the widely-observed 1/f frequency noise, applying a methodology developed for fixed-spacer cavities for laser frequency stabilization. Semiconductor-laser's short cavity, small beam radius, and lossy components are expected to emphasize thermal-noise-limited frequency noise. Our simple model largely explains the different 1/f noise levels observed in various semiconductor lasers, and provides a framework where the noise may be reduced with proper design.

  18. Target DNA sequence directly regulates the frequency of activation-induced deaminase-dependent mutations.

    PubMed

    Chen, Zhangguo; Viboolsittiseri, Sawanee S; O'Connor, Brian P; Wang, Jing H

    2012-10-15

    Activation-induced deaminase (AID) catalyses class switch recombination (CSR) and somatic hypermutation (SHM) in B lymphocytes to enhance Ab diversity. CSR involves breaking and rejoining highly repetitive switch (S) regions in the IgH (Igh) locus. S regions appear to be preferential targets of AID. To determine whether S region sequence per se, independent of Igh cis regulatory elements, can influence AID targeting efficiency and mutation frequency, we established a knock-in mouse model by inserting a core Sγ1 region into the first intron of proto-oncogene Bcl6, which is a non-Ig target of SHM. We found that the mutation frequency of the inserted Sγ1 region was dramatically higher than that of the adjacent Bcl6 endogenous sequence. Mechanistically, S region-enhanced SHM was associated with increased recruitment of AID and RNA polymerase II, together with Spt5, albeit to a lesser extent. Our studies demonstrate that target DNA sequences influence mutation frequency via regulating AID recruitment. We propose that the nucleotide sequence preference may serve as an additional layer of AID regulation by restricting its mutagenic activity to specific sequences despite the observation that AID has the potential to access the genome widely.

  19. Frequency and origins of hemoglobin S mutation in African-derived Brazilian populations.

    PubMed

    De Mello Auricchio, Maria Teresa Balester; Vicente, João Pedro; Meyer, Diogo; Mingroni-Netto, Regina Célia

    2007-12-01

    Africans arrived in Brazil as slaves in great numbers, mainly after 1550. Before the abolition of slavery in Brazil in 1888, many communities, called quilombos, were formed by runaway or abandoned African slaves. These communities are presently referred to as remnants of quilombos, and many are still partially genetically isolated. These remnants can be regarded as relicts of the original African genetic contribution to the Brazilian population. In this study we assessed frequencies and probable geographic origins of hemoglobin S (HBB*S) mutations in remnants of quilombo populations in the Ribeira River valley, São Paulo, Brazil, to reconstruct the history of African-derived populations in the region. We screened for HBB*S mutations in 11 quilombo populations (1,058 samples) and found HBB*S carrier frequencies that ranged from 0% to 14%. We analyzed beta-globin gene cluster haplotypes linked to the HBB*S mutation in 86 chromosomes and found the four known African haplotypes: 70 (81.4%) Bantu (Central Africa Republic), 7 (8.1%) Benin, 7 (8.1%) Senegal, and 2 (2.3%) Cameroon haplotypes. One sickle cell homozygote was Bantu/Bantu and two homozygotes had Bantu/Benin combinations. The high frequency of the sickle cell trait and the diversity of HBB*S linked haplotypes indicate that Brazilian remnants of quilombos are interesting repositories of genetic diversity present in the ancestral African populations.

  20. Molecular spectrum of KRAS, BRAF, and PIK3CA gene mutation: determination of frequency, distribution pattern in Indian colorectal carcinoma.

    PubMed

    Bisht, Swati; Ahmad, Firoz; Sawaimoon, Satyakam; Bhatia, Simi; Das, Bibhu Ranjan

    2014-09-01

    Molecular evaluation of KRAS, BRAF, and PIK3CA mutation has become an important part in colorectal carcinoma evaluation, and their alterations may determine the therapeutic response to anti-EGFR therapy. The current study demonstrates the evaluation of KRAS, BRAF, and PIK3CA mutation using direct sequencing in 204 samples. The frequency of KRAS, BRAF, and PIK3CA mutations was 23.5, 9.8, and 5.9 %, respectively. Five different substitution mutations at KRAS codon 12 (G12S, G12D, G12A, G12V, and G12C) and one substitution type at codon 13 (G13D) were observed. KRAS mutations were significantly higher in patients who were >50 years, and were associated with moderate/poorly differentiated tumors and adenocarcinomas. All mutations in BRAF gene were of V600E type, which were frequent in patients who were ≤ 50 years. Unlike KRAS mutations, BRAF mutations were more frequent in well-differentiated tumors and right-sided tumors. PIK3CA-E545K was the most recurrent mutation while other mutations detected were T544I, Q546R, H1047R, G1049S, and D1056N. No significant association of PIK3CA mutation with age, tumor differentiation, location, and other parameters was noted. No concomitant mutation of KRAS and BRAF mutations was observed, while, interestingly, five cases showed concurrent mutation of KRAS and PIK3CA mutations. In conclusion, to our knowledge, this is the first study to evaluate the PIK3CA mutation in Indian CRC patients. The frequency of KRAS, BRAF, and PIK3CA was similar to worldwide reports. Furthermore, identification of molecular markers has unique strengths, and can provide insights into the pathogenic process and help optimize personalized prevention and therapy.

  1. Charcot-Marie-Tooth disease due to a de novo mutation of the RAB7 gene.

    PubMed

    Meggouh, F; Bienfait, H M E; Weterman, M A J; de Visser, M; Baas, F

    2006-10-24

    We report a 32-year-old patient with Charcot-Marie-Tooth (CMT2B) including foot ulcerations. Genetic analysis identified a de novo mutation in the small GTP-ase late endosomal RAB7 gene, consisting of a c.471G>C, p.Lys157Asn missense mutation. This observation strongly supports the hypothesis that RAB7 mutations are responsible for CMT2B. PMID:17060578

  2. [Population frequency and age of c.806C > T mutation in CYB5R3 gene as cause of recessive congenital methemoglobinemia in Yakutia].

    PubMed

    Galeeva, N M; Voevoda, M I; Spiridonova, M G; Stepanov, V A; Poliakov, A V

    2013-04-01

    Type-1recessive congenital methemoglobinemia (RCM) is a rare autosomal disease characterized by a deficiency of the soluble form of nicotineamide adenine dinucleotide (NADH)-cytochrome b5 reductase (b5R) and clinically manifests as cyanosis of skin and mucous membranes. In the Russian Federation, type-I RCM is widely disturbed in Yakutia due to the local founder effect. The molecular genetics cause of type-I RCM in Yakutia is mutation c.806C > T in the CYB5R3 gene. In this work we used 13 polymorphic markers, which flanking the CYB5R3 gene to establish the founder haplotype. The age of the mutation was estimated as about 285 +/- 135 years. In this work, we have evaluated the frequency of the c.806 C > T mutation in Yakutia, which averaged 55 : 1000 Yakuts. The calculated frequency of disease was 1: 1250 Yakuts. PMID:23866629

  3. Familial acromegaly due to aryl hydrocarbon receptor-interacting protein (AIP) gene mutation in a Turkish cohort.

    PubMed

    Niyazoglu, Mutlu; Sayitoglu, Muge; Firtina, Sinem; Hatipoglu, Esra; Gazioglu, Nurperi; Kadioglu, Pinar

    2014-06-01

    Aryl hydrocarbon receptor-interacting protein (AIP) is associated with 15-20% of familial isolated pituitary adenomas and 50-80% of cases with AIP mutation exhibit a somatotropinoma. Herein we report clinical characteristics of a large family where AIP R304X variants have been identified. AIP mutation analysis was performed on a large (n = 52) Turkish family across six generations. Sella MRIs of 30 family members were obtained. Basal pituitary hormone levels were evaluated in 13 family members harboring an AIP mutation. Thirteen of 52 family members (25%) were found to have a heterozygous nonsense germline R304X mutation in the AIP gene. Seven of the 13 mutation carriers (53.8%) had current or previous history of pituitary adenoma. Of these 7 mutation carriers, all but one had somatotropinoma/somatolactotropinoma (85.7% of the pituitary adenomas). Of the 6 acromegaly patients with AIP mutation (F/M: 3/3) the mean age at diagnosis of acromegaly was 32 ± 10.3 years while the mean age of symptom onset was 24.8 ± 9.9 years. Three of the six (50%) acromegaly cases with AIP mutation within the family presented with a macroadenoma and none presented with gigantism. Biochemical disease control was achieved in 66.6% (4/6) of the mutation carriers with acromegaly after a mean follow-up period of 18.6 ± 17.6 years. Common phenotypic characteristics of familial pituitary adenoma or somatotropinoma due to AIP mutation vary between families or even between individuals within a family. PMID:23743763

  4. Evidence of a wide spectrum of cardiac involvement due to ACAD9 mutations: Report on nine patients.

    PubMed

    Dewulf, Joseph P; Barrea, Catherine; Vincent, Marie-Françoise; De Laet, Corinne; Van Coster, Rudy; Seneca, Sara; Marie, Sandrine; Nassogne, Marie-Cécile

    2016-07-01

    Acyl-CoA dehydrogenase 9 (ACAD9) is a mitochondrial protein involved in oxidative phosphorylation complex I biogenesis. This protein also exhibits acyl-CoA dehydrogenase (ACAD) activity. ACAD9-mutated patients have been reported to suffer from primarily heart, muscle, liver, and nervous system disorders. ACAD9 mutation is suspected in cases of elevated lactic acid levels combined with complex I deficiency, and confirmed by ACAD9 gene analysis. At least 18 ACAD9-mutated patients have previously been reported, usually displaying severe cardiac involvement. We retrospectively studied nine additional patients from three unrelated families with a wide spectrum of cardiac involvement between the families as well as the patients from the same families. All patients exhibited elevated lactate levels. Deleterious ACAD9 mutations were identified in all patients except one for whom it was not possible to recover DNA. To our knowledge, this is one of the first reports on isolated mild ventricular hypertrophy due to ACAD9 mutation in a family with moderate symptoms during adolescence. This report also confirms that dilated cardiomyopathy may occur in conjunction with ACAD9 mutation and that some patients may respond clinically to riboflavin treatment. Of note, several patients suffered from patent ductus arteriosus (PDA), with one exhibiting a complex congenital heart defect. It is yet unknown whether these cardiac manifestations were related to ACAD9 mutation. In conclusion, this disorder should be suspected in the presence of lactic acidosis, complex I deficiency, and any cardiac involvement, even mild. PMID:27233227

  5. Evidence of a wide spectrum of cardiac involvement due to ACAD9 mutations: Report on nine patients.

    PubMed

    Dewulf, Joseph P; Barrea, Catherine; Vincent, Marie-Françoise; De Laet, Corinne; Van Coster, Rudy; Seneca, Sara; Marie, Sandrine; Nassogne, Marie-Cécile

    2016-07-01

    Acyl-CoA dehydrogenase 9 (ACAD9) is a mitochondrial protein involved in oxidative phosphorylation complex I biogenesis. This protein also exhibits acyl-CoA dehydrogenase (ACAD) activity. ACAD9-mutated patients have been reported to suffer from primarily heart, muscle, liver, and nervous system disorders. ACAD9 mutation is suspected in cases of elevated lactic acid levels combined with complex I deficiency, and confirmed by ACAD9 gene analysis. At least 18 ACAD9-mutated patients have previously been reported, usually displaying severe cardiac involvement. We retrospectively studied nine additional patients from three unrelated families with a wide spectrum of cardiac involvement between the families as well as the patients from the same families. All patients exhibited elevated lactate levels. Deleterious ACAD9 mutations were identified in all patients except one for whom it was not possible to recover DNA. To our knowledge, this is one of the first reports on isolated mild ventricular hypertrophy due to ACAD9 mutation in a family with moderate symptoms during adolescence. This report also confirms that dilated cardiomyopathy may occur in conjunction with ACAD9 mutation and that some patients may respond clinically to riboflavin treatment. Of note, several patients suffered from patent ductus arteriosus (PDA), with one exhibiting a complex congenital heart defect. It is yet unknown whether these cardiac manifestations were related to ACAD9 mutation. In conclusion, this disorder should be suspected in the presence of lactic acidosis, complex I deficiency, and any cardiac involvement, even mild.

  6. Combined deficiency of factor V and factor VIII is due to mutations in either LMAN1 or MCFD2

    PubMed Central

    Zhang, Bin; McGee, Beth; Yamaoka, Jennifer S.; Guglielmone, Hugo; Downes, Katharine A.; Minoldo, Salvador; Jarchum, Gustavo; Peyvandi, Flora; de Bosch, Norma B.; Ruiz-Saez, Arlette; Chatelain, Bernard; Olpinski, Marian; Bockenstedt, Paula; Sperl, Wolfgang; Kaufman, Randal J.; Nichols, William C.; Tuddenham, Edward G. D.; Ginsburg, David

    2006-01-01

    Mutations in LMAN1 (ERGIC-53) or MCFD2 cause combined deficiency of factor V and factor VIII (F5F8D). LMAN1 and MCFD2 form a protein complex that functions as a cargo receptor ferrying FV and FVIII from the endoplasmic reticulum to the Golgi. In this study, we analyzed 10 previously reported and 10 new F5F8D families. Mutations in the LMAN1 or MCFD2 genes accounted for 15 of these families, including 3 alleles resulting in no LMAN1 mRNA accumulation. Combined with our previous reports, we have identified LMAN1 or MCFD2 mutations as the causes of F5F8D in 71 of 76 families. Among the 5 families in which no mutations were identified, 3 were due to misdiagnosis, with the remaining 2 likely carrying LMAN1 or MCFD2 mutations that were missed by direct sequencing. Our results suggest that mutations in LMAN1 and MCFD2 may account for all cases of F5F8D. Immunoprecipitation and Western blot analysis detected a low level of LMAN1-MCFD2 complex in lymphoblasts derived from patients with missense mutations in LMAN1 (C475R) or MCFD2 (I136T), suggesting that complete loss of the complex may not be required for clinically significant reduction in FV and FVIII. PMID:16304051

  7. Breast and ovarian cancer predisposition due to de novo BRCA1 and BRCA2 mutations.

    PubMed

    Golmard, L; Delnatte, C; Laugé, A; Moncoutier, V; Lefol, C; Abidallah, K; Tenreiro, H; Copigny, F; Giraudeau, M; Guy, C; Barbaroux, C; Amorim, G; Briaux, A; Guibert, V; Tarabeux, J; Caputo, S; Collet, A; Gesta, P; Ingster, O; Stern, M-H; Rouleau, E; de Pauw, A; Gauthier-Villars, M; Buecher, B; Bézieau, S; Stoppa-Lyonnet, D; Houdayer, C

    2016-03-10

    BRCA1 and BRCA2 are the two major genes predisposing to breast and ovarian cancer. Whereas high de novo mutation rates have been demonstrated for several genes, only 11 cases of de novo BRCA1/2 mutations have been reported to date and the BRCA1/2 de novo mutation rate remains unknown. The present study was designed to fill this gap based on a series of 12 805 consecutive unrelated patients diagnosed with breast and/or ovarian cancer who met the inclusion criteria for BRCA1/2 gene analysis according to French guidelines. BRCA1/2 mutations were detected in 1527 (12%) patients, and three BRCA1 mutations and one BRCA2 mutation were de novo. The BRCA1/2 de novo mutation rate was estimated to be 0.3% (0.1%; 0.7%). Although rare, it may be useful to take the possibility of de novo BRCA1/2 mutation into account in genetic counseling of relatives and to improve the understanding of complex family histories of breast and ovarian cancers.

  8. Exome sequencing can detect pathogenic mosaic mutations present at low allele frequencies.

    PubMed

    Pagnamenta, Alistair T; Lise, Stefano; Harrison, Victoria; Stewart, Helen; Jayawant, Sandeep; Quaghebeur, Gerardine; Deng, Alexander T; Murphy, Valerie Elizabeth; Sadighi Akha, Elham; Rimmer, Andy; Mathieson, Iain; Knight, Samantha J L; Kini, Usha; Taylor, Jenny C; Keays, David A

    2012-01-01

    The development of next generation sequencing (NGS) has radically transformed the scientific landscape, making it possible to sequence the exome of any given individual in a cost-effective way. The power of this approach has been demonstrated by a number of groups who have identified pathogenic mutations in small pedigrees that have been resistant to traditional genetic mapping. Recently it has become clear that exome sequencing has great potential with respect to sporadic disease and the identification of de novo mutations. This is highlighted by studies reporting whole-exome sequencing of patient-parental trios affected by learning disability, autism and schizophrenia. It is widely anticipated that the introduction of this technique into a clinical setting will revolutionise genetic diagnosis. However, the sensitivity of NGS exome sequencing is currently unclear. Here, we describe the exome sequencing of DNA samples from a patient with double cortex syndrome and her parents, resulting in the detection of a mosaic splicing mutation in LIS1. This variant was found at an allele frequency of just 18%, demonstrating that NGS methods have the capacity to identify pathogenic mosaic mutations present at a low level. PMID:22129557

  9. Hepatic fibrinogen storage disease due to the fibrinogen γ375 Arg → Trp mutation "fibrinogen Aguadilla" is present in Arabs.

    PubMed

    Al-Hussaini, Abdulrahman; Altalhi, Abdulhadi; El Hag, Imad; AlHussaini, Hussa; Francalanci, Paola; Giovannoni, Isabella; Callea, Francesco

    2014-01-01

    The mutation γ375Arg → Trp (fibrinogen Aguadilla) is one of four mutations (Brescia, Aguadilla, Angers, and AI duPont) capable of causing hepatic storage of fibrinogen. It has been observed in four children from the Caribbean, Europe, and Japan, suffering from cryptogenic liver disease. We report the first case of hepatic fibrinogen storage disease in Arabs due to a mutation in the fibrinogen γ-chain gene in a 3-year-old Syrian girl presenting with elevated liver enzymes. The finding of an impressive accumulation of fibrinogen in liver cells raised the suspicion of endoplasmic reticulum storage disease. Sequencing of the fibrinogen genes revealed a γ375Arg → Trp mutation (fibrinogen Aguadilla) in the child and in her father. In conclusion, when confronted with chronic hepatitis of unknown origin, one should check the plasma fibrinogen level and look carefully for the presence of hepatocellular intracytoplasmic globular inclusions to exclude hepatic fibrinogen storage disease.

  10. Mutation frequencies of X-linked mental retardation genes in families from the EuroMRX consortium.

    PubMed

    de Brouwer, Arjan P M; Yntema, Helger G; Kleefstra, Tjitske; Lugtenberg, Dorien; Oudakker, Astrid R; de Vries, Bert B A; van Bokhoven, Hans; Van Esch, Hilde; Frints, Suzanne G M; Froyen, Guy; Fryns, Jean-Pierre; Raynaud, Martine; Moizard, Marie-Pierre; Ronce, Nathalie; Bensalem, Anissa; Moraine, Claude; Poirier, Karine; Castelnau, Laetitia; Saillour, Yoann; Bienvenu, Thierry; Beldjord, Chérif; des Portes, Vincent; Chelly, Jamel; Turner, Gillian; Fullston, Tod; Gecz, Jozef; Kuss, Andreas W; Tzschach, Andreas; Jensen, Lars Riff; Lenzner, Steffen; Kalscheuer, Vera M; Ropers, Hans-Hilger; Hamel, Ben C J

    2007-02-01

    The EuroMRX family cohort consists of about 400 families with non-syndromic and 200 families with syndromic X-linked mental retardation (XLMR). After exclusion of Fragile X (Fra X) syndrome, probands from these families were tested for mutations in the coding sequence of 90 known and candidate XLMR genes. In total, 73 causative mutations were identified in 21 genes. For 42% of the families with obligate female carriers, the mental retardation phenotype could be explained by a mutation. There was no difference between families with (lod score >2) or without (lod score <2) significant linkage to the X chromosome. For families with two to five affected brothers (brother pair=BP families) only 17% of the MR could be explained. This is significantly lower (P=0.0067) than in families with obligate carrier females and indicates that the MR in about 40% (17/42) of the BP families is due to a single genetic defect on the X chromosome. The mutation frequency of XLMR genes in BP families is lower than can be expected on basis of the male to female ratio of patients with MR or observed recurrence risks. This might be explained by genetic risk factors on the X chromosome, resulting in a more complex etiology in a substantial portion of XLMR patients. The EuroMRX effort is the first attempt to unravel the molecular basis of cognitive dysfunction by large-scale approaches in a large patient cohort. Our results show that it is now possible to identify 42% of the genetic defects in non-syndromic and syndromic XLMR families with obligate female carriers.

  11. Frequency and spectrum of hemoglobinopathy mutations in a Uruguayan pediatric population

    PubMed Central

    Luz, Julio Da; Ávila, Amalia; Icasuriaga, Sandra; Gongóra, María; Castillo, Luis; Serrón, Alejandra; Kimura, Elza Miyuki; Costa, Fernando Ferreira; Sans, Mónica; Sonati, Maria de Fátima

    2013-01-01

    Hemoglobinopathies are the most common recessive diseases worldwide but their prevalence in Uruguay has not been investigated. In this study, 397 unrelated outpatient children from the Pereira Rosell Hospital Center (CHPR), as well as 31 selected patients with microcytic anemia and 28 β-thalassemia carriers were analyzed for hemoglobinopathies by using biochemical and molecular biology methods. Parametric and non-parametric methods were used to compare the hematological indices between groups of genotypes. Of the 397 patients in the first group, approximately 1% (0.76% HbS and 0.25% β-thalassemia) had a mutation in the HBB gene and 3.3% had β-thalassemia. These mutations had a heterogeneous distribution that varied according to individual ancestry. HbS was found exclusively in individuals with declared African ancestry and had a carrier frequency of 2.2%. The frequency of α-thalassemia carriers in outpatients of European and African ancestry was 1.2% and 6.5%, respectively. In contrast, the frequency of α-thalassemia carriers in patients with microcytic anemia was 25.8%, significantly higher (p < 0.01) than that observed in the sample as a whole and in Afro-descendants and Euro-descendants. Significant differences were observed in the hematological parameters between individuals with thalassemia genotypes and those with a normal genotype. These results indicate that hemoglobinopathies are a relevant health problem in Uruguay. PMID:24130436

  12. High carriers frequency of an apparently ancient founder mutation p.Tyr322X in the ERCC8 gene responsible for Cockayne syndrome among Christian Arabs in Northern Israel.

    PubMed

    Khayat, Morad; Hardouf, Hagar; Zlotogora, Joel; Shalev, Stavit Allon

    2010-12-01

    Most autosomal recessive diseases are rare in the general population, but in genetically isolated communities specific condition might be frequent, mainly due to founder effect. Recognition of common inherited disorders in defined populations may be effective in improving public health care. Cockayne syndrome (CS) is a rare autosomal recessive disorder common in Christian Arabs due to a p.Tyr322X mutation. Genetic screening of the p.Tyr322X mutation of the ERCC8 gene in this population documented a carrier frequency of 6.79% (95% confidence interval: 3.84-9.74%). The haplotype analysis data, as well as the high carriers frequency of CS, suggested that the Israeli Arab Christian CS mutation (p.Tyr322X) is an ancient founder mutation that may have originated in the Christian Lebanese community. As a result of this pilot study the Christian CS mutation was included in the genetic screening program offered to the Israeli Arab Christian community.

  13. Congenital neurogenic muscular atrophy in megaconial myopathy due to a mutation in CHKB gene.

    PubMed

    Castro-Gago, Manuel; Dacruz-Alvarez, David; Pintos-Martínez, Elena; Beiras-Iglesias, Andrés; Arenas, Joaquín; Martín, Miguel Ángel; Martínez-Azorín, Francisco

    2016-01-01

    Choline kinase beta gene (CHKB) mutations have been identified in Megaconial Congenital Muscular Dystrophy (MDCMC) patients, a very rare inborn error of metabolism with 21 cases reported worldwide. We report the case of a Spanish boy of Caucasian origin who presented a generalized congenital muscular hypotonia, more intense at lower limb muscles, mildly elevated creatine kinase (CK), serum aspartate transaminase (AST) and lactate. Electromyography (EMG) showed neurogenic potentials in the proximal muscles. Histological studies of a muscle biopsy showed neurogenic atrophy with enlarged mitochondria in the periphery of the fibers, and complex I deficiency. Finally, genetic analysis showed the presence of a homozygous mutation in the gene for choline kinase beta (CHKB: NM_005198.4:c.810T>A, p.Tyr270(∗)). We describe here the second Spanish patient whit mutation in CHKB gene, who despite having the same mutation, presented an atypical aspect: congenital neurogenic muscular atrophy progressing to a combined neuropathic and myopathic phenotype (mixed pattern).

  14. Beating frequency and amplitude modulation of the piano tone due to coupling of tones

    NASA Astrophysics Data System (ADS)

    Cartling, Bo

    2005-04-01

    The influence on a piano tone from weak coexcitation of damped adjacent tones due to coupling via the bridge is studied. The frequency and amplitude modulation of the sound resulting from coexcitation of one strong and one or two weak tones is analyzed. One weak tone causes frequency and amplitude modulation of the sound, and two weak tones produce beating frequency and amplitude modulation, where the beatings of the two modulations are of opposite phase. By digital recording of the sound of piano tones, the appearance of these phenomena is verified. The audibility of the observed frequency and amplitude modulation is discussed in terms of previously determined detection thresholds. The beating character of both frequency and amplitude modulations, however, distinguishes the phenomena from those previously studied and prompts further psychoacoustic investigations. It is shown that detuning of unison strings may significantly increase the frequency deviation of the frequency modulation in conjunction with affected amplitude modulation. The modulatory effects of coupling to adjacent tones therefore may possibly be utilized in the tuning process. A coupling of tones analogous to the situation in a piano may arise in other stringed musical instruments transferring string vibrations to a soundboard via a bridge. .

  15. Beating frequency and amplitude modulation of the piano tone due to coupling of tones.

    PubMed

    Cartling, Bo

    2005-04-01

    The influence on a piano tone from weak coexcitation of damped adjacent tones due to coupling via the bridge is studied. The frequency and amplitude modulation of the sound resulting from coexcitation of one strong and one or two weak tones is analyzed. One weak tone causes frequency and amplitude modulation of the sound, and two weak tones produce beating frequency and amplitude modulation, where the beatings of the two modulations are of opposite phase. By digital recording of the sound of piano tones, the appearance of these phenomena is verified. The audibility of the observed frequency and amplitude modulation is discussed in terms of previously determined detection thresholds. The beating character of both frequency and amplitude modulations, however, distinguishes the phenomena from those previously studied and prompts further psychoacoustic investigations. It is shown that detuning of unison strings may significantly increase the frequency deviation of the frequency modulation in conjunction with affected amplitude modulation. The modulatory effects of coupling to adjacent tones therefore may possibly be utilized in the tuning process. A coupling of tones analogous to the situation in a piano may arise in other stringed musical instruments transferring string vibrations to a soundboard via a bridge. PMID:15898666

  16. Severe manifestation of Leber's hereditary optic neuropathy due to 11778G>A mtDNA mutation in a female with hypoestrogenism due to Perrault syndrome.

    PubMed

    Badura-Stronka, Magdalena; Wawrocka, Anna; Zawieja, Krzysztof; Silska, Sylwia; Krawczyński, Maciej Robert

    2013-11-01

    Perrault syndrome (PS) is a rare autosomal recessive condition with ovarian dysgenesis, hearing deficit and neurological abnormalities in female patients. The molecular basis of the syndrome is heterogeneous, mutations in the HSD17B4 gene have been identified in one family and mutations in the HARS2 gene have been found in another one. We have excluded pathogenic changes in the HSD17B4 gene and in the HARS2 gene by a direct sequencing of all coding exons in a female with clinical hallmarks of PS, ataxia and mild mental retardation. In addition, the patient suffers from severe Leber's hereditary optic neuropathy (LHON) due to 11778G>A mtDNA mutation. This case is the first reported patient with PS and LHON. Possible influence of hypoestrogenism on the manifestation of optic neuropathy in this patient is discussed in the context of recent findings concerning the crucial role of estrogens in supporting the vision capacity in LHON-related mtDNA mutation carriers.

  17. Hyperphosphatasia-mental retardation syndrome due to PIGV mutations: expanded clinical spectrum.

    PubMed

    Horn, Denise; Krawitz, Peter; Mannhardt, Anca; Korenke, Georg Christoph; Meinecke, Peter

    2011-08-01

    Hyperphosphatasia-mental retardation syndrome is a recently delineated disorder associated with a recognizable facial phenotype and brachytelephalangy. This autosomal recessive condition is caused by homozygous and compound heterozygous missense mutations of PIGV, encoding a member of the GPI-anchor biosynthesis pathway. Here, we report on two further, unrelated patients with developmental delay, elevated serum levels of AP, distinctive facial features, hypoplastic terminal phalanges, anal atresia in one and Hirschsprung disease in the other patient. By sequencing PIGV we detected compound heterozygous mutations c.467G>A and c.1022C>A in Patient 1 and a homozygous mutation c.1022C>A in Patient 2. We reviewed the eight reported cases with proven PIGV mutations and re-defined the phenotypic spectrum associated with PIGV mutations: intellectual disability, the distinct facial gestalt, brachytelephalangy, and hyperphosphatasia are constant features but also anorectal malformations and Hirschsprung disease as well as cleft lip/palate and hearing impairment should be considered as part of the clinical spectrum. Moreover, seizures and muscular hypotonia are frequently associated with PIGV mutations. PMID:21739589

  18. The frequency of CCR5 promoter polymorphisms and CCR5 Δ 32 mutation in Iranian populations.

    PubMed

    Zare-Bidaki, Mohammad; Karimi-Googheri, Masoud; Hassanshahi, Gholamhossein; Zainodini, Nahid; Arababadi, Mohammad Kazemi

    2015-04-01

    Evidence showed that chemokines serve as pro-migratory factors for immune cells. CCL3, CCL4 and CCL5, as the main CC chemokines subfamily members, activate immune cells through binding to CC chemokine receptor 5 or CCR5. Macrophages, NK cells and T lymphocytes express CCR5 and thus, affected CCR5 expression or functions could be associated with altered immune responses. Deletion of 32 base pairs (Δ 32) in the exon 1 of the CCR5 gene, which is known as CCR5 Δ 32 mutation causes down regulation and malfunction of the molecule. Furthermore, it has been evidenced that three polymorphisms in the promoter region of CCR5 modulate its expression. Altered CCR5 expression in microbial infection and immune related diseases have been reported by several researchers but the role of CCR5 promoter polymorphisms and CCR5 Δ 32 mutation in Iranian patients suffering from these diseases are controversial. Due to the fact that Iranian people have different genetic backgrounds compared to other ethnics, hence, CCR5 promoter polymorphisms and CCR5 32 mutation association with the diseases may be different in Iranian patients. Therefore, this review addresses the most recent information regarding the prevalence as well as association of the mutation and polymorphisms in Iranian patients with microbial infection and immune related diseases as along with normal population.

  19. Mathematical modeling of drug resistance due to KRAS mutation in colorectal cancer.

    PubMed

    Sameen, Sheema; Barbuti, Roberto; Milazzo, Paolo; Cerone, Antonio; Del Re, Marzia; Danesi, Romano

    2016-01-21

    The most challenging task in colorectal cancer research nowadays is to understand the development of acquired resistance to anti-EGFR drugs. The key reason for this problem is the KRAS mutations appearance after the treatment with monoclonal antibodies (moAb). Here we present a mathematical model for the analysis of KRAS mutations behavior in colorectal cancer with respect to moAb treatments. To evaluate the drug performance we have developed equations for two types of tumors cells, KRAS mutated and KRAS wild-type. Both tumor cell populations were treated with a combination of moAb and chemotherapy drugs. It was observed that even the minimal initial concentration of KRAS mutation before the treatment has the ability to make the tumor refractory to the treatment. Minor population of KRAS mutations has strong influence on large number of wild-type cells as well rendering them resistant to chemotherapy. Patient׳s immune responses are specifically taken into considerations and it is found that, in case of KRAS mutations, the immune strength does not affect medication efficacy. Finally, cetuximab (moAb) and irinotecan (chemotherapy) drugs are analyzed as first-line treatment of colorectal cancer with few KRAS mutated cells. Results show that this combined treatment could be only effective for patients with high immune strengths and it should not be recommended as first-line therapy for patients with moderate immune strengths or weak immune systems because of a potential risk of relapse, with KRAS mutant cells acquired resistance involved with them. PMID:26551156

  20. Phenotypic Switching in Mycoplasma gallisepticum Hemadsorption Is Governed by a High-Frequency, Reversible Point Mutation

    PubMed Central

    Winner, Florian; Markovà, Ivana; Much, Peter; Lugmair, Albin; Siebert-Gulle, Karin; Vogl, Gunther; Rosengarten, Renate; Citti, Christine

    2003-01-01

    Mycoplasma gallisepticum is a flask-shaped organism that commonly induces chronic respiratory disease in chickens and infectious sinusitis in turkeys. Phenotypic switching in M. gallisepticum hemadsorption (HA) was found to correlate with phase variation of the GapA cytadhesin concurrently with that of the CrmA protein, which exhibits cytadhesin-related features and is encoded by a gene located downstream of the gapA gene as part of the same transcription unit. In clones derived from strain Rlow, detailed genetic analyses further revealed that on-off switching in GapA expression is governed by a reversible base substitution occurring at the beginning of the gapA structural gene. In HA− variants, this event generates a stop codon that results in the premature termination of GapA translation and consequently affects the expression of CrmA. Sequences flanking the mutation spot do not feature any repeated motifs that could account for error-prone mutation via DNA slippage and the exact mechanism underlying this high-frequency mutational event remains to be elucidated. An HA− mutant deficient in producing CrmA, mHAD3, was obtained by disrupting the crmA gene by using transposition mutagenesis. Despite a fully functional gapA gene, the amount of GapA detected in this mutant was considerably lower than in HA+ clonal variants, suggesting that, in absence of CrmA, GapA might be subjected to a higher turnover. PMID:12595441

  1. Mutation frequencies of the cytochrome CYP2D6 gene in Parkinson disease patients and in families

    SciTech Connect

    Lucotte, G.; Turpin, J.C.; Gerard, N.

    1996-07-26

    The frequencies of five mutations of the debrisoquine 4-hydroxylase (CYP2D6) gene (mutations D6-A, B, C, D, and T), corresponding to poor metabolizer (PM) phenotypes, were determined by restriction fragment length polymorphism (RFLP) and polymerase chain reaction (PCR) in 47 patients with Parkinson disease, and compared with the findings in 47 healthy controls. These mutant alleles were about twice as frequent among patients as in controls, with an approximate relative risk ratio of 2.12 (95% confidence interval, 1.41-2.62). There seem to be no significant differences in frequencies of mutant genotypes in patients among gender and modalities of response with levodopa therapy; but frequency of the mutations was slightly enhanced after age-at-onset of 60 years. Mutations D6-B, D, and T were detected in 7 patients belonging to 10 Parkinson pedigrees. 25 refs., 1 fig., 2 tabs.

  2. High frequency of W1327X mutation in glycogen storage disease type III patients from central Tunisia.

    PubMed

    Cherif, Wafa; Ben Rhouma, Faten; Messai, Habib; Mili, Amira; Gribaa, Moez; Kefi, Rym; Ayadi, Abdelkarim; Boughamoura, Lamia; Chemli, Jelel; Saad, Ali; Kaabachi, Naziha; Sfar, Mohamed Tahar; Ben Dridi, Marie-Françoise; Tebib, Neji; Abdelhak, Sonia

    2012-01-01

    Glycogen storage disease type III (GSD III) is an autosomal recessive disorder caused by the deficiency of glycogen debranching enzyme (AGL). It is characterized by hepatomegaly, progressive myopathy, cardiomyopathy and fasting hypoglycemia. Several mutations in AGL gene have been described in different populations. The W1327X mutation was reported in one Tunisian patient resident in Italy. We looked in this report to determine the frequency of W1327X mutation among Tunisian patients. The W1327X mutation was screening in 26 GSD III patients originated from various geographic locations in Tunisia. The sequence analysis revealed that among nine patients carried the W1327X mutation. Eight of them were from six unrelated families and they were originated from Mahdia (centre of Tunisia) suggesting the existence of a founder effect in this region. Taking into account historical migratory waves, screening for this mutation should be performed in priority for molecular diagnosis confirmation of GSD III in North African populations.

  3. Isolated pancreatic aplasia due to a hypomorphic PTF1A mutation

    PubMed Central

    Flanagan, Sarah E.; de Franco, Elisa; Caswell, Richard; Hussain, Khalid; Mohamed, Sarar; Abdulrasoul, Majedah; Hattersley, Andrew T.; MacDonald, Raymond J.; Ellard, Sian

    2016-01-01

    Homozygous truncating mutations in the helix-loop-helix transcription factor PTF1A are a rare cause of pancreatic and cerebellar agenesis. The correlation of Ptf1a dosage with pancreatic phenotype in a mouse model suggested the possibility of finding hypomorphic PTF1A mutations in patients with pancreatic agenesis or neonatal diabetes but no cerebellar phenotype. Genome wide SNP typing in two siblings with neonatal diabetes from a consanguineous pedigree revealed a large shared homozygous region (31 Mb) spanning PTF1A. Sanger sequencing of PTF1A identified a novel missense mutation, p.P191T. Testing of 259 additional patients using a targeted next generation sequencing assay for 23 neonatal diabetes genes detected one additional proband and an affected sibling with the same homozygous mutation. All 4 cases were diagnosed with diabetes at birth and are insulin treated. Two of the 4 had exocrine pancreatic insufficiency requiring replacement but none of the affected individuals have neurodevelopmental delay. Transient transfection assays of the mutant protein demonstrated a 75% reduction in transactivation activity. This study shows that the functional severity of a homozygous mutation impacts on the severity of clinical features found in patients. PMID:27284104

  4. Isolated Pancreatic Aplasia Due to a Hypomorphic PTF1A Mutation.

    PubMed

    Houghton, Jayne A L; Swift, Galvin H; Shaw-Smith, Charles; Flanagan, Sarah E; de Franco, Elisa; Caswell, Richard; Hussain, Khalid; Mohamed, Sarar; Abdulrasoul, Majedah; Hattersley, Andrew T; MacDonald, Raymond J; Ellard, Sian

    2016-09-01

    Homozygous truncating mutations in the helix-loop-helix transcription factor PTF1A are a rare cause of pancreatic and cerebellar agenesis. The correlation of Ptf1a dosage with pancreatic phenotype in a mouse model suggested the possibility of finding hypomorphic PTF1A mutations in patients with pancreatic agenesis or neonatal diabetes but no cerebellar phenotype. Genome-wide single nucleotide polymorphism typing in two siblings with neonatal diabetes from a consanguineous pedigree revealed a large shared homozygous region (31 Mb) spanning PTF1A Sanger sequencing of PTF1A identified a novel missense mutation, p.P191T. Testing of 259 additional patients using a targeted next-generation sequencing assay for 23 neonatal diabetes genes detected one additional proband and an affected sibling with the same homozygous mutation. All four patients were diagnosed with diabetes at birth and were treated with insulin. Two of the four patients had exocrine pancreatic insufficiency requiring replacement therapy but none of the affected individuals had neurodevelopmental delay. Transient transfection assays of the mutant protein demonstrated a 75% reduction in transactivation activity. This study shows that the functional severity of a homozygous mutation impacts the severity of clinical features found in patients. PMID:27284104

  5. Nature and frequency of mutations in the [alpha]-galactosidase A gene that cause Fabry disease

    SciTech Connect

    Eng, C.M.; Resnick-Silverman, L.A.; Niehaus, D.J.; Astrin, K.H.; Desnick, R.J. )

    1993-12-01

    To determine the nature and frequency of the molecular lesions causing the classical and milder-variant Fabry phenotypes, and for precise carrier detection in Fabry families, the [alpha]-Gal A transcripts or genomic sequences from unrelated Fabry hemizygotes were analyzed. In patients with the classical phenotype, 18 new mutations were identified: N34S, C56G, W162R, R227Q, R227X, D264V, D266V, S297F, D313Y, G328A, W340X, E398X, IVS2+2, IVS5[delta]-2,3, 773[delta]2, 954[delta]5, 1016[delta]11, and 1123[delta]53. Unrelated asymptomatic or mildly affected patients with symptoms confined to the heart had a missense mutation, N215S, that expressed residual enzymatic activity. Related, moderately affected patients with late-onset cardiac and pulmonary manifestations had a small deletion, 1208[delta]3, that predicted the in-frame deletion of arginine 404 near the terminus of the 429 residue enzyme polypeptide. In addition, five small gene rearrangements involving exonic sequences were identified in unrelated classically affected patients. Two small deletions and one small duplication had short direct repeats at their respective breakpoint junctions and presumably resulted from slipped mispairing. A deletion occurred at a potential polymerase [alpha] arrest site, while the breakpoints of another deletion occurred at an inverted tetranucleotide repeat. Screening of unrelated Fabry patients with allele-specific oligonucleotides for seven mutations revealed that these were private, with the notable exception of N215S, R227Q, and R227X, which were each found in several unrelated families from different ethnic backgrounds. The CpG dinucleotide at codon 227 was the most common site of mutation, having been altered in 5% of the 148 unrelated Fabry alleles. These studies revealed that most [alpha]-Gal A lesions were private, that codon 227 was a mutational hot spot, and that certain mutations predicted a milder disease phenotype. 40 refs., 8 figs., 3 tabs.

  6. Frequency of spontaneous mutations that confer antibiotic resistance in Chlamydia spp.

    PubMed

    Binet, Rachel; Maurelli, Anthony T

    2005-07-01

    Mutations in rRNA genes (rrn) that confer resistance to ribosomal inhibitors are typically recessive or weakly codominant and have been mostly reported for clinical strains of pathogens possessing only one or two rrn operons, such as Helicobacter pylori and Mycobacterium spp. An analysis of the genome sequences of several members of the Chlamydiaceae revealed that these obligate intracellular bacteria harbor only one or two sets of rRNA genes. To study the contribution of rRNA mutations to the emergence of drug resistance in the Chlamydiaceae, we used the sensitivities of Chlamydia trachomatis L2 (two rrn operons) and Chlamydophila psittaci 6BC (one rrn operon) to the aminoglycoside spectinomycin as a model. Confluent cell monolayers were infected in a plaque assay with about 10(8) wild-type infectious particles and then treated with the antibiotic. After a 2-week incubation time, plaques formed by spontaneous spectinomycin-resistant (Spc(r)) mutants appeared with a frequency of 5 x 10(-5) for C. psittaci 6BC. No Spc(r) mutants were isolated for C. trachomatis L2, although the frequencies of rifampin resistance were in the same range for both strains (i.e., 10(-7)). The risk of emergence of Chlamydia strains resistant to tetracyclines and macrolides, the ribosomal drugs currently used to treat chlamydial infections, is discussed.

  7. VNTR allele frequency distributions under the stepwise mutation model: A computer simulation approach

    SciTech Connect

    Shriver, M.D.; Jin, L.; Chakraborty, R.; Boerwinkle, E. )

    1993-07-01

    Variable numbers of tandem repeats (VNTRs) are a class of highly informative and widely dispersed genetic markers. Despite their wide application in biological science, little is known about their mutational mechanisms or population dynamics. The objective of this work was to investigate four summary measures of VNTR allele frequency distributions: number of alleles, number of modes, range in allele size, and heterozygosity, using computer simulations of the one-step stepwise mutation model (SMM). The authors estimated these measures and their probability distributions for a wide range of mutation rates and compared the simulation results with predictions from analytical formulations of the one-step SMM. The average heterozygosity from the simulations agreed with the analytical expectation under the SMM. The average number of alleles, however, was larger in the simulations than the analytical expectation of the SMM. The authors then compared simulation expectations with actual data reported in the literature. They used the sample size and observed heterozygosity to determine the expected value, 5th and 95th percentiles for the other three summary measures, allelic size range, number of modes and number of alleles. The loci analyzed were classified into three groups based on the size of the repeat unit: microsatellites (1-2 base pair (bp) repeat unit), short tandem repeats [(STR) 3-5 bp repeat unit], and minisatellites (15-70 bp repeat unit). In general, STR loci were most similar to the simulation results under the SMM for the three summary measures (number of alleles, number of modes and range in allele size), followed by the microsatellite loci and then by the minisatellite loci, which showed deviations in the direction of the infinite allele model (IAM). Based on these differences, it is hypothesized that these three classes of loci are subject to different mutational forces.

  8. Mitochondrial Cardioencephalomyopathy Due to a Novel SCO2 Mutation in a Brazilian Patient

    PubMed Central

    Gurgel-Giannetti, Juliana; Oliveira, Guilherme; Filho, Geraldo Brasileiro; Martins, Poliana; Vainzof, Mariz; Hirano, Michio

    2016-01-01

    Objectives To review all patients with SCO2 mutations and to describe a Brazilian patient with cardioencephalomyopathy carrying compound heterozygous mutations in SCO2, one being the known pathogenic p.E140K mutation and the other a novel 12–base pair (bp) deletion at nucleotides 1519 through 1530 (c.1519_1530del). Design Case report and literature review. Setting University hospital Patient Infant girl presenting with an encephalomyopathy, inspiratory stridor, ventilator failure, progressive hypotonia, and weakness, leading to death. Main Outcome Measures Clinical features, neuro-imaging findings, muscle biopsy with histochemical analysis, and genetic studies. Results This infant girl was the first child of healthy, nonconsanguineous parents. She developed progressive muscular hypotonia and ventilatory failure. At the end of the first month of life, she developed cardiomegaly and signs of cardiac failure. Routine blood tests showed lactic acidosis and mild elevation of the creatine kinase level. Brain magnetic resonance imaging showed increased T2 and fluid-attenuated inversion recovery signals in the putamen bilaterally. Nerve conduction studies showed severe axonal sensorimotor neuropathy. Muscle biopsy revealed a neurogenic pattern with mitochondrial proliferation and total absence of cytochrome-c oxidase histochemical stain. Sequencing of SCO2 showed that the patient had compound heterozygote SCO2 mutations: the previously described c.1541G A (p.E140K) mutation and a novel 12-bp deletion at nucleotides 1519 through 1530 (c.1519_1530del). The patient died at age 45 days. Conclusions Our findings and the literature review indicate that it is important to consider the diagnosis of mitochondrial disease in newborns with hypotonia and cardiomyopathy. In our case, the accurate diagnosis of SCO2 mutations is particularly important for genetic counseling. PMID:23407777

  9. Acroangiodermatitis of Mali in protein C deficiency due to a novel PROC gene mutation.

    PubMed

    Wei-Min Tan, Aaron; Lee, Joyce Siong-See; Pramono, Zacharias A D; Chong, Wei-Sheng

    2012-04-01

    Acroangiodermatitis of Mali is a dermatologic condition of kaposiform skin lesions that has been associated with chronic venous insufficiency. Here we report a case of a 28-year-old Chinese man with acroangiodermatitis which co-existed with chronic lower limb deep vein thrombosis. Investigations revealed protein C deficiency and a frame shift mutation, c246_247dupCT, of the PROC gene. Our report lengthens the list of male acroangiodermatitis of Mali cases with a Chinese patient harboring a novel PROC mutation with manifest protein C deficiency.

  10. Splicing mosaic of the myophosphorylase gene due to a silent mutation in McArdle disease.

    PubMed

    Fernandez-Cadenas, I; Andreu, A L; Gamez, J; Gonzalo, R; Martín, M A; Rubio, J C; Arenas, J

    2003-11-25

    The authors report the molecular findings in a patient with McArdle disease who harbored a silent polymorphism (K608K) in the myophosphorylase gene. cDNA studies demonstrated that this polymorphism leads to a severe mosaic alteration in mRNA splicing, including exon skipping, activation of cryptic splice-sites, and exon-intron reorganizations. These findings suggest that, in patients with McArdle disease in whom no pathogenic mutation has been found, any a priori silent polymorphism should be re-evaluated as a putative splicing mutation.

  11. Influence of a contaminated fish diet on germline expanded-simple-tandem-repeat mutation frequency in mice.

    PubMed

    Somers, Christopher M; Valdes, Eduardo V; Kjoss, Victoria A; Vaillancourt, Andre L; Quinn, James S

    2008-04-01

    Herring gulls (Larus argentatus) in polluted areas on the North American Great Lakes were previously shown to have elevated germline mutation frequencies at minisatellite DNA loci. Airborne or dietary contaminants likely caused induced mutations, but the importance of each exposure type was unknown. Follow-up experiments with lab mice determined that air pollution significantly induced germline mutations; however, an evaluation of mutations induced by the diet of herring gulls has not yet been conducted. To address this issue, we fed mice a high-fish diet (58% wet mass) of the most common prey species for herring gulls nesting in Hamilton Harbour, a polluted industrial area on Lake Ontario. We bred the mice and screened pedigrees for germline mutations at expanded-simple-tandem-repeat (ESTR) DNA loci. Mutation frequencies were compared to those in a reference group that was fed fish from Atlantic Canada, and a control group that was fed commercial chow. Germline mutation frequencies were highest in mice fed contaminated fish, but were only marginally or not significantly affected by diet treatment. Statistical power to detect differences among treatment groups was low, and the effect of diet may have more clearly emerged if larger sample sizes were available. Levels of organic pollutants in the fish from Hamilton Harbour were higher than those from Atlantic Canada, but their ability to induce ESTR mutations is unknown. Our findings suggest that a contaminated fish diet may contribute to the elevated germline mutation frequencies observed previously in gulls at this site, but air pollution is likely a more important route of exposure.

  12. CCT2 Mutations Evoke Leber Congenital Amaurosis due to Chaperone Complex Instability.

    PubMed

    Minegishi, Yuriko; Sheng, XunLun; Yoshitake, Kazutoshi; Sergeev, Yuri; Iejima, Daisuke; Shibagaki, Yoshio; Monma, Norikazu; Ikeo, Kazuho; Furuno, Masaaki; Zhuang, Wenjun; Liu, Yani; Rong, Weining; Hattori, Seisuke; Iwata, Takeshi

    2016-01-01

    Leber congenital amaurosis (LCA) is a hereditary early-onset retinal dystrophy that is accompanied by severe macular degeneration. In this study, novel compound heterozygous mutations were identified as LCA-causative in chaperonin-containing TCP-1, subunit 2 (CCT2), a gene that encodes the molecular chaperone protein, CCTβ. The zebrafish mutants of CCTβ are known to exhibit the eye phenotype while its mutation and association with human disease have been unknown. The CCT proteins (CCT α-θ) forms ring complex for its chaperon function. The LCA mutants of CCTβ, T400P and R516H, are biochemically instable and the affinity for the adjacent subunit, CCTγ, was affected distinctly in both mutants. The patient-derived induced pluripotent stem cells (iPSCs), carrying these CCTβ mutants, were less proliferative than the control iPSCs. Decreased proliferation under Cct2 knockdown in 661W cells was significantly rescued by wild-type CCTβ expression. However, the expression of T400P and R516H didn't exhibit the significant effect. In mouse retina, both CCTβ and CCTγ are expressed in the retinal ganglion cells and connecting cilium of photoreceptor cells. The Cct2 knockdown decreased its major client protein, transducing β1 (Gβ1). Here we report the novel LCA mutations in CCTβ and the impact of chaperon disability by these mutations in cellular biology. PMID:27645772

  13. CCT2 Mutations Evoke Leber Congenital Amaurosis due to Chaperone Complex Instability

    PubMed Central

    Minegishi, Yuriko; Sheng, XunLun; Yoshitake, Kazutoshi; Sergeev, Yuri; Iejima, Daisuke; Shibagaki, Yoshio; Monma, Norikazu; Ikeo, Kazuho; Furuno, Masaaki; Zhuang, Wenjun; Liu, Yani; Rong, Weining; Hattori, Seisuke; Iwata, Takeshi

    2016-01-01

    Leber congenital amaurosis (LCA) is a hereditary early-onset retinal dystrophy that is accompanied by severe macular degeneration. In this study, novel compound heterozygous mutations were identified as LCA-causative in chaperonin-containing TCP-1, subunit 2 (CCT2), a gene that encodes the molecular chaperone protein, CCTβ. The zebrafish mutants of CCTβ are known to exhibit the eye phenotype while its mutation and association with human disease have been unknown. The CCT proteins (CCT α-θ) forms ring complex for its chaperon function. The LCA mutants of CCTβ, T400P and R516H, are biochemically instable and the affinity for the adjacent subunit, CCTγ, was affected distinctly in both mutants. The patient-derived induced pluripotent stem cells (iPSCs), carrying these CCTβ mutants, were less proliferative than the control iPSCs. Decreased proliferation under Cct2 knockdown in 661W cells was significantly rescued by wild-type CCTβ expression. However, the expression of T400P and R516H didn’t exhibit the significant effect. In mouse retina, both CCTβ and CCTγ are expressed in the retinal ganglion cells and connecting cilium of photoreceptor cells. The Cct2 knockdown decreased its major client protein, transducing β1 (Gβ1). Here we report the novel LCA mutations in CCTβ and the impact of chaperon disability by these mutations in cellular biology. PMID:27645772

  14. Hypomorphic mutation in mouse Nppc gene causes retarded bone growth due to impaired endochondral ossification

    SciTech Connect

    Tsuji, Takehito Kondo, Eri; Yasoda, Akihiro; Inamoto, Masataka; Kiyosu, Chiyo; Nakao, Kazuwa; Kunieda, Tetsuo

    2008-11-07

    Long bone abnormality (lbab/lbab) is a spontaneous mutant mouse characterized by dwarfism with shorter long bones. A missense mutation was reported in the Nppc gene, which encodes C-type natriuretic peptide (CNP), but it has not been confirmed whether this mutation is responsible for the dwarf phenotype. To verify that the mutation causes the dwarfism of lbab/lbab mice, we first investigated the effect of CNP in lbab/lbab mice. By transgenic rescue with chondrocyte-specific expression of CNP, the dwarf phenotype in lbab/lbab mice was completely compensated. Next, we revealed that CNP derived from the lbab allele retained only slight activity to induce cGMP production through its receptor. Histological analysis showed that both proliferative and hypertrophic zones of chondrocytes in the growth plate of lbab/lbab mice were markedly reduced. Our results demonstrate that lbab/lbab mice have a hypomorphic mutation in the Nppc gene that is responsible for dwarfism caused by impaired endochondral ossification.

  15. CCT2 Mutations Evoke Leber Congenital Amaurosis due to Chaperone Complex Instability

    PubMed Central

    Minegishi, Yuriko; Sheng, XunLun; Yoshitake, Kazutoshi; Sergeev, Yuri; Iejima, Daisuke; Shibagaki, Yoshio; Monma, Norikazu; Ikeo, Kazuho; Furuno, Masaaki; Zhuang, Wenjun; Liu, Yani; Rong, Weining; Hattori, Seisuke; Iwata, Takeshi

    2016-01-01

    Leber congenital amaurosis (LCA) is a hereditary early-onset retinal dystrophy that is accompanied by severe macular degeneration. In this study, novel compound heterozygous mutations were identified as LCA-causative in chaperonin-containing TCP-1, subunit 2 (CCT2), a gene that encodes the molecular chaperone protein, CCTβ. The zebrafish mutants of CCTβ are known to exhibit the eye phenotype while its mutation and association with human disease have been unknown. The CCT proteins (CCT α-θ) forms ring complex for its chaperon function. The LCA mutants of CCTβ, T400P and R516H, are biochemically instable and the affinity for the adjacent subunit, CCTγ, was affected distinctly in both mutants. The patient-derived induced pluripotent stem cells (iPSCs), carrying these CCTβ mutants, were less proliferative than the control iPSCs. Decreased proliferation under Cct2 knockdown in 661W cells was significantly rescued by wild-type CCTβ expression. However, the expression of T400P and R516H didn’t exhibit the significant effect. In mouse retina, both CCTβ and CCTγ are expressed in the retinal ganglion cells and connecting cilium of photoreceptor cells. The Cct2 knockdown decreased its major client protein, transducing β1 (Gβ1). Here we report the novel LCA mutations in CCTβ and the impact of chaperon disability by these mutations in cellular biology. PMID:27645772

  16. Real-time PCR genotyping and frequency of the myostatin F94L mutation in beef cattle breeds.

    PubMed

    Vankan, D M; Waine, D R; Fortes, M R S

    2010-04-01

    This research developed two real-time PCR assays, employing high-resolution melt and allele-specific analysis to accurately genotype the F94L mutation in cattle. This mutation (g.433C > A) in the growth differentiation factor 8 or myostatin gene has recently been shown to be functionally associated with increased muscle mass and carcass yield in cattle. The F94L mutation is not, like other myostatin mutations, associated with reduced fertility and dystocia. It is therefore a candidate for introgression into other breeds to improve retail beef yield and the development of a simple and accurate test to genotype this specific mutation is warranted. Variations in the efficiency of enzyme cleavage compromised the accuracy of genotyping by published methods, potentially resulting in an overestimation of the frequency of the mutant allele. The frequency of the F94L mutation was determined by real-time PCR in 1140 animals from 15 breeds of cattle in Australia. The mutation was present in Simmental (0.8%), Piedmontese (2%), Droughtmaster (4%) and Limousin (94.2%) but not found in Salers, Angus, Poll Hereford, Hereford, Gelbvieh, Charolais, Jersey, Brahman, Holstein, Shorthorn or Maine Anjou. The low prevalence of F94L in all beef breeds except Limousin indicates the significant potential for this mutation to improve retail yield in Australian beef cattle. PMID:22444040

  17. Mutations in elongation factor EF-1 alpha affect the frequency of frameshifting and amino acid misincorporation in Saccharomyces cerevisiae.

    PubMed

    Sandbaken, M G; Culbertson, M R

    1988-12-01

    A mutational analysis of the eukaryotic elongation factor EF-1 alpha indicates that this protein functions to limit the frequency of errors during genetic code translation. We found that both amino acid misincorporation and reading frame errors are controlled by EF-1 alpha. In order to examine the function of this protein, the TEF2 gene, which encodes EF-1 alpha in Saccharomyces cerevisiae, was mutagenized in vitro with hydroxylamine. Sixteen independent TEF2 alleles were isolated by their ability to suppress frameshift mutations. DNA sequence analysis identified eight different sites in the EF-1 alpha protein that elevate the frequency of mistranslation when mutated. These sites are located in two different regions of the protein. Amino acid substitutions located in or near the GTP-binding and hydrolysis domain of the protein cause suppression of frameshift and nonsense mutations. These mutations may effect mistranslation by altering the binding or hydrolysis of GTP. Amino acid substitutions located adjacent to a putative aminoacyl-tRNA binding region also suppress frameshift and nonsense mutations. These mutations may alter the binding of aminoacyl-tRNA by EF-1 alpha. The identification of frameshift and nonsense suppressor mutations in EF-1 alpha indicates a role for this protein in limiting amino acid misincorporation and reading frame errors. We suggest that these types of errors are controlled by a common mechanism or closely related mechanisms. PMID:3066688

  18. Real-time PCR genotyping and frequency of the myostatin F94L mutation in beef cattle breeds.

    PubMed

    Vankan, D M; Waine, D R; Fortes, M R S

    2010-04-01

    This research developed two real-time PCR assays, employing high-resolution melt and allele-specific analysis to accurately genotype the F94L mutation in cattle. This mutation (g.433C > A) in the growth differentiation factor 8 or myostatin gene has recently been shown to be functionally associated with increased muscle mass and carcass yield in cattle. The F94L mutation is not, like other myostatin mutations, associated with reduced fertility and dystocia. It is therefore a candidate for introgression into other breeds to improve retail beef yield and the development of a simple and accurate test to genotype this specific mutation is warranted. Variations in the efficiency of enzyme cleavage compromised the accuracy of genotyping by published methods, potentially resulting in an overestimation of the frequency of the mutant allele. The frequency of the F94L mutation was determined by real-time PCR in 1140 animals from 15 breeds of cattle in Australia. The mutation was present in Simmental (0.8%), Piedmontese (2%), Droughtmaster (4%) and Limousin (94.2%) but not found in Salers, Angus, Poll Hereford, Hereford, Gelbvieh, Charolais, Jersey, Brahman, Holstein, Shorthorn or Maine Anjou. The low prevalence of F94L in all beef breeds except Limousin indicates the significant potential for this mutation to improve retail yield in Australian beef cattle.

  19. The Phenotypic Spectrum of DYT24 Due to ANO3 Mutations

    PubMed Central

    Stamelou, Maria; Charlesworth, Gavin; Cordivari, Carla; Schneider, Susanne A; Kägi, Georg; Sheerin, Una-Marie; Rubio-Agusti, Ignacio; Batla, Amit; Houlden, Henry; Wood, Nicholas W; Bhatia, Kailash P

    2014-01-01

    Genes causing primary dystonia are rare. Recently, pathogenic mutations in the anoctamin 3 gene (ANO3) have been identified to cause autosomal dominant craniocervical dystonia and have been assigned to the dystonia locus dystonia-24 (DYT24). Here, we expand on the phenotypic spectrum of DYT24 and provide demonstrative videos. Moreover, tremor recordings were performed, and back-averaged electroencephalography, sensory evoked potentials, and C-reflex studies were carried out in two individuals who carried two different mutations in ANO3. Ten patients from three families are described. The age at onset ranged from early childhood to the forties. Cervical dystonia was the most common site of onset followed by laryngeal dystonia. The characteristic feature in all affected individuals was the presence of tremor, which contrasts DYT24 from the typical DYT6 phenotype. Tremor was the sole initial manifestation in some individuals with ANO3 mutations, leading to misdiagnosis as essential tremor. Electrophysiology in two patients with two different mutations showed co-contraction of antagonist muscles, confirming dystonia, and a 6-Hz arm tremor at rest, which increased in amplitude during action. In one of the studied patients, clinically superimposed myoclonus was observed. The duration of the myoclonus was in the range of 250 msec at about 3 Hz, which is more consistent with subcortical myoclonus. In summary, ANO3 causes a varied phenotype of young-onset or adult-onset craniocervical dystonia with tremor and/or myoclonic jerks. Patients with familial cervical dystonia who also have myoclonus-dystonia as well as patients with prominent tremor and mild dystonia should be tested for ANO3 mutations. © 2014 The Authors. Movement Disorders published by International Parkinson and Movement Disorder Society PMID:24442708

  20. Phenotypic and molecular insights into spinal muscular atrophy due to mutations in BICD2

    PubMed Central

    Rossor, Alexander M.; Oates, Emily C.; Salter, Hannah K.; Liu, Yang; Murphy, Sinead M.; Schule, Rebecca; Gonzalez, Michael A.; Scoto, Mariacristina; Phadke, Rahul; Sewry, Caroline A.; Houlden, Henry; Jordanova, Albena; Tournev, Iyailo; Chamova, Teodora; Litvinenko, Ivan; Zuchner, Stephan; Herrmann, David N.; Blake, Julian; Sowden, Janet E.; Acsadi, Gyuda; Rodriguez, Michael L.; Menezes, Manoj P.; Clarke, Nigel F.; Auer Grumbach, Michaela; Bullock, Simon L.; Muntoni, Francesco; North, Kathryn N.

    2015-01-01

    Spinal muscular atrophy is a disorder of lower motor neurons, most commonly caused by recessive mutations in SMN1 on chromosome 5q. Cases without SMN1 mutations are subclassified according to phenotype. Spinal muscular atrophy, lower extremity-predominant, is characterized by lower limb muscle weakness and wasting, associated with reduced numbers of lumbar motor neurons and is caused by mutations in DYNC1H1, which encodes a microtubule motor protein in the dynein-dynactin complex and one of its cargo adaptors, BICD2. We have now identified 32 patients with BICD2 mutations from nine different families, providing detailed insights into the clinical phenotype and natural history of BICD2 disease. BICD2 spinal muscular atrophy, lower extremity predominant most commonly presents with delayed motor milestones and ankle contractures. Additional features at presentation include arthrogryposis and congenital dislocation of the hips. In all affected individuals, weakness and wasting is lower-limb predominant, and typically involves both proximal and distal muscle groups. There is no evidence of sensory nerve involvement. Upper motor neuron signs are a prominent feature in a subset of individuals, including one family with exclusively adult-onset upper motor neuron features, consistent with a diagnosis of hereditary spastic paraplegia. In all cohort members, lower motor neuron features were static or only slowly progressive, and the majority remained ambulant throughout life. Muscle MRI in six individuals showed a common pattern of muscle involvement with fat deposition in most thigh muscles, but sparing of the adductors and semitendinosus. Muscle pathology findings were highly variable and included pseudomyopathic features, neuropathic features, and minimal change. The six causative mutations, including one not previously reported, result in amino acid changes within all three coiled-coil domains of the BICD2 protein, and include a possible ‘hot spot’ mutation, p.Ser107

  1. Hepatic Copper Accumulation: A Novel Feature in Transient Infantile Liver Failure Due to TRMU Mutations?

    PubMed

    Grover, Z; Lewindon, P; Clousten, A; Shaag, A; Elpeleg, O; Coman, D

    2015-01-01

    Defects in the mitochondrial respiratory chain can induce a heterogeneous range of clinical and biochemical manifestations. Hepatic involvement includes acute fulminant hepatic failure, microvesicular steatosis, neonatal non-alloimmune haemochromatosis and cirrhosis. Recently pathogenic mutations in tRNA 5-methylaminomethyl-2-thiouridylate methyltransferase (TRMU) gene (OMIM 610230) have been demonstrated to cause transient infantile liver failure (OMIM 613070). The human TRMU gene encodes a mitochondrial protein, 5-methylaminomethyl-2-thiouridylate methyltransferase, whose molecular function is that of mitochondrial tRNA modification.We report an infant who presented with acute liver failure, in whom we observed hepatic copper intoxication and cirrhosis on liver biopsy. We postulate that the hepatic copper intoxication observed in our patient is most likely a secondary event associated with cholangiopathy. Periportal copper accumulation has been implicated in causing secondary mitochondrial dysfunction; the impact of copper accumulation in patients with TRMU mutations is unclear and warrants long-term clinical follow-up.

  2. CLINICAL VARIABILITY IN TWO SISTERS WITH KEUTEL SYNDROME DUE TO A HOMOZYGOUS MUTATION IN MGP GENE.

    PubMed

    Tüysüz, B; Cinar, B; Laçiner, S; Onay, H; Mittaz-Crettol, L

    2015-01-01

    Keutel syndrome (KS) is an autosomal recessive disease characterised by abnormal cartilage calcification, brachytelephalangism, peripheral pulmonary artery stenosis, hearing loss and midface retrusion. KS is caused by homozygous mutations in MGP, a gene encoding Matrix Gla protein which acts as a calcification inhibitor in extracellular matrix. We present two Turkish sisters (22 and 13 years old) who had abnormal cartilage calcification, brachytelephalangism, congenital heart defect and chronic asthmatic bronchitis. The patients were homozygous for c.62-2A>G (IVS1-2 A>G) mutation in MGP gene. Abnormal cartilage calcification, brachytelephalangism and midfacial retrusion are the hallmarks of KS. It was observed that the younger sister had striking cartilaginous calcifications, midfacial retrusion and severe brachytelephalangism while her older sister had mild costal cartilaginous calcifications and brachytelephalangism without any midfacial retrusion. Intrafamiliar clinical variability for KS has not been described previously. PMID:26349188

  3. [Severe type A insulin resistance syndrome due to a mutation in the insulin receptor gene].

    PubMed

    Ros, P; Colino-Alcol, E; Grasso, V; Barbetti, F; Argente, J

    2015-01-01

    Insulin resistance syndromes without lipodystrophy are an infrequent and heterogeneous group of disorders with variable clinical phenotypes, associated with hyperglycemia and hyperinsulinemia. The three conditions related to mutations in the insulin receptor gene are leprechaunism or Donohue syndrome, Rabson-Mendenhall syndrome, and Type A syndrome. A case is presented on a patient diagnosed with type A insulin resistance, defined by the triad of extreme insulin resistance, acanthosis nigricans, and hyperandrogenism, carrying a heterozygous mutation in exon 19 of the insulin receptor gene coding for its tyrosine kinase domain that is crucial for the catalytic activity of the receptor. The molecular basis of the syndrome is reviewed, focusing on the structure-function relationships of the insulin receptor, knowing that the criteria for survival are linked to residual insulin receptor function. It is also pointed out that, although type A insulin resistance appears to represent a somewhat less severe condition, these patients have a high morbidity and their treatment is still unsatisfactory.

  4. Congenital myasthenic syndromes due to mutations in ALG2 and ALG14.

    PubMed

    Cossins, Judith; Belaya, Katsiaryna; Hicks, Debbie; Salih, Mustafa A; Finlayson, Sarah; Carboni, Nicola; Liu, Wei Wei; Maxwell, Susan; Zoltowska, Katarzyna; Farsani, Golara Torabi; Laval, Steven; Seidhamed, Mohammed Zain; Donnelly, Peter; Bentley, David; McGowan, Simon J; Müller, Juliane; Palace, Jacqueline; Lochmüller, Hanns; Beeson, David

    2013-03-01

    Congenital myasthenic syndromes are a heterogeneous group of inherited disorders that arise from impaired signal transmission at the neuromuscular synapse. They are characterized by fatigable muscle weakness. We performed linkage analysis, whole-exome and whole-genome sequencing to determine the underlying defect in patients with an inherited limb-girdle pattern of myasthenic weakness. We identify ALG14 and ALG2 as novel genes in which mutations cause a congenital myasthenic syndrome. Through analogy with yeast, ALG14 is thought to form a multiglycosyltransferase complex with ALG13 and DPAGT1 that catalyses the first two committed steps of asparagine-linked protein glycosylation. We show that ALG14 is concentrated at the muscle motor endplates and small interfering RNA silencing of ALG14 results in reduced cell-surface expression of muscle acetylcholine receptor expressed in human embryonic kidney 293 cells. ALG2 is an alpha-1,3-mannosyltransferase that also catalyses early steps in the asparagine-linked glycosylation pathway. Mutations were identified in two kinships, with mutation ALG2p.Val68Gly found to severely reduce ALG2 expression both in patient muscle, and in cell cultures. Identification of DPAGT1, ALG14 and ALG2 mutations as a cause of congenital myasthenic syndrome underscores the importance of asparagine-linked protein glycosylation for proper functioning of the neuromuscular junction. These syndromes form part of the wider spectrum of congenital disorders of glycosylation caused by impaired asparagine-linked glycosylation. It is likely that further genes encoding components of this pathway will be associated with congenital myasthenic syndromes or impaired neuromuscular transmission as part of a more severe multisystem disorder. Our findings suggest that treatment with cholinesterase inhibitors may improve muscle function in many of the congenital disorders of glycosylation. PMID:23404334

  5. Delayed onset of congenital hereditary endothelial dystrophy due to compound heterozygous SLC4A11 mutations

    PubMed Central

    Kumawat, Babu Lal; Gupta, Ranjan; Sharma, Arundhati; Sen, Seema; Gupta, Shikha; Tandon, Radhika

    2016-01-01

    Background: Congenital hereditary endothelial dystrophy (CHED) is an autosomal recessive disorder characterized by bilateral, symmetrical, noninflammatory corneal clouding (edema) present at birth or shortly thereafter. This study reports on an unusual delayed presentation of CHED with compound heterozygous SLC4A11 mutations. Materials and Methods: A 45-year-old female, presenting with bilateral decreased vision since childhood that deteriorated in the last 5 years, was evaluated to rule out trauma, viral illness, chemical injury, glaucoma, and corneal endothelial dystrophies. Tear sample was sent for herpes simplex viral (HSV) antigen testing. Genomic DNA from peripheral blood was screened for mutations in all exons of SLC4A11 by direct sequencing. Full-thickness penetrating keratoplasty was done and corneal button was sent for histopathological examination. Results: Slit-lamp findings revealed bilateral diffuse corneal edema and left eye spheroidal degeneration with scarring. Increased corneal thickness (762 μm and 854 μm in the right and left eyes, respectively), normal intraocular pressure (12 mmHg and 16 mmHg in the right and left eyes, respectively), inconclusive confocal scan, and specular microscopy, near normal tear film parameters, were the other clinical features. HSV-polymerase chain reaction was negative. Histopathological examination revealed markedly thickened Descemet's membrane with subepithelial spheroidal degeneration. SLC4A11 screening showed a novel variant p.Ser415Asn, reported mutation p.Cys386Arg and two polymorphisms, all in the heterozygous state and not identified in 100 controls. Conclusions: The study shows, for the first time, compound heterozygous SLC4A11 mutations impair protein function leading to delayed onset of the disease. PMID:27609159

  6. Gigantism and Acromegaly Due to Xq26 Microduplications and GPR101 Mutation

    PubMed Central

    Trivellin, G.; Daly, A.F.; Faucz, F.R.; Yuan, B.; Rostomyan, L.; Larco, D.O.; Schernthaner-Reiter, M.H.; Szarek, E.; Leal, L.F.; Caberg, J.-H.; Castermans, E.; Villa, C.; Dimopoulos, A.; Chittiboina, P.; Xekouki, P.; Shah, N.; Metzger, D.; Lysy, P.A.; Ferrante, E.; Strebkova, N.; Mazerkina, N.; Zatelli, M.C.; Lodish, M.; Horvath, A.; de Alexandre, R. Bertollo; Manning, A.D.; Levy, I.; Keil, M.F.; de la Luz Sierra, M.; Palmeira, L.; Coppieters, W.; Georges, M.; Naves, L.A.; Jamar, M.; Bours, V.; Wu, T.J.; Choong, C.S.; Bertherat, J.; Chanson, P.; Kamenický, P.; Farrell, W.E.; Barlier, A.; Quezado, M.; Bjelobaba, I.; Stojilkovic, S.S.; Wess, J.; Costanzi, S.; Liu, P.; Lupski, J.R.; Beckers, A.; Stratakis, C.A.

    2015-01-01

    BACKGROUND Increased secretion of growth hormone leads to gigantism in children and acromegaly in adults; the genetic causes of gigantism and acromegaly are poorly understood. METHODS We performed clinical and genetic studies of samples obtained from 43 patients with gigantism and then sequenced an implicated gene in samples from 248 patients with acromegaly. RESULTS We observed microduplication on chromosome Xq26.3 in samples from 13 patients with gigantism; of these samples, 4 were obtained from members of two unrelated kindreds, and 9 were from patients with sporadic cases. All the patients had disease onset during early childhood. Of the patients with gigantism who did not carry an Xq26.3 microduplication, none presented before the age of 5 years. Genomic characterization of the Xq26.3 region suggests that the microduplications are generated during chromosome replication and that they contain four protein-coding genes. Only one of these genes, GPR101, which encodes a G-protein–coupled receptor, was overexpressed in patients’ pituitary lesions. We identified a recurrent GPR101 mutation (p.E308D) in 11 of 248 patients with acromegaly, with the mutation found mostly in tumors. When the mutation was transfected into rat GH3 cells, it led to increased release of growth hormone and proliferation of growth hormone–producing cells. CONCLUSIONS We describe a pediatric disorder (which we have termed X-linked acrogigantism [X-LAG]) that is caused by an Xq26.3 genomic duplication and is characterized by early-onset gigantism resulting from an excess of growth hormone. Duplication of GPR101 probably causes X-LAG. We also found a recurrent mutation in GPR101 in some adults with acromegaly. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and others.) PMID:25470569

  7. Congenital contractural arachnodactyly due to a novel splice site mutation in the FBN2 gene

    PubMed Central

    Mehar, Virendra; Yadav, Dinesh; Kumar, Ravindra; Yadav, Summi; Singh, Kuldeep; Callewaert, Bert; Pathan, Shahnawaz; De Paepe, Anne; Coucke, Paul J.

    2014-01-01

    Congenital contractural arachnodactyly is a rare autosomal dominant disorder characterized by crumpled ears, congenital contractures, arachnodactyly and scoliosis. Only few cases have been described to date. Here we report a newborn with congenital contractures, crumpled ears and scoliosis. Molecular analysis revealed a novel fibrillin-2 mutation at the donor splice site of intron 28. We discuss the differential diagnosis of neonates with congenital contractures and review the current knowledge on congenital contractural arachnodactyly. PMID:27625873

  8. Late-onset hereditary sensory neuropathy type I due to SPTLC1 mutation: autopsy findings.

    PubMed

    Lindahl, Andrea J; Lhatoo, Sam D; Campbell, Malcolm J; Nicholson, Garth; Love, Seth

    2006-12-01

    There is little published information on the autopsy findings in hereditary sensory neuropathy type I (HSN I), and none in genetically confirmed cases. We report the neuropathological findings in a 93-year-old woman with a disease of unusually late onset, who was part of a large HSN I kindred and in whom genetic analysis confirmed an SPTLC1 T399G mutation. PMID:16271825

  9. MERRF/MELAS overlap syndrome due to the m.3291T>C mutation.

    PubMed

    Liu, Kaiming; Zhao, Hui; Ji, Kunqian; Yan, Chuanzhu

    2014-03-01

    We report the case of a 19-year-old Chinese female harboring the m.3291T>C mutation in the MT-TL1 gene encoding the mitochondrial transfer RNA for leucine. She presented with a complex phenotype characterized by progressive cerebellar ataxia, frequent myoclonus seizures, recurrent stroke-like episodes, migraine-like headaches with nausea and vomiting, and elevated resting lactate blood level. It is known that the myoclonus epilepsy with ragged-red fibers (MERRF) is characterized by cerebellar ataxia and myoclonus epilepsy, while that the mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) is characterized by recurrent stroke-like episodes, migraine-like headaches, and elevated resting lactate blood level. So the patient's clinical manifestations suggest the presence of a MERRF/MELAS overlap syndrome. Muscle biopsy of the patient showed the presence of numerous scattered ragged-red fibers, some cytochrome c oxidase-deficient fibers, and several strongly succinate dehygrogenase-reactive vessels, suggestive of a mitochondrial disorder. Direct sequencing of the complete mitochondrial genome of the proband revealed no mutations other than the T-to-C transition at nucleotide position 3291. Restriction fragment length polymorphism analysis of the proband and her family revealed maternal inheritance of the mutation in a heteroplasmic manner. The analysis of aerobic respiration and glycolysis demonstrated that the fibroblasts from the patient had mitochondrial dysfunction. Our results suggest that the m.3291T>C is pathogenic. This study is the first to describe the m.3291T>C mutation in association with the MERRF/MELAS overlap syndrome.

  10. Congenital contractural arachnodactyly due to a novel splice site mutation in the FBN2 gene.

    PubMed

    Mehar, Virendra; Yadav, Dinesh; Kumar, Ravindra; Yadav, Summi; Singh, Kuldeep; Callewaert, Bert; Pathan, Shahnawaz; De Paepe, Anne; Coucke, Paul J

    2014-09-01

    Congenital contractural arachnodactyly is a rare autosomal dominant disorder characterized by crumpled ears, congenital contractures, arachnodactyly and scoliosis. Only few cases have been described to date. Here we report a newborn with congenital contractures, crumpled ears and scoliosis. Molecular analysis revealed a novel fibrillin-2 mutation at the donor splice site of intron 28. We discuss the differential diagnosis of neonates with congenital contractures and review the current knowledge on congenital contractural arachnodactyly. PMID:27625873

  11. Idiopathic Short Stature due to Novel Heterozygous Mutation of the Aggrecan Gene

    PubMed Central

    Quintos, Jose Bernardo; Guo, Michael H.; Dauber, Andrew

    2015-01-01

    Background Recently, whole exome sequencing identified heterozygous defects in the Aggrecan gene (ACAN) in three families with short stature and advanced bone age. Objective We report a novel frameshift mutation in ACAN in a family with dominantly inherited short stature, advanced bone age, and premature growth cessation. This is the first case of targeted sequencing of ACAN in this phenotype and confirms that ACAN sequencing is warranted in patients with this rare constellation of findings. Results We present a 5 1/2 year old male with a family history of short stature in 3 generations. The maternal grandfather stands 144.5 cm (Ht SDS -4.7), mother 147.7 cm (Ht SDS -2.6), and index case 99.2 cm (Ht SDS -2.7). Our prepubertal patient has significant bone age advancement (bone age 8 years at chronologic age 5 1/2 years) resulting in a poor predicted adult height of 142 cm (Ht SDS -5.1). DNA sequencing identified a novel heterozygous variant in ACAN, which encodes aggrecan, a proteoglycan in the extracellular matrix of growth plate and other cartilaginous tissues. The mutation (p.Gly1797Glyfs*52) results in premature truncation and presumed loss of protein function. Conclusion Mutations in aggrecan gene should be included in the differential diagnosis of the child with idiopathic short stature or familial short stature and bone age advancement. PMID:25741789

  12. Hypoglycosylation of alpha-dystroglycan in patients with hereditary IBM due to GNE mutations.

    PubMed

    Huizing, Marjan; Rakocevic, Goran; Sparks, Susan E; Mamali, Ioanna; Shatunov, Alexey; Goldfarb, Lev; Krasnewich, Donna; Gahl, William A; Dalakas, Marinos C

    2004-03-01

    Hereditary inclusion body myopathy (HIBM) is an adult onset neuromuscular disorder associated with mutations in the gene UDP-N-acetylglucosamine-2-epimerase/N-acetylmannosamine kinase (GNE), whose product is the rate limiting bi-functional enzyme catalyzing the first two steps of sialic acid biosynthesis. Loss of GNE activity in HIBM is thought to impair sialic acid production and interfere with proper sialylation of glycoconjugates, but it remains unclear how such a defect would lead to muscle destruction and muscle weakness. Hypoglycosylation of alpha-dystroglycan, a central protein of the skeletal muscle dystrophin-glycoprotein complex, results in disturbed interactions with extracellular matrix proteins. This has recently been identified as the pathomechanism involved in several congenital muscular dystrophies. We examined the glycosylation status of alpha-dystroglycan in muscle biopsies of four HIBM patients of non-Iranian Jewish origin (one American, two Indians, and one Greek). Two of these patients carry novel compound heterozygous GNE mutations on exon 2 and exon 9. All four muscle biopsies showed absent or markedly reduced immunolabeling with two different antibodies (VIA4 and IIH6) to glycosylated epitopes of alpha-dystroglycan. Normal labeling was found using antibodies to the core alpha-dystroglycan protein, beta-dystroglycan, and laminin alpha-2. These findings resemble those found for other congenital muscular dystrophies, suggesting that HIBM may be a "dystroglycanopathy," and providing an explanation for the muscle weakness of patients with GNE mutations.

  13. Intragenic modifiers of hereditary spastic paraplegia due to spastin gene mutations.

    PubMed

    Svenson, Ingrid K; Kloos, Mark T; Gaskell, P Craig; Nance, Martha A; Garbern, James Y; Hisanaga, Shin-ichi; Pericak-Vance, Margaret A; Ashley-Koch, Allison E; Marchuk, Douglas A

    2004-09-01

    Hereditary spastic paraplegia (HSP) is a genetically heterogeneous neurodegenerative disease characterized by wide variability in phenotypic expression, both within and among families. The most-common cause of autosomal dominant HSP is mutation of the gene encoding spastin, a protein of uncertain function. We report the existence of intragenic polymorphisms of spastin that modify the HSP phenotype. One (S44L) is a previously described recessively acting allele and the second is a novel allele affecting the adjacent amino acid residue (P45Q). In 4 HSP families in which either L44 or Q45 segregates independently of a missense or splicing mutation in the AAA domain of spastin, L44 and Q45 are each associated with a striking decrease in age at onset in the presence of the AAA domain mutations. Using a bioinformatics approach, we found that the highly conserved S44 is predicted to be phosphorylated by a number of family members of the proline-directed serine/threonine cyclin-dependent kinases (Cdks). Cdk1 and Cdk5 showed no kinase activity toward synthetic spastin peptide in an in vitro kinase assay, suggesting that this serine residue may be phosphorylated by a different Cdk. Our identification of S44L and P45Q as modifiers of the HSP phenotype suggests a role for spastin phosphorylation by Cdks in the neurodegeneration of the most-common form of HSP. PMID:15248095

  14. Dejerine-Sottas syndrome and vestibular loss due to a point mutation in the PMP22 gene.

    PubMed

    Jen, Joanna; Baloh, Robert H; Ishiyama, Akira; Baloh, Robert W

    2005-10-15

    We describe a father and daughter with Dejerine-Sottas syndrome and bilateral vestibular loss due to an L71P missense mutation in the peripheral myelin protein 22 (PMP22). The combination of vestibular loss and peripheral neuropathy led to profound imbalance at a young age. It is important to recognize this combination of peripheral nerve and vestibular deficits since rehabilitation strategies and prognosis are different. PMID:15992829

  15. Peptides from aminoacyl-tRNA synthetases can cure the defects due to mutations in mt tRNA genes.

    PubMed

    Francisci, Silvia; Montanari, Arianna; De Luca, Cristina; Frontali, Laura

    2011-11-01

    Recent results from several laboratories have confirmed that human and yeast leucyl- and valyl-tRNA synthetases can rescue the respiratory defects due to mutations in mitochondrial tRNA genes. In this report we show that this effect cannot be ascribed to the catalytic activity per se and that isolated domains of aminoacyl-tRNA synthetases and even short peptides thereof have suppressing effects.

  16. Frequency gradients of DHCR7 mutations in patients with Smith-Lemli-Opitz syndrome in Europe: evidence for different origins of common mutations.

    PubMed

    Witsch-Baumgartner, M; Ciara, E; Löffler, J; Menzel, H J; Seedorf, U; Burn, J; Gillessen-Kaesbach, G; Hoffmann, G F; Fitzky, B U; Mundy, H; Clayton, P; Kelley, R I; Krajewska-Walasek, M; Utermann, G

    2001-01-01

    Smith-Lemli-Opitz syndrome/RSH (SLOS) is a multiple congenital anomaly syndrome caused by mutations in the gene for Delta7-sterol reductase (DHCR7) which catalyses the last step in the biosynthesis of cholesterol. SLOS is among the common recessive disorders in Europeans but almost absent in most other populations. More than 40 mutations in the DHCR7 gene some of which are frequent have been described in SLOS patients of various origins. Here we report mutation analysis of the DHCR7 gene in SLOS patients from Poland (n = 15), Germany/Austria (n = 22) and Great Britain (n = 22). Altogether 35 different mutations were identified and the two null mutations IVS8-1G > C and W151X were the most frequent in the total sample. In all three populations three mutations accounted for >0.5 of SLOS chromosomes. The mutational spectra were, however, significantly different across these populations with each of the common mutations showing an east-west gradient (W151X, V326L) or vice versa (IVS8-1G > C). W151X is the most frequent (0.33) mutation in Polish SLOS patients. It has an intermediate frequency in German/Austrian patients (0.18) and is rare among British patients (0.02). V326L shows the same distribution pattern (Poland 0.23, Germany/Austria 0.18, Britain 0.02). In contrast IVS8-1G > C is most frequent in Britain (0.34) intermediate in Germany/Austria (0.20) and rare in Poland (0.03). All analysed IVS8-1G > C and V326L alleles shared the same DHCR7 haplotype, whereas the W151X mutation occurred on different haplotypes. There is evidence for both recurrent mutations and founder effects. Together this suggests that the common SLOS mutations in Europe have different geographic and historic origins and spread across the continent in opposite directions. PMID:11175299

  17. Cerebro-retinal microangiopathy with calcifications and cysts due to recessive mutations in the CTC1 gene.

    PubMed

    Bisserbe, A; Tertian, G; Buffet, C; Turhan, A; Lambotte, O; Nasser, G; Alvin, P; Tardieu, M; Riant, F; Bergametti, F; Tournier-Lasserve, E; Denier, C

    2015-05-01

    Cerebro-retinal microangiopathy with calcifications and cysts (CRMCC) or Coats plus syndrome is a pleiotropic disorder affecting the eyes, brain, bone and gastrointestinal tract. Its primary pathogenesis involves small vessel obliterative microangiopathy. Recently, autosomal recessively inherited mutations in CTC1 have been reported in CRMCC patients. We herein report an adolescent referred to our hospital following new seizures in a context of an undefined multisystem disorder. Cerebral imaging disclosed asymmetrical leukopathy, intracranial calcifications and cysts. In addition, he presented other typical CRMCC features i.e. a history of intrauterine growth retardation, skeletal demineralization and osteopenia, bilateral exudative vitreo-retinopathy reminiscent of Coats disease, recurrent gastrointestinal hemorrhages secondary to watermelon stomach and variceal bleeding of the esophagus due to idiopathic portal hypertension and telangiectatic and angiodysplasic changes in the small intestine and colon, and anemia due to recurrent bleeding and bone marrow abnormalities. The patient was diagnosed with Coats plus syndrome. CTC1 gene screening confirmed the diagnosis with the identification of heterozygous deleterious mutations. CRMCC due to CTC1 mutations has a broad clinical expressivity. Our case report illustrates the main possible associated phenotypes and their complications, demonstrating the need for a careful etiological search in order to initiate appropriate therapeutic and preventive measures.

  18. Tipping the mutation-selection balance: Limited migration increases the frequency of deleterious mutants.

    PubMed

    Cooper, Jacob D; Neuhauser, Claudia; Dean, Antony M; Kerr, Benjamin

    2015-09-01

    Typical mutation-selection models assume well-mixed populations, but dispersal and migration within many natural populations is spatially limited. Such limitations can lead to enhanced variation among locations as different types become clustered in different places. Such clustering weakens competition between unlike types relative to competition between like types; thus, the rate by which a fitter type displaces an inferior competitor can be affected by the spatial scale of movement. In this paper, we use a birth-death model to show that limited migration can affect asexual populations by creating competitive refugia. We use a moment closure approach to show that as population structure is introduced by limiting migration, the equilibrial frequency of deleterious mutants increases. We support and extend the model through stochastic simulation, and we use a spatially explicit cellular automaton approach to corroborate the results. We discuss the implications of these results for standing variation in structured populations and adaptive valley crossing in Wright's "shifting balance" process.

  19. Carrier frequencies of eleven mutations in eight genes associated with primary ciliary dyskinesia in the Ashkenazi Jewish population.

    PubMed

    Fedick, Anastasia M; Jalas, Chaim; Treff, Nathan R; Knowles, Michael R; Zariwala, Maimoona A

    2015-03-01

    Primary ciliary dyskinesia (PCD) is a genetically heterogeneous, autosomal recessive disorder that results from functional and ultrastructural abnormalities of motile cilia. Patients with PCD have diverse clinical phenotypes that include chronic upper and lower respiratory tract infections, situs inversus, heterotaxy with or without congenital heart disease, and male infertility, among others. In this report, the carrier frequencies for eleven mutations in eight PCD-associated genes (DNAI1, DNAI2, DNAH5, DNAH11, CCDC114, CCDC40, CCDC65, and C21orf59) that had been found in individuals of Ashkenazi Jewish descent were investigated in order to advise on including them in existing clinical mutation panels for this population. Results showed relatively high carrier frequencies for the DNAH5 c.7502G>C mutation (0.58%), the DNAI2 c.1304G>A mutation (0.50%), and the C21orf59 c.735C>G mutation (0.48%), as well as lower frequencies for mutations in DNAI1, CCDC65, CCDC114, and DNAH11 (0.10-0.29%). These results suggest that several of these genes should be considered for inclusion in carrier screening panels in the Ashkenazi Jewish population. PMID:25802884

  20. Microsatellite frequencies vary with body mass and body temperature in mammals, suggesting correlated variation in mutation rate

    PubMed Central

    Filipe, Laura N.S.

    2014-01-01

    Substitution rate is often found to correlate with life history traits such as body mass, a predictor of population size and longevity, and body temperature. The underlying mechanism is unclear but most models invoke either natural selection or factors such as generation length that change the number of mutation opportunities per unit time. Here we use published genome sequences from 69 mammals to ask whether life history traits impact another form of genetic mutation, the high rates of predominantly neutral slippage in microsatellites. We find that the length-frequency distributions of three common dinucleotide motifs differ greatly between even closely related species. These frequency differences correlate with body mass and body temperature and can be used to predict the phenotype of an unknown species. Importantly, different length microsatellites show complicated patterns of excess and deficit that cannot be explained by a simple model where species with short generation lengths have experienced more mutations. Instead, the patterns probably require changes in mutation rate that impact alleles of different length to different extents. Body temperature plausibly influences mutation rate by modulating the propensity for slippage. Existing hypotheses struggle to account for a link between body mass and mutation rate. However, body mass correlates inversely with population size, which in turn predicts heterozygosity. We suggest that heterozygote instability, HI, the idea that heterozygous sites show increased mutability, could provide a plausible link between body mass and mutation rate. PMID:25392761

  1. Frequency of mutations in the genes associated with hereditary sensory and autonomic neuropathy in a UK cohort.

    PubMed

    Davidson, G L; Murphy, S M; Polke, J M; Laura, M; Salih, M A M; Muntoni, F; Blake, J; Brandner, S; Davies, N; Horvath, R; Price, S; Donaghy, M; Roberts, M; Foulds, N; Ramdharry, G; Soler, D; Lunn, M P; Manji, H; Davis, M B; Houlden, H; Reilly, M M

    2012-08-01

    The hereditary sensory and autonomic neuropathies (HSAN, also known as the hereditary sensory neuropathies) are a clinically and genetically heterogeneous group of disorders, characterised by a progressive sensory neuropathy often complicated by ulcers and amputations, with variable motor and autonomic involvement. To date, mutations in twelve genes have been identified as causing HSAN. To study the frequency of mutations in these genes and the associated phenotypes, we screened 140 index patients in our inherited neuropathy cohort with a clinical diagnosis of HSAN for mutations in the coding regions of SPTLC1, RAB7, WNK1/HSN2, FAM134B, NTRK1 (TRKA) and NGFB. We identified 25 index patients with mutations in six genes associated with HSAN (SPTLC1, RAB7, WNK1/HSN2, FAM134B, NTRK1 and NGFB); 20 of which appear to be pathogenic giving an overall mutation frequency of 14.3%. Mutations in the known genes for HSAN are rare suggesting that further HSAN genes are yet to be identified. The p.Cys133Trp mutation in SPTLC1 is the most common cause of HSAN in the UK population and should be screened first in all patients with sporadic or autosomal dominant HSAN.

  2. Frequency of mutations in the genes associated with hereditary sensory and autonomic neuropathy in a UK cohort

    PubMed Central

    Davidson, G. L.; Murphy, S. M.; Polke, J. M.; Laura, M.; Salih, M. A. M.; Muntoni, F.; Blake, J.; Brandner, S.; Davies, N.; Horvath, R.; Price, S.; Donaghy, M.; Roberts, M.; Foulds, N.; Ramdharry, G.; Soler, D.; Lunn, M. P.; Manji, H.; Davis, M. B.; Houlden, H.; Reilly, M. M.

    2013-01-01

    The hereditary sensory and autonomic neuropathies (HSAN, also known as the hereditary sensory neuropathies) are a clinically and genetically heterogeneous group of disorders, characterised by a progressive sensory neuropathy often complicated by ulcers and amputations, with variable motor and autonomic involvement. To date, mutations in twelve genes have been identified as causing HSAN. To study the frequency of mutations in these genes and the associated phenotypes, we screened 140 index patients in our inherited neuropathy cohort with a clinical diagnosis of HSAN for mutations in the coding regions of SPTLC1, RAB7, WNK1/HSN2, FAM134B, NTRK1 (TRKA) and NGFB. We identified 25 index patients with mutations in six genes associated with HSAN (SPTLC1, RAB7, WNK1/HSN2, FAM134B, NTRK1 and NGFB); 20 of which appear to be pathogenic giving an overall mutation frequency of 14.3%. Mutations in the known genes for HSAN are rare suggesting that further HSAN genes are yet to be identified. The p.Cys133Trp mutation in SPTLC1 is the most common cause of HSAN in the UK population and should be screened first in all patients with sporadic or autosomal dominant HSAN. PMID:22302274

  3. Microsatellite frequencies vary with body mass and body temperature in mammals, suggesting correlated variation in mutation rate.

    PubMed

    Amos, William; Filipe, Laura N S

    2014-01-01

    Substitution rate is often found to correlate with life history traits such as body mass, a predictor of population size and longevity, and body temperature. The underlying mechanism is unclear but most models invoke either natural selection or factors such as generation length that change the number of mutation opportunities per unit time. Here we use published genome sequences from 69 mammals to ask whether life history traits impact another form of genetic mutation, the high rates of predominantly neutral slippage in microsatellites. We find that the length-frequency distributions of three common dinucleotide motifs differ greatly between even closely related species. These frequency differences correlate with body mass and body temperature and can be used to predict the phenotype of an unknown species. Importantly, different length microsatellites show complicated patterns of excess and deficit that cannot be explained by a simple model where species with short generation lengths have experienced more mutations. Instead, the patterns probably require changes in mutation rate that impact alleles of different length to different extents. Body temperature plausibly influences mutation rate by modulating the propensity for slippage. Existing hypotheses struggle to account for a link between body mass and mutation rate. However, body mass correlates inversely with population size, which in turn predicts heterozygosity. We suggest that heterozygote instability, HI, the idea that heterozygous sites show increased mutability, could provide a plausible link between body mass and mutation rate. PMID:25392761

  4. Frequency of mutations in the genes associated with hereditary sensory and autonomic neuropathy in a UK cohort.

    PubMed

    Davidson, G L; Murphy, S M; Polke, J M; Laura, M; Salih, M A M; Muntoni, F; Blake, J; Brandner, S; Davies, N; Horvath, R; Price, S; Donaghy, M; Roberts, M; Foulds, N; Ramdharry, G; Soler, D; Lunn, M P; Manji, H; Davis, M B; Houlden, H; Reilly, M M

    2012-08-01

    The hereditary sensory and autonomic neuropathies (HSAN, also known as the hereditary sensory neuropathies) are a clinically and genetically heterogeneous group of disorders, characterised by a progressive sensory neuropathy often complicated by ulcers and amputations, with variable motor and autonomic involvement. To date, mutations in twelve genes have been identified as causing HSAN. To study the frequency of mutations in these genes and the associated phenotypes, we screened 140 index patients in our inherited neuropathy cohort with a clinical diagnosis of HSAN for mutations in the coding regions of SPTLC1, RAB7, WNK1/HSN2, FAM134B, NTRK1 (TRKA) and NGFB. We identified 25 index patients with mutations in six genes associated with HSAN (SPTLC1, RAB7, WNK1/HSN2, FAM134B, NTRK1 and NGFB); 20 of which appear to be pathogenic giving an overall mutation frequency of 14.3%. Mutations in the known genes for HSAN are rare suggesting that further HSAN genes are yet to be identified. The p.Cys133Trp mutation in SPTLC1 is the most common cause of HSAN in the UK population and should be screened first in all patients with sporadic or autosomal dominant HSAN. PMID:22302274

  5. MRI characteristics and scoring in HDLS due to CSF1R gene mutations

    PubMed Central

    Sundal, Christina; Van Gerpen, Jay A.; Nicholson, Alexandra M.; Wider, Christian; Shuster, Elizabeth A.; Aasly, Jan; Spina, Salvatore; Ghetti, Bernardino; Roeber, Sigrun; Garbern, James; Borjesson-Hanson, Anne; Tselis, Alex; Swerdlow, Russell H.; Miller, Bradley B.; Fujioka, Shinsuke; Heckman, Michael G.; Uitti, Ryan J.; Josephs, Keith A.; Baker, Matt; Andersen, Oluf; Rademakers, Rosa; Dickson, Dennis W.; Broderick, Daniel

    2012-01-01

    Objective: To describe the brain MRI characteristics of hereditary diffuse leukoencephalopathy with spheroids (HDLS) with known mutations in the colony-stimulating factor 1 receptor gene (CSF1R) on chromosome 5. Methods: We reviewed 20 brain MRI scans of 15 patients with autopsy- or biopsy-verified HDLS and CSF1R mutations. We assessed sagittal T1-, axial T1-, T2-, proton density-weighted and axial fluid-attenuated inversion recovery images for distribution of white matter lesions (WMLs), gray matter involvement, and atrophy. We calculated a severity score based on a point system (0−57) for each MRI scan. Results: Of the patients, 93% (14 of 15) demonstrated localized WMLs with deep and subcortical involvement, whereas one patient revealed generalized WMLs. All WMLs were bilateral but asymmetric and predominantly frontal. Fourteen patients had a rapidly progressive clinical course with an initial MRI mean total severity score of 16.7 points (range 10−33.5). Gray matter pathology and brainstem atrophy were absent, and the corticospinal tracts were involved late in the disease course. There was no enhancement, and there was minimal cerebellar pathology. Conclusion: Recognition of the typical MRI patterns of HDLS and the use of an MRI severity score might help during the diagnostic evaluation to characterize the natural history and to monitor potential future treatments. Indicators of rapid disease progression were symptomatic disease onset before 45 years, female sex, WMLs extending beyond the frontal regions, a MRI severity score greater than 15 points, and mutation type of deletion. PMID:22843259

  6. Preimplantation genetic diagnosis (embryo screening) for enlarged vestibular aqueduct due to SLC26A4 mutation.

    PubMed

    Wu, Chen-Chi; Lin, Shin-Yu; Su, Yi-Nin; Fang, Mei-Ya; Chen, Shee-Uan; Hsu, Chuan-Jen

    2010-01-01

    Preimplantation genetic diagnosis (PGD) is used to analyze embryos genetically before their transfer into the uterus. For families with genetic diseases, PGD offers a chance to have an unaffected child, without facing termination of pregnancy. Although PGD has been performed for many monogenic disorders, such as cystic fibrosis and beta-thalassemia, the application of PGD to hereditary hearing impairment has not been explored. In the present study, we reported the development and application of PGD protocols to address enlarged vestibular aqueduct (EVA), which is a common type of hereditary hearing impairment associated with mutations in the SLC26A4 gene. The family requesting PGD had a history of EVA, segregating the SLC26A4 c.919-2A-->G mutation. In short, the PGD process was composed of two steps: the development of a single-cell testing protocol and clinical PGD cycles (i.e., selection and implantation of unaffected embryos using the single-cell testing protocol). First, protocols for genetic testing in a single cell were established for the c.919-2A-->G mutation using GenomiPhi technology and primer extension mini-sequencing. These protocols were validated on single lymphocytes collected from both parents and their affected child. Two clinical PGD cycles were then performed for the parents, with the second cycle successfully leading to a singleton pregnancy. The baby was homozygous for the wild-type SLC26A4 allele and revealed a normal audiological phenotype after birth. To our knowledge, this is the first report in the literature describing successful PGD in families with genetic hearing impairment. In our opinion, the application of PGD in the field of hereditary hearing impairment involves fewer ethical controversies than other novel applications of PGD and traditional indications for PGD for other monogenic diseases. Therefore, the approach demonstrated in the present study can also be used in a large number of families with other types of hereditary

  7. DMD and BMD in the same family due to two distinct mutations

    SciTech Connect

    Morandi, L.; Mora, M.; Di Blasi, C.; Brugnoni, R.

    1995-12-04

    We report on a family with a boy affected by Duchenne muscular dystrophy (DMD) and an asymptomatic cousin with a Becker-type dystrophin abnormality, diagnosed by chance. Dystrophin gene analysis showed that these conditions were caused by two distinct deletions with breakpoints in different exons. In Xp21 families, DNA analysis and dystrophin testing of asymptomatic males with high CK plasma levels might detect different dystrophin mutations in separate haplotypes as in our family, although we stress there should be clear clinical or familial indications for such testing. 24 refs., 5 figs.

  8. Properties and Modeling of GWAS when Complex Disease Risk Is Due to Non-Complementing, Deleterious Mutations in Genes of Large Effect

    PubMed Central

    Thornton, Kevin R.; Foran, Andrew J.; Long, Anthony D.

    2013-01-01

    Current genome-wide association studies (GWAS) have high power to detect intermediate frequency SNPs making modest contributions to complex disease, but they are underpowered to detect rare alleles of large effect (RALE). This has led to speculation that the bulk of variation for most complex diseases is due to RALE. One concern with existing models of RALE is that they do not make explicit assumptions about the evolution of a phenotype and its molecular basis. Rather, much of the existing literature relies on arbitrary mapping of phenotypes onto genotypes obtained either from standard population-genetic simulation tools or from non-genetic models. We introduce a novel simulation of a 100-kilobase gene region, based on the standard definition of a gene, in which mutations are unconditionally deleterious, are continuously arising, have partially recessive and non-complementing effects on phenotype (analogous to what is widely observed for most Mendelian disorders), and are interspersed with neutral markers that can be genotyped. Genes evolving according to this model exhibit a characteristic GWAS signature consisting of an excess of marginally significant markers. Existing tests for an excess burden of rare alleles in cases have low power while a simple new statistic has high power to identify disease genes evolving under our model. The structure of linkage disequilibrium between causative mutations and significantly associated markers under our model differs fundamentally from that seen when rare causative markers are assumed to be neutral. Rather than tagging single haplotypes bearing a large number of rare causative alleles, we find that significant SNPs in a GWAS tend to tag single causative mutations of small effect relative to other mutations in the same gene. Our results emphasize the importance of evaluating the power to detect associations under models that are genetically and evolutionarily motivated. PMID:23437004

  9. Critical Diamond-Blackfan anemia due to ribosomal protein S19 missense mutation.

    PubMed

    Ozono, Shuichi; Mitsuo, Miho; Noguchi, Maiko; Nakagawa, Shin-Ichiro; Ueda, Koichiro; Inada, Hiroko; Ohga, Shouichi; Ito, Etsuro

    2016-09-01

    Diamond-Blackfan anemia (DBA) is a rare congenital disorder characterized by pure erythrocyte aplasia, and approximately 70% of patients carry mutations in the genes encoding ribosomal proteins (RP). Here, we report the case of a male infant with DBA who presented with anemic crisis (hemoglobin [Hb] concentration 1.5 g/dL) at 58 days after birth. On admission, the infant was pale and had tachypnea, but recovered with intensive care, including red blood cell transfusions, and prednisolone. Based on the clinical diagnosis of DBA, the father of the infant had cyclosporine-A-dependent anemia. On analysis of RP genes when the infant was 6 months old, both the infant and the father, but not the mother, were found to harbor a mutation of RPS19 (c.167G > C, p. R56P). Therefore, genetic background search and early neonatal health check-ups are recommended for families with a history of inherited bone marrow failure syndromes. PMID:27601194

  10. Critical Diamond-Blackfan anemia due to ribosomal protein S19 missense mutation.

    PubMed

    Ozono, Shuichi; Mitsuo, Miho; Noguchi, Maiko; Nakagawa, Shin-Ichiro; Ueda, Koichiro; Inada, Hiroko; Ohga, Shouichi; Ito, Etsuro

    2016-09-01

    Diamond-Blackfan anemia (DBA) is a rare congenital disorder characterized by pure erythrocyte aplasia, and approximately 70% of patients carry mutations in the genes encoding ribosomal proteins (RP). Here, we report the case of a male infant with DBA who presented with anemic crisis (hemoglobin [Hb] concentration 1.5 g/dL) at 58 days after birth. On admission, the infant was pale and had tachypnea, but recovered with intensive care, including red blood cell transfusions, and prednisolone. Based on the clinical diagnosis of DBA, the father of the infant had cyclosporine-A-dependent anemia. On analysis of RP genes when the infant was 6 months old, both the infant and the father, but not the mother, were found to harbor a mutation of RPS19 (c.167G > C, p. R56P). Therefore, genetic background search and early neonatal health check-ups are recommended for families with a history of inherited bone marrow failure syndromes.

  11. Gene mutation discovery research of non-smoking lung cancer patients due to indoor radon exposure.

    PubMed

    Choi, Jung Ran; Park, Seong Yong; Noh, O Kyu; Koh, Young Wha; Kang, Dae Ryong

    2016-01-01

    Although the incidence and mortality for most cancers such as lung and colon are decreasing in several countries, they are increasing in several developed countries because of an unhealthy western lifestyles including smoking, physical inactivity and consumption of calorie-dense food. The incidences for lung and colon cancers in a few of these countries have already exceeded those in the United States and other western countries. Among them, lung cancer is the main cause of cancer death in worldwide. The cumulative survival rate at five years differs between 13 and 21 % in several countries. Although the most important risk factors are smoking for lung cancer, however, the increased incidence of lung cancer in never smokers(LCINS) is necessary to improve knowledge concerning other risk factors. Environmental factors and genetic susceptibility are also thought to contribute to lung cancer risk. Patients with lung adenocarcinoma who have never smoking frequently contain mutation within tyrosine kinase domain of the epidermal growth factor receptor(EGFR) gene. Also, K-ras mutations are more common in individuals with a history of smoking use and are related with resistance to EFGR-tyrosine kinase inhibitors. Recently, radon(Rn), natural and noble gas, has been recognized as second common reason of lung cancer. In this review, we aim to know whether residential radon is associated with an increased risk for developing lung cancer and regulated by several genetic polymorphisms.

  12. Complexity of the Class B Phenotype in Autosomal Dominant Retinitis Pigmentosa Due to Rhodopsin Mutations

    PubMed Central

    Jacobson, Samuel G.; McGuigan, David B.; Sumaroka, Alexander; Roman, Alejandro J.; Gruzensky, Michaela L.; Sheplock, Rebecca; Palma, Judy; Schwartz, Sharon B.; Aleman, Tomas S.; Cideciyan, Artur V.

    2016-01-01

    Purpose Previously, patients with RHO mutations and a class A phenotype were found to have severe early-onset loss of rod function, whereas patients with a class B phenotype retained rod function at least in certain retinal regions. Here class B patients were studied at different disease stages to understand the topographic details of the phenotype in preparation for therapies of this regionalized retinopathy. Methods A cohort of patients with RHO mutations and class B phenotype (n = 28; ages 10–80 years) were studied with rod and cone perimetry and optical coherence tomography (OCT). Results At least three components of the phenotype were identified in these cross-sectional studies. Patients could have hemifield dysfunction, pericentral loss of function, or a diffuse rod sensitivity loss across the visual field. Combinations of these different patterns were also found. Colocalized photoreceptor layer thicknesses were in agreement with the psychophysical results. Conclusions These disorders with regional retinal variation of severity require pre-evaluations before enrollment into clinical trials to seek answers to questions about where in the retina would be appropriate to deliver focal treatments, and, for retina-wide treatment strategies, where in the retina should be monitored for therapeutic efficacy (or safety). PMID:27654411

  13. Gene mutation discovery research of non-smoking lung cancer patients due to indoor radon exposure.

    PubMed

    Choi, Jung Ran; Park, Seong Yong; Noh, O Kyu; Koh, Young Wha; Kang, Dae Ryong

    2016-01-01

    Although the incidence and mortality for most cancers such as lung and colon are decreasing in several countries, they are increasing in several developed countries because of an unhealthy western lifestyles including smoking, physical inactivity and consumption of calorie-dense food. The incidences for lung and colon cancers in a few of these countries have already exceeded those in the United States and other western countries. Among them, lung cancer is the main cause of cancer death in worldwide. The cumulative survival rate at five years differs between 13 and 21 % in several countries. Although the most important risk factors are smoking for lung cancer, however, the increased incidence of lung cancer in never smokers(LCINS) is necessary to improve knowledge concerning other risk factors. Environmental factors and genetic susceptibility are also thought to contribute to lung cancer risk. Patients with lung adenocarcinoma who have never smoking frequently contain mutation within tyrosine kinase domain of the epidermal growth factor receptor(EGFR) gene. Also, K-ras mutations are more common in individuals with a history of smoking use and are related with resistance to EFGR-tyrosine kinase inhibitors. Recently, radon(Rn), natural and noble gas, has been recognized as second common reason of lung cancer. In this review, we aim to know whether residential radon is associated with an increased risk for developing lung cancer and regulated by several genetic polymorphisms. PMID:26985396

  14. Double muscling in cattle due to mutations in the myostatin gene

    PubMed Central

    McPherron, Alexandra C.; Lee, Se-Jin

    1997-01-01

    Myostatin (GDF-8) is a member of the transforming growth factor β superfamily of secreted growth and differentiation factors that is essential for proper regulation of skeletal muscle mass in mice. Here we report the myostatin sequences of nine other vertebrate species and the identification of mutations in the coding sequence of bovine myostatin in two breeds of double-muscled cattle, Belgian Blue and Piedmontese, which are known to have an increase in muscle mass relative to conventional cattle. The Belgian Blue myostatin sequence contains an 11-nucleotide deletion in the third exon which causes a frameshift that eliminates virtually all of the mature, active region of the molecule. The Piedmontese myostatin sequence contains a missense mutation in exon 3, resulting in a substitution of tyrosine for an invariant cysteine in the mature region of the protein. The similarity in phenotypes of double-muscled cattle and myostatin null mice suggests that myostatin performs the same biological function in these two species and is a potentially useful target for genetic manipulation in other farm animals. PMID:9356471

  15. Origin of terminal voltage variations due to self-mixing in terahertz frequency quantum cascade lasers.

    PubMed

    Grier, Andrew; Dean, Paul; Valavanis, Alexander; Keeley, James; Kundu, Iman; Cooper, Jonathan D; Agnew, Gary; Taimre, Thomas; Lim, Yah Leng; Bertling, Karl; Rakić, Aleksandar D; Li, Lianhe H; Harrison, Paul; Linfield, Edmund H; Ikonić, Zoran; Davies, A Giles; Indjin, Dragan

    2016-09-19

    We explain the origin of voltage variations due to self-mixing in a terahertz (THz) frequency quantum cascade laser (QCL) using an extended density matrix (DM) approach. Our DM model allows calculation of both the current-voltage (I-V) and optical power characteristics of the QCL under optical feedback by changing the cavity loss, to which the gain of the active region is clamped. The variation of intra-cavity field strength necessary to achieve gain clamping, and the corresponding change in bias required to maintain a constant current density through the heterostructure is then calculated. Strong enhancement of the self-mixing voltage signal due to non-linearity of the (I-V) characteristics is predicted and confirmed experimentally in an exemplar 2.6 THz bound-to-continuum QCL.

  16. Origin of terminal voltage variations due to self-mixing in terahertz frequency quantum cascade lasers.

    PubMed

    Grier, Andrew; Dean, Paul; Valavanis, Alexander; Keeley, James; Kundu, Iman; Cooper, Jonathan D; Agnew, Gary; Taimre, Thomas; Lim, Yah Leng; Bertling, Karl; Rakić, Aleksandar D; Li, Lianhe H; Harrison, Paul; Linfield, Edmund H; Ikonić, Zoran; Davies, A Giles; Indjin, Dragan

    2016-09-19

    We explain the origin of voltage variations due to self-mixing in a terahertz (THz) frequency quantum cascade laser (QCL) using an extended density matrix (DM) approach. Our DM model allows calculation of both the current-voltage (I-V) and optical power characteristics of the QCL under optical feedback by changing the cavity loss, to which the gain of the active region is clamped. The variation of intra-cavity field strength necessary to achieve gain clamping, and the corresponding change in bias required to maintain a constant current density through the heterostructure is then calculated. Strong enhancement of the self-mixing voltage signal due to non-linearity of the (I-V) characteristics is predicted and confirmed experimentally in an exemplar 2.6 THz bound-to-continuum QCL. PMID:27661929

  17. [Portal-splenic-mesenteric venous thrombosis in a patients with protein S deficiency due to novel PROS1 gene mutation].

    PubMed

    Hwang, Eui Tae; Kang, Won Sik; Park, Jin Woo; Lee, Ji Hyun; Han, Hyun Jeong; Shin, Sang Yong; Kim, Hee Jin; Choi, Ja Sung

    2014-08-01

    Protein S (PS), a vitamin K-dependent glycoprotein, performs an important role in the anticoagulation cascade as a cofactor of protein C. Because of the presence of a pseudogene and two different forms of PS in the plasma, protein S deficiency (PSD) is one of the most difficult thrombophilias to study and a rare blood disorder associated with an increased risk of thrombosis. We describe a unusual case of previously healthy 37-year-old man diagnosed with portal-splenic-mesenteric vein thrombosis secondary to PSD. The patient was admitted to the hospital due to continuous nonspecific abdominal pain and nausea. Abdominal computed tomography revealed acute venous thrombosis from inferior mesenteric vein to left portal vein via splenic vein, and laboratory test revealed decreased PS antigen level and PS functional activity. Conventional polymerase chain reaction and direct DNA sequencing analysis of the PROS1 gene demonstrated duplication of the 166th base in exon 2 resulting in frame-shift mutation (p.Arg56Lysfs*10) which is the first description of the new PROS1 gene mutation to our knowledge. Results from other studies suggest that the inherited PSD due to a PROS1 gene mutation may cause venous thrombosis in a healthy young man without any known predisposing factor.

  18. Mitigation of impedance changes due to electroporation therapy using bursts of high-frequency bipolar pulses

    PubMed Central

    2015-01-01

    Background For electroporation-based therapies, accurate modeling of the electric field distribution within the target tissue is important for predicting the treatment volume. In response to conventional, unipolar pulses, the electrical impedance of a tissue varies as a function of the local electric field, leading to a redistribution of the field. These dynamic impedance changes, which depend on the tissue type and the applied electric field, need to be quantified a priori, making mathematical modeling complicated. Here, it is shown that the impedance changes during high-frequency, bipolar electroporation therapy are reduced, and the electric field distribution can be approximated using the analytical solution to Laplace's equation that is valid for a homogeneous medium of constant conductivity. Methods Two methods were used to examine the agreement between the analytical solution to Laplace's equation and the electric fields generated by 100 µs unipolar pulses and bursts of 1 µs bipolar pulses. First, pulses were applied to potato tuber tissue while an infrared camera was used to monitor the temperature distribution in real-time as a corollary to the electric field distribution. The analytical solution was overlaid on the thermal images for a qualitative assessment of the electric fields. Second, potato ablations were performed and the lesion size was measured along the x- and y-axes. These values were compared to the analytical solution to quantify its ability to predict treatment outcomes. To analyze the dynamic impedance changes due to electroporation at different frequencies, electrical impedance measurements (1 Hz to 1 MHz) were made before and after the treatment of potato tissue. Results For high-frequency bipolar burst treatment, the thermal images closely mirrored the constant electric field contours. The potato tissue lesions differed from the analytical solution by 39.7 ± 1.3 % (x-axis) and 6.87 ± 6.26 % (y-axis) for conventional unipolar pulses

  19. Incomplete activation of Escherichia coli hemolysin (HlyA) due to mutations in the 3' region of hlyC.

    PubMed Central

    Guzmán-Verri, C; García, F; Arvidson, S

    1997-01-01

    Mutational analysis of the carboxy-terminal region of Escherichia coli HlyC was performed by site-directed mutagenesis. Replacement of residue Val-127 or Lys-129 reduced the activity of HlyC to about 30 or 60%, respectively, of that of the wild type, while replacement of Gly-128 reduced the activity to less than 1% of the wild-type level. Complete inactivation of HlyC was caused by a double mutation, replacement of Gly-128 with valine and of Lys-129 with isoleucine. Analysis of culture supernatants from mutants with reduced hemolytic activity by two-dimensional gel electrophoresis revealed the production and simultaneous secretion of nonacylated, monoacylated, and fully acylated HlyA forms, demonstrating impairment of the acylation reaction, possibly due to a decreased affinity of HlyC for the individual HlyA acylation sites. PMID:9294460

  20. A new overgrowth syndrome is due to mutations in RNF125.

    PubMed

    Tenorio, Jair; Mansilla, Alicia; Valencia, María; Martínez-Glez, Víctor; Romanelli, Valeria; Arias, Pedro; Castrejón, Nerea; Poletta, Fernando; Guillén-Navarro, Encarna; Gordo, Gema; Mansilla, Elena; García-Santiago, Fé; González-Casado, Isabel; Vallespín, Elena; Palomares, María; Mori, María A; Santos-Simarro, Fernando; García-Miñaur, Sixto; Fernández, Luis; Mena, Rocío; Benito-Sanz, Sara; del Pozo, Ángela; Silla, Juan Carlos; Ibañez, Kristina; López-Granados, Eduardo; Martín-Trujillo, Alex; Montaner, David; Heath, Karen E; Campos-Barros, Ángel; Dopazo, Joaquín; Nevado, Julián; Monk, David; Ruiz-Pérez, Víctor L; Lapunzina, Pablo

    2014-12-01

    Overgrowth syndromes (OGS) are a group of disorders in which all parameters of growth and physical development are above the mean for age and sex. We evaluated a series of 270 families from the Spanish Overgrowth Syndrome Registry with no known OGS. We identified one de novo deletion and three missense mutations in RNF125 in six patients from four families with overgrowth, macrocephaly, intellectual disability, mild hydrocephaly, hypoglycemia, and inflammatory diseases resembling Sjögren syndrome. RNF125 encodes an E3 ubiquitin ligase and is a novel gene of OGS. Our studies of the RNF125 pathway point to upregulation of RIG-I-IPS1-MDA5 and/or disruption of the PI3K-AKT and interferon signaling pathways as the putative final effectors.

  1. Frequency and spectrum of mutations at codons 12 and 13 of the C-K-ras gene in human tumors

    SciTech Connect

    Capella, G.; Cronauer-Mitra, S.; Peinado, M.A.; Perucho, M. )

    1991-06-01

    The frequency of point mutations at codons 12 and 13 of the c-K-ras gene has been determined in a panel of more than 400 human tumors. Mutant c-K-ras genes were detected in about 75% of adenocarcinomas of the pancreas; 40% of adenomas and carcinomas of the colon and rectum; 30% of carcinomas of the bile duct; 25% of carcinomas of the lung, and in lower frequency in other carcinomas, including liver, stomach, and kidney. No mutations were found in carcinomas of the breast, prostate, esophagus, and gall bladder, among others. Comparative analysis of the spectrum of mutations show that while G to A transitions were the most frequent mutations in pancreatic and colo-rectal tumors, G to T transversions were more prevalent in lung carcinomas. The aspartic acid mutation at codon 13 (GGC {r arrow} GAC) was relatively frequent in colo-rectal tumors but rare in pancreatic and lung carcinomas. The differences in the mutation spectrum of the c-K-ras gene in cancers of the gastrointestinal and respiratory tracts are suggestive of differential exposure to genotoxic agents.

  2. The carrier frequency of the BRCA1 185delAG mutation is approximately 1 percent in Ashkenazi Jewish individuals.

    PubMed

    Struewing, J P; Abeliovich, D; Peretz, T; Avishai, N; Kaback, M M; Collins, F S; Brody, L C

    1995-10-01

    Since BRCA1, the first major gene responsible for inherited breast cancer, was cloned, more than 50 unique mutations have been detected in the germline of individuals with breast and ovarian cancer. In high-risk pedigrees, female carriers of BRCA1 mutations have an 80-90% lifetime risk of breast cancer, and a 40-50% risk of ovarian cancer. However, the mutation stats of individuals unselected for breast or ovarian cancer has not been determined, and it is not known whether mutations in such individuals confer the same risk of cancer as in individuals from the high-risk families studied so far. Following the finding of a 185delAG frameshift mutation in several Ashkenazi Jewish breast/ovarian families, we have determined the frequency of this mutation in 858 Ashkenazim seeking genetic testing for conditions unrelated to cancer, and in 815 reference individuals not selected for ethnic origin. We observed the 185delAG mutation in 0.9% of Ashkenazim (95% confidence limit, 0.4-1.8%) and in none of the reference samples. Our results suggest that one in a hundred women of Ashkenazi descent may be at especially high risk of developing breast and/or ovarian cancer.

  3. Inherited erythromelalgia due to mutations in SCN9A: natural history, clinical phenotype and somatosensory profile.

    PubMed

    McDonnell, Aoibhinn; Schulman, Betsy; Ali, Zahid; Dib-Hajj, Sulayman D; Brock, Fiona; Cobain, Sonia; Mainka, Tina; Vollert, Jan; Tarabar, Sanela; Waxman, Stephen G

    2016-04-01

    Inherited erythromelalgia, the first human pain syndrome linked to voltage-gated sodium channels, is widely regarded as a genetic model of human pain. Because inherited erythromelalgia was linked to gain-of-function changes of sodium channel Na(v)1.7 only a decade ago, the literature has mainly consisted of reports of genetic and/or clinical characterization of individual patients. This paper describes the pattern of pain, natural history, somatosensory profile, psychosocial status and olfactory testing of 13 subjects with primary inherited erythromelalgia with mutations of SCN9A, the gene encoding Na(v)1.7. Subjects were clinically profiled using questionnaires, quantitative sensory testing and olfaction testing during the in-clinic phase of the study. In addition, a detailed pain phenotype for each subject was obtained over a 3-month period at home using diaries, enabling subjects to self-report pain attacks, potential triggers, duration and severity of pain. All subjects reported pain and heat in the extremities (usually feet and/or hands), with pain attacks triggered by heat or exercise and relieved mainly by non-pharmacological manoeuvres such as cooling. A large proportion of pain attacks (355/1099; 32%) did not involve a specific trigger. There was considerable variability in the number, duration and severity of pain attacks between subjects, even those carrying the same mutation within a family, and within individuals over the 12-13 week observation period. Most subjects (11/13) had pain between attacks. For these subjects, mean pain severity between pain attacks was usually lower than that during an attack. Olfaction testing using the Sniffin'T test did not demonstrate hyperosmia. One subject had evidence of orthostatic hypotension. Overall, there was a statistically significant correlation between total Hospital Anxiety and Depression Scale scores (P= 0.005) and pain between attacks and for Hospital Anxiety and Depression Scale Depression scores and pain

  4. Measuring frequency changes due to microwave power variations as a function of C-field setting in a rubidium frequency standard

    NASA Technical Reports Server (NTRS)

    Sarosy, E. B.; Johnson, Walter A.; Karuza, Sarunas K.; Voit, Frank J.

    1992-01-01

    It has been shown in previous studies that in some cesium frequency standards there exist certain C-field settings that minimize frequency changes that are due to variations in the microwave power. In order to determine whether similar results could be obtained with rubidium (Rb) frequency standards (clocks), we performed a similar study, using a completely automated measurement system, on a commercial Rb standard. From our measurements we found that changing the microwave power to the filter cell resulted in significant changes in frequency, and that the magnitude of these frequency changes at low C-field levels went to zero and decreased as the C-field was increased.

  5. Hypermanganesemia with Dystonia, Polycythemia and Cirrhosis (HMDPC) due to mutation in the SLC30A10 gene.

    PubMed

    Mukhtiar, Khairunnisa; Ibrahim, Shahnaz; Tuschl, Karin; Mills, Phillipa

    2016-10-01

    Manganese (Mn) is an essential element for metabolic pathways but it can be toxic when present in excessive amounts in the body. Hypermanganesemia along with dystonia, polycythemia, characteristic MRI brain findings in the basal ganglia, and chronic liver disease are the hallmarks of an inherited Mn transporter defect due to mutations in the SLC30A10 gene. We are reporting three siblings who presented with features of dystonia, polycythemia, MRI brain showing basal ganglia hyperintensity on T1 weighted images and chronic liver disease. Blood Mn levels were markedly elevated in the affected patients. Mutation analysis of DNA samples of the affected children confirmed a homozygous missense mutation in SLC30A10. Chelation therapy with intravenous disodium calcium edetate was started in two siblings and led to a marked decrease in whole blood Mn. Oral Penicillamine was later added to the therapy which further improved blood Mn levels. This is a rare disorder and is one of the potentially treatable inherited metal storage disorders. It can be fatal if left untreated. Penicillamine may be an effective alternative to disodium calcium edetate.

  6. Biotinidase deficiency due to a de novo mutation or gonadal mosaicism in a first child.

    PubMed

    Tonin, Rodolfo; Caciotti, Anna; Funghini, Silvia; la Marca, Giancarlo; Pasquini, Elisabetta; Cayton, Erica; Mooney, Sean D; Guerrini, Renzo; Morrone, Amelia

    2015-05-20

    Biotinidase deficiency (BD), which is caused by BTD genetic lesions, if untreated, can result in neurological and cutaneous manifestations. Biotin supplementation can improve or prevent symptoms. We herewith present a family, which we studied at biochemical and molecular level, after identifying the proband through a newborn screening programme. BTD gene molecular analysis showed the proband to be compound heterozygous for the c.1330G>C p.(Asp444His) mild known variant, and for the c.1475 C>T p.(Thr492Ile) new variant. Bioinformatic analysis allowed us to confirm the pathogenic role of the newly identified variant. The proband's father, who exhibited low biotinidase (BTD) enzyme activity, was homozygous for the mild variant, whereas the proband's mother, who exhibited borderline BTD values, the BTD mutation carrier status could not be detected. This is the first description of a patient with BD harbouring a variant whose origin is either de novo or the consequence of gonadal mosaicism. BTD molecular analysis and bioinformatic tools for the evaluation of pathogenicity of newly identified variants are necessary for diagnostic purposes (i.e., clarifying borderline enzyme assays and the carrier status of parents), and for genetic counselling. PMID:25795614

  7. Translational approach to address therapy in myotonia permanens due to a new SCN4A mutation

    PubMed Central

    Carbonara, Roberta; D'Amico, Adele; Modoni, Anna; Roussel, Julien; Imbrici, Paola; Pagliarani, Serena; Lucchiari, Sabrina; Lo Monaco, Mauro; Conte Camerino, Diana

    2016-01-01

    Objective: We performed a clinical, functional, and pharmacologic characterization of the novel p.P1158L Nav1.4 mutation identified in a young girl presenting a severe myotonic phenotype. Methods: Wild-type hNav1.4 channel and P1158L mutant were expressed in tsA201 cells for functional and pharmacologic studies using patch-clamp. Results: The patient shows pronounced myotonia, slowness of movements, and generalized muscle hypertrophy. Because of general discomfort with mexiletine, she was given flecainide with satisfactory response. In vitro, mutant channels show a slower current decay and a rightward shift of the voltage dependence of fast inactivation. The voltage dependence of activation and slow inactivation were not altered. Mutant channels were less sensitive to mexiletine, whereas sensitivity to flecainide was not altered. The reduced inhibition of mutant channels by mexiletine was also observed using clinically relevant drug concentrations in a myotonic-like condition. Conclusions: Clinical phenotype and functional alterations of P1158L support the diagnosis of myotonia permanens. Impairment of fast inactivation is consistent with the possible role of the channel domain III S4-S5 loop in the inactivation gate docking site. The reduced sensitivity of P1158L to mexiletine may have contributed to the unsatisfactory response of the patient. The success of flecainide therapy underscores the usefulness of in vitro functional studies to help in the choice of the best drug for each individual. PMID:27164696

  8. Strong Meissner screening change in superconducting radio frequency cavities due to mild baking

    SciTech Connect

    Romanenko, A. Grassellino, A.; Barkov, F.; Suter, A.; Salman, Z.; Prokscha, T.

    2014-02-17

    We investigate “hot” regions with anomalous high field dissipation in bulk niobium superconducting radio frequency cavities for particle accelerators by using low energy muon spin rotation (LE-μSR) on corresponding cavity cutouts. We demonstrate that superconducting properties at the hot region are well described by the non-local Pippard/BCS model for niobium in the clean limit with a London penetration depth λ{sub L}=23±2 nm. In contrast, a cutout sample from the 120 ∘C baked cavity shows a much larger λ>100 nm and a depth dependent mean free path, likely due to gradient in vacancy concentration. We suggest that these vacancies can efficiently trap hydrogen and hence prevent the formation of hydrides responsible for rf losses in hot regions.

  9. Decoherence of coupled Josephson charge qubits due to partially correlated low-frequency noise

    SciTech Connect

    Hu, Yong; Zhou, Zheng-Wei; Cai, Jian-Ming; Guo, Guang-Can

    2007-05-15

    Josephson charge qubits are promising candidates for scalable quantum computing. However, their performances are strongly degraded by decoherence due to low-frequency background noise, typically with a 1/f spectrum. In this paper, we investigate the decoherence process of two Cooper pair boxes (CPBs) coupled via a capacitor. Going beyond the common and uncorrelated noise models and the Bloch-Redfield formalism of previous works, we study the coupled system's quadratic dephasing under the condition of partially correlated noise sources. Based on reported experiments and generally accepted noise mechanisms, we introduce a reasonable assumption for the noise correlation, with which the calculation of multiqubit decoherence can be simplified to a problem on the single-qubit level. For the conventional Gaussian 1/f noise case, our results demonstrate that the quadratic dephasing rates are not very sensitive to the spatial correlation of the noises. Furthermore, we discuss the feasibility and efficiency of dynamical decoupling in the coupled CPBs.

  10. Colon cancer metastasis in mouse liver is not affected by hypercoagulability due to Factor V Leiden mutation

    PubMed Central

    Klerk, CPW; Smorenburg, SM; Spek, CA; Van Noorden, CJF

    2007-01-01

    Abstract Clinical trials have shown life-prolonging effects of antithrombotics in cancer patients, but the molecular mechanisms remain unknown due to the multitude of their effects. We investigated in a mouse model whether one of the targets of antithrombotic therapy, fibrin deposition, stimulates tumour development. Fibrin may provide either protection of cancer cells in the circulation against mechanical stress and the immune system, or form a matrix for tumours and/or angiogenesis in tumours to develop. Mice homozygous for Factor V Leiden (FVL), a mutation in one of the coagulation factors that facilitates fibrin formation, were used to investigate whether hypercoagulability affects tumour development in an experimental metastasis model. Liver metastases of colon cancer were induced in mice with the FVL mutation and wild-type littermates. At day 21, number and size of tumours at the liver surface, fibrin/fibrinogen distribution, vessel density and the presence of newly formed vessels in tumours were analysed. Number and size of tumours did not differ between mice with and without the FVL mutation. Fibrin/fibrinogen was found in the cytoplasm of hepatocytes and cancer cells, in blood vessels in liver and tumour tissue and diffusely distributed outside vessels in tumours, indicating leaky vessels. Vessel density and angiogenesis varied widely between tumours, but a pre-dominance for vessel-rich or vessel-poor tumours or vessel formation could not be found in either genotype. In conclusion, the FVL mutation has no effect on the development of secondary tumours of colon cancer in livers of mice. Fibrin deposition and thus inhibition of fibrin formation by anticoagulants do not seem to affect tumour development in this model. PMID:17635646

  11. ANTIMUTAGENIC EFFECT OF CINNEMALDEHYDE DUE TO INHIBITION OF MUTATIONS AT GC SITES BUT NOT AT SITES IN SALMONELLA TA104

    EPA Science Inventory

    Vanillin and cinnemaldehyde are dietary antimutagens that reduce the spontaneous mutant frequency in Salmonella strain TA104 (hisG428, rfa, duvrB, pKM101) by 50%. To date, no study has ever demonstrated whether the antimutagenic effect of an agent is due to a reduction in all cla...

  12. An epidemiological investigation of a Forkhead box protein E3 founder mutation underlying the high frequency of sclerocornea, aphakia, and microphthalmia in a Mexican village

    PubMed Central

    Pantoja-Melendez, Carlos; Ali, Manir

    2013-01-01

    Purpose To investigate the molecular epidemiological basis for the unusually high incidence of sclerocornea, aphakia, and microphthalmia in a village in the Tlaxcala province of central Mexico. Methods A population census was performed in a village to identify all sclerocornea, aphakia, and microphthalmia cases. Molecular analysis of the previously identified Forkhead box protein E3 (FOXE3) mutation, c.292T>C (p.Y98H), was performed with PCR amplification and direct DNA sequencing. In addition, DNA from 405 randomly selected unaffected villagers was analyzed to establish the carrier frequency of the causal mutation. To identify the number of generations since the mutation arose in the village, 17 polymorphic markers distributed in a region of 6 Mb around the mutated locus were genotyped in the affected individuals, followed by DMLE software analysis to calculate mutation age. Results A total of 22 patients with sclerocornea, aphakia, and microphthalmia were identified in the village, rendering a disease prevalence of 2.52 cases per 1,000 habitants (1 in 397). The FOXE3 homozygous mutation was identified in all 17 affected subjects who consented to molecular analysis. Haplotype analysis indicated that the mutation arose 5.0–6.5 generations ago (approximately 106–138 years). Among the 405 unaffected villagers who were genotyped, ten heterozygote carriers were identified, yielding a population carrier frequency of approximately 1 in 40 and a predicted incidence of affected of 1 in 6,400 based on random marriages between two carriers in the village. Conclusions This study demonstrates that a cluster of patients with sclerocornea, aphakia, and microphthalmia in a small Mexican village is due to a FOXE3 p.Y98H founder mutation that arose in the village just over a century ago at a time when a population migrated from a nearby village because of land disputes. The actual disease incidence is higher than the calculated predicted value and suggests non-random marriages

  13. Hypogonadotropic hypogonadism due to GnRH receptor mutation in a sibling.

    PubMed

    Fichna, Piotr; Fichna, Marta; Zurawek, Magdalena; Nowak, Jerzy

    2011-01-01

    Hypogonadotropic hypogonadism (HH) is characterised by delayed puberty and infertility. Congenital HH comprises Kallmann syndrome with hypo-/anosmia and idiopathic HH (IHH). The genetic origin remains unknown in most cases, but the defective GnRH receptor gene (GNRHR) accounts for a considerable proportion of IHH. Here we describe a pair of siblings diagnosed with IHH. Aged 17 years, the boy was referred because of short stature (162 cm) and overweight (62.5 kg). He presented no signs of puberty, bone age of 14.5 years and insulin resistance. His sister, aged 16 years, also displayed delayed puberty. She was 166 cm tall and weighed 52 kg; her bone age was 12.5 years. Pelvic ultrasonography showed an infantile uterus and fibrous ovaries. In both siblings, serum gonadotropins were extremely low, and non-responsive to GnRH. Testosterone (1.38 nmol/l) and IGF1 (273 ng/ml) were decreased in the boy, although the girl did not present IFG1 deficiency. Her serum oestradiol was 10 pg/ml. MRIs of the hypothalamo-pituitary region and olfactory bulbs revealed them to be normal. The patients' sense of smell was unaltered. Their parents appeared to be first degree cousins. Considering the clinical data and potentially autosomal recessive HH transmission, the GNRHR gene was screened. The siblings turned out to be homozygous for the G416A transition, which had previously been identified in other HH individuals. The parents were heterozygous mutation carriers. The proband, moderately responding to LH, was started on low dose testosterone replacement, and his sister on transdermal oestradiol. Molecular data indicative of GnRH resistance could guide their future therapy should they desire fertility restoration. Further observations of the male patient may provide insights into androgen's influence on body mass, growth and insulin sensitivity. PMID:21717411

  14. Audibility, speech perception and processing of temporal cues in ribbon synaptic disorders due to OTOF mutations.

    PubMed

    Santarelli, Rosamaria; del Castillo, Ignacio; Cama, Elona; Scimemi, Pietro; Starr, Arnold

    2015-12-01

    Mutations in the OTOF gene encoding otoferlin result in a disrupted function of the ribbon synapses with impairment of the multivesicular glutamate release. Most affected subjects present with congenital hearing loss and abnormal auditory brainstem potentials associated with preserved cochlear hair cell activities (otoacoustic emissions, cochlear microphonics [CMs]). Transtympanic electrocochleography (ECochG) has recently been proposed for defining the details of potentials arising in both the cochlea and auditory nerve in this disorder, and with a view to shedding light on the pathophysiological mechanisms underlying auditory dysfunction. We review the audiological and electrophysiological findings in children with congenital profound deafness carrying two mutant alleles of the OTOF gene. We show that cochlear microphonic (CM) amplitude and summating potential (SP) amplitude and latency are normal, consistently with a preserved outer and inner hair cell function. In the majority of OTOF children, the SP component is followed by a markedly prolonged low-amplitude negative potential replacing the compound action potential (CAP) recorded in normally-hearing children. This potential is identified at intensities as low as 90 dB below the behavioral threshold. In some ears, a synchronized CAP is superimposed on the prolonged responses at high intensity. Stimulation at high rates reduces the amplitude and duration of the prolonged potentials, consistently with their neural generation. In some children, however, the ECochG response only consists of the SP, with no prolonged potential. Cochlear implants restore hearing sensitivity, speech perception and neural CAP by electrically stimulating the auditory nerve fibers. These findings indicate that an impaired multivesicular glutamate release in OTOF-related disorders leads to abnormal auditory nerve fiber activation and a consequent impairment of spike generation. The magnitude of these effects seems to vary, ranging from

  15. Autosomal recessive cerebellar ataxia of adult onset due to STUB1 mutations.

    PubMed

    Depondt, Chantal; Donatello, Simona; Simonis, Nicolas; Rai, Myriam; van Heurck, Roxane; Abramowicz, Marc; D'Hooghe, Marc; Pandolfo, Massimo

    2014-05-13

    Autosomal recessive ataxias affect about 1 person in 20,000. Friedreich ataxia accounts for one-third of the cases in Caucasians; the others are due to a growing list of very rare molecular defects, including mild forms of metabolic diseases. In nearly 50%, the genetic cause remains undetermined.

  16. Population structure, antimicrobial resistance, and mutation frequencies of Streptococcus pneumoniae isolates from cystic fibrosis patients.

    PubMed

    del Campo, Rosa; Morosini, María-Isabel; de la Pedrosa, Elia Gómez-G; Fenoll, Asunción; Muñoz-Almagro, Carmen; Máiz, Luis; Baquero, Fernando; Cantón, Rafael

    2005-05-01

    Forty-eight Streptococcus pneumoniae isolates recovered from sputum samples from 26 cystic fibrosis (CF) patients attending our CF unit (1995 to 2003) were studied. Mean yearly incidence of isolation was 5.5%, and all were strains recovered from young patients (< or = 12 years). The isolation was linked to clinical exacerbation in 35% of the cases, but only 27% of these were not accompanied by other CF pathogens. Fifty percent of the patients presented with two to four isolates over the studied period. Pulsed-field gel electrophoresis-SmaI digestion revealed a high heterogeneity (32 pulsotypes among 48 isolates) and the persistence over a 6-month period of a single clone (clone A) in two patients. This clone, presenting a varied multiresistance phenotype, was identified as the Spain23F-1 clone and was also recognized in six other patients, including two out of nine patients from the CF unit of Sant Joan de Deu Hospital, Barcelona, Spain. In our isolates, 16 different serotypes were recognized, the most frequent being 23F (33.3%), 19F (18.8%), 6A (6.2%), and 6B (6.2%). High overall resistance rates were observed: to penicillin, 73%; to cefotaxime, 33%; to erythromycin, 42%; to tetracycline, 58%; to chloramphenicol, 48%; and to trimethoprim-sulfamethoxazole, 67%. Resistance to fluoroquinolones was not detected. Multiresistance was a common feature (60%). The percentage of S. pneumoniae strains with increased frequencies of mutation to rifampin resistance (> or = 7.5 x 10(-8)) was significantly higher (P = 0.02) in CF (60%) than among non-CF (37%) isolates in the same institution (M. I. Morosini et al., Antimicrob. Agents Chemother. 47:1464-1467, 2003). Even though a clear association with acute exacerbations could not be observed, long-term clonal persistence and variability, high frequency of antibiotic resistance, and hypermutability indicate the plasticity for adaptation of S. pneumoniae to the CF lung environment. PMID:15872243

  17. Population Structure, Antimicrobial Resistance, and Mutation Frequencies of Streptococcus pneumoniae Isolates from Cystic Fibrosis Patients

    PubMed Central

    del Campo, Rosa; Morosini, María-Isabel; de la Pedrosa, Elia Gómez-G.; Fenoll, Asunción; Muñoz-Almagro, Carmen; Máiz, Luis; Baquero, Fernando; Cantón, Rafael

    2005-01-01

    Forty-eight Streptococcus pneumoniae isolates recovered from sputum samples from 26 cystic fibrosis (CF) patients attending our CF unit (1995 to 2003) were studied. Mean yearly incidence of isolation was 5.5%, and all were strains recovered from young patients (≤12 years). The isolation was linked to clinical exacerbation in 35% of the cases, but only 27% of these were not accompanied by other CF pathogens. Fifty percent of the patients presented with two to four isolates over the studied period. Pulsed-field gel electrophoresis-SmaI digestion revealed a high heterogeneity (32 pulsotypes among 48 isolates) and the persistence over a 6-month period of a single clone (clone A) in two patients. This clone, presenting a varied multiresistance phenotype, was identified as the Spain23F-1 clone and was also recognized in six other patients, including two out of nine patients from the CF unit of Sant Joan de Dèu Hospital, Barcelona, Spain. In our isolates, 16 different serotypes were recognized, the most frequent being 23F (33.3%), 19F (18.8%), 6A (6.2%), and 6B (6.2%). High overall resistance rates were observed: to penicillin, 73%; to cefotaxime, 33%; to erythromycin, 42%; to tetracycline, 58%; to chloramphenicol, 48%; and to trimethoprim-sulfamethoxazole, 67%. Resistance to fluoroquinolones was not detected. Multiresistance was a common feature (60%). The percentage of S. pneumoniae strains with increased frequencies of mutation to rifampin resistance (≥7.5 × 10−8) was significantly higher (P = 0.02) in CF (60%) than among non-CF (37%) isolates in the same institution (M. I. Morosini et al., Antimicrob. Agents Chemother. 47:1464-1467, 2003). Even though a clear association with acute exacerbations could not be observed, long-term clonal persistence and variability, high frequency of antibiotic resistance, and hypermutability indicate the plasticity for adaptation of S. pneumoniae to the CF lung environment. PMID:15872243

  18. Different mosaicism frequencies for proximal and distal Duchenne muscular dystrophy (DMD) mutations indicate difference in etiology and recurrence risk

    SciTech Connect

    Passos-Bueno, M.R.; Takata, R.I.; Rapaport, D.; Bakker, E.; Kneppers, A.L.J.; Dunnen, J.T. den; Ommen, J.B. van

    1992-11-01

    In about 65% of the cases of Duchenne muscular dystrophy (DMD) a partial gene deletion or duplication in the dystrophin gene can be detected. These mutations are clustered at two hot spots: 30% at the hot spot in the proximal part of the gene and about 70% at a more distal hot spot. Unexpectedly the authors observed a higher frequency of proximal gene rearrangements among proved germ line' mosaic cases. Of the 24 mosaic cases they are aware of, 19 (79%) have a proximal mutation, while only 5 (21%) have a distal mutation. This finding indicates that the mutations at the two hot spots in the dystrophin gene differ in origin. Independent support for the different mosaicism frequency was found by comparing the mutation spectra observed in isolated cases of DMD and familial cases (ratio 1:1). The authors conclude from these data that proximal deletions most likely occur early in embryonic development, causing them to have a higher chance of becoming familial, while distal deletions occur later and have a higher chance of causing only isolated cases. Finally, the findings have important consequences for the calculation of recurrence-risk estimates according to the site of the deletion: a [open quote]proximal[close quote] new mutant has an increased recurrence risk of approximately 30%, and a [open quote]distal[close quote] new mutant has a decreased recurrence risk of approximately 4%. 28 refs., 2 figs., 2 tabs.

  19. An animal model of type A cystinuria due to spontaneous mutation in 129S2/SvPasCrl mice.

    PubMed

    Livrozet, Marine; Vandermeersch, Sophie; Mesnard, Laurent; Thioulouse, Elizabeth; Jaubert, Jean; Boffa, Jean-Jacques; Haymann, Jean-Philippe; Baud, Laurent; Bazin, Dominique; Daudon, Michel; Letavernier, Emmanuel

    2014-01-01

    Cystinuria is an autosomal recessive disease caused by the mutation of either SLC3A1 gene encoding for rBAT (type A cystinuria) or SLC7A9 gene encoding for b0,+AT (type B cystinuria). Here, we evidenced in a commonly used congenic 129S2/SvPasCrl mouse substrain a dramatically high frequency of kidney stones that were similar to those of patients with cystinuria. Most of 129S2/SvPasCrl exhibited pathognomonic cystine crystals in urine and an aminoaciduria profile similar to that of patients with cystinuria. In addition, we observed a heterogeneous inflammatory infiltrate and cystine tubular casts in the kidney of cystinuric mice. As compared to another classical mouse strain, C57BL/6J mice, 129S2/SvPasCrl mice had an increased mortality associated with bilateral obstructive hydronephrosis. In 129S2/SvPasCrl mice, the heavy subunit rBAT of the tetrameric transporter of dibasic amino acids was absent in proximal tubules and we identified a single pathogenic mutation in a highly conserved region of the Slc3a1 gene. This novel mouse model mimicking human disease would allow us further pathophysiological studies and may be useful to analyse the crystal/tissue interactions in cystinuria. PMID:25048459

  20. Frequency and phenotype of patients carrying TPM2 and TPM3 gene mutations in a cohort of 94 patients with congenital myopathy.

    PubMed

    Citirak, Gülsenay; Witting, Nanna; Duno, Morten; Werlauff, Ulla; Petri, Helle; Vissing, John

    2014-04-01

    Congenital myopathies are difficult to classify correctly through molecular testing due to the size and heterogeneity of the genes involved. Therefore, the prevalence of the various genetic causes of congenital myopathies is largely unknown. In our cohort of 94 patients with congenital myopathy, two related female patients and two sporadic, male patients were found to carry mutations in the tropomyosin 2 (TPM2) and tropomyosin 3 (TPM3) genes, respectively. This indicates a low (4.3%) frequency of TPM2 and TPM3 mutations as a cause of congenital myopathy. Compared to previously described patients carrying the same mutations as found in our study (c.503G>A, and c.502C>T in TPM3, and c.415_417delGAG in TPM2), clinical presentation and muscle morphological findings differed in our patients. Differences included variation in distribution of muscle weakness, presence of scoliosis and ptosis, physical performance and joint contractures. The variation in clinical profiles emphasizes the phenotypic heterogeneity. However, common features were also present, such as onset of symptoms in infancy or childhood, musculoskeletal deformities and normal or low plasma levels of creatine kinase. One patient had nemaline myopathy and fiber size disproportion, while three patients had congenital fiber type disproportion (CFTD) on muscle biopsies. TPM2-related CFTD has only been described in two cases, indicating that mutations in TPM2 are rare causes of CFTD. PMID:24507666

  1. Type and frequency of IDH1 and IDH2 mutations are related to astrocytic and oligodendroglial differentiation and age: a study of 1,010 diffuse gliomas.

    PubMed

    Hartmann, Christian; Meyer, Jochen; Balss, Jörg; Capper, David; Mueller, Wolf; Christians, Arne; Felsberg, Jörg; Wolter, Marietta; Mawrin, Christian; Wick, Wolfgang; Weller, Michael; Herold-Mende, Christel; Unterberg, Andreas; Jeuken, Judith W M; Wesseling, Peter; Reifenberger, Guido; von Deimling, Andreas

    2009-10-01

    Somatic mutations in the IDH1 gene encoding cytosolic NADP+-dependent isocitrate dehydrogenase have been shown in the majority of astrocytomas, oligodendrogliomas and oligoastrocytomas of WHO grades II and III. IDH2 encoding mitochondrial NADP+-dependent isocitrate dehydrogenase is also mutated in these tumors, albeit at much lower frequencies. Preliminary data suggest an importance of IDH1 mutation for prognosis showing that patients with anaplastic astrocytomas, oligodendrogliomas and oligoastrocytomas harboring IDH1 mutations seem to fare much better than patients without this mutation in their tumors. To determine mutation types and their frequencies, we examined 1,010 diffuse gliomas. We detected 716 IDH1 mutations and 31 IDH2 mutations. We found 165 IDH1 (72.7%) and 2 IDH2 mutations (0.9%) in 227 diffuse astrocytomas WHO grade II, 146 IDH1 (64.0%) and 2 IDH2 mutations (0.9%) in 228 anaplastic astrocytomas WHO grade III, 105 IDH1 (82.0%) and 6 IDH2 mutations (4.7%) in 128 oligodendrogliomas WHO grade II, 121 IDH1 (69.5%) and 9 IDH2 mutations (5.2%) in 174 anaplastic oligodendrogliomas WHO grade III, 62 IDH1 (81.6%) and 1 IDH2 mutations (1.3%) in 76 oligoastrocytomas WHO grade II and 117 IDH1 (66.1%) and 11 IDH2 mutations (6.2%) in 177 anaplastic oligoastrocytomas WHO grade III. We report on an inverse association of IDH1 and IDH2 mutations in these gliomas and a non-random distribution of the mutation types within the tumor entities. IDH1 mutations of the R132C type are strongly associated with astrocytoma, while IDH2 mutations predominantly occur in oligodendroglial tumors. In addition, patients with anaplastic glioma harboring IDH1 mutations were on average 6 years younger than those without these alterations.

  2. Isolated trisomy 13 defines a homogeneous AML subgroup with high frequency of mutations in spliceosome genes and poor prognosis.

    PubMed

    Herold, Tobias; Metzeler, Klaus H; Vosberg, Sebastian; Hartmann, Luise; Röllig, Christoph; Stölzel, Friedrich; Schneider, Stephanie; Hubmann, Max; Zellmeier, Evelyn; Ksienzyk, Bianka; Jurinovic, Vindi; Pasalic, Zlatana; Kakadia, Purvi M; Dufour, Annika; Graf, Alexander; Krebs, Stefan; Blum, Helmut; Sauerland, Maria Cristina; Büchner, Thomas; Berdel, Wolfgang E; Woermann, Bernhard J; Bornhäuser, Martin; Ehninger, Gerhard; Mansmann, Ulrich; Hiddemann, Wolfgang; Bohlander, Stefan K; Spiekermann, Karsten; Greif, Philipp A

    2014-08-21

    In acute myeloid leukemia (AML), isolated trisomy 13 (AML+13) is a rare chromosomal abnormality whose prognostic relevance is poorly characterized. We analyzed the clinical course of 34 AML+13 patients enrolled in the German AMLCG-1999 and SAL trials and performed exome sequencing, targeted candidate gene sequencing and gene expression profiling. Relapse-free (RFS) and overall survival (OS) of AML+13 patients were inferior compared to other ELN Intermediate-II patients (n=855) (median RFS, 7.8 vs 14.1 months, P = .006; median OS 9.3 vs. 14.8 months, P = .004). Besides the known high frequency of RUNX1 mutations (75%), we identified mutations in spliceosome components in 88%, including SRSF2 codon 95 mutations in 81%. Recurring mutations were detected in ASXL1 (44%) and BCOR (25%). Two patients carried mutations in CEBPZ, suggesting that CEBPZ is a novel recurrently mutated gene in AML. Gene expression analysis revealed a homogeneous expression profile including upregulation of FOXO1 and FLT3 and downregulation of SPRY2. This is the most comprehensive clinical and biological characterization of AML+13 to date, and reveals a striking clustering of lesions in a few genes, defining AML+13 as a genetically homogeneous subgroup with alterations in a few critical cellular pathways. Clinicaltrials.gov identifiers: AMLCG-1999: NCT00266136; AML96: NCT00180115; AML2003: NCT00180102; and AML60+: NCT00893373. PMID:24923295

  3. Regulatory T Cell Deficiency and Immune dysregulation, Polyendocrinopathy, Enteropathy, X-Linked-Like Disorder Due to Loss of Function Mutations in LRBA

    PubMed Central

    Charbonnier, Louis-Marie; Janssen, Erin; Chou, Janet; Ohsumi, Toshiro K.; Keles, Sevgi; Hsu, Joyce T.; Massaad, Michel J.; Garcia-Lloret, Maria; Hanna-Wakim, Rima; Dbaibo, Ghassan; Alangari, Abdullah A.; Alsultan, Abdulrahman; Al-Zahrani, Daifulah; Geha, Raif S.; Chatila, Talal A.

    2014-01-01

    Background A number of heritable immune dysregulatory diseases result from defects affecting T regulatory (TR) cell development and/or function. They include Immune dysregulation, Polyendocrinopathy, Enteropathy, X-Linked (IPEX), due to mutations in FOXP3, and IPEX-like disorders caused by mutations in IL2RA, STAT5b and STAT1. However, the genetic defects underlying many cases of IPEX-like disorders remain unknown. Objective We sought to identify the genetic abnormalities in subjects with idiopathic IPEX-like disorders. Methods We performed whole exome and targeted gene sequencing, and phenotypic and functional analyses of TR cells. Results A child who presented with an IPEX-like syndrome and severe TR cell deficiency was found to harbor a nonsense mutation in the gene encoding LPS-responsive beige-like anchor (LRBA), previously implicated as cause of common variable immunodeficiency with autoimmunity. Analysis of subjects with LRBA deficiency revealed marked TR cell depletion, profoundly decreased expression of canonical TR cell markers, including FOXP3, CD25, Helios, and CTLA4 and impaired TR cell-mediated suppression. There was skewing in favor of memory T cells and intense autoantibody production with marked expansion of T follicular helper and contraction of T follicular regulatory cells. Whereas the frequency of recent thymic emigrants and the differentiation of induced TR cells were normal, LRBA-deficient T cells exhibited increased apoptosis and reduced activities of the metabolic sensors mammalian target of rapamycin 1 and 2 complexes. Conclusion LRBA deficiency is a novel cause of IPEX-like syndrome and TR cell deficiency associated with metabolic dysfunction and increased apoptosis of TR cells. PMID:25468195

  4. Yearly variation of spontaneous somatic mutation frequency in the stamen hairs of Tradescantia clone KU 9 grown outdoors, which showed a significant increase after the Chernobyl accident.

    PubMed

    Ichikawa, S; Nakano, A; Kenmochi, M; Yamamoto, I; Murai, M; Takahashi, E; Yamaguchi, A; Watanabe, K; Tomiyama, M; Sugiyama, K; Yogo, A; Yazaki, T; Okumura, M; Shima, N; Satoh, M; Yoshimoto, M; Xiao, L Z

    1996-02-01

    Scoring of spontaneous somatic pink mutation frequency in the stamen hairs of Tradescantia clone KU 9, a heterozygote for flower color (blue/pink; the blue color being dominant), was carried out for 11 years on plants grown outdoors, during the period of May 11-31 (for 3 weeks) in every year from 1982 to 1992. Weekly and yearly variations of the spontaneous mutation frequency were observed, and such variations could mostly be correlated to the difference in temperature. That is, the mutation frequency was generally higher in the weeks and years when the temperature was relatively low, showing the strongest negative correlation with the average minimum temperature. The variations were also correlated to the diurnal temperature difference, the mutation frequency being higher with larger diurnal temperature difference in general. However, the mutation frequency observed in 1986 was exceptionally higher than that expected from the temperature for this year, and was very significantly higher than for other years. The scoring of mutation frequency was thus continued in 1986 for an additional 4 weeks (June 1-28), and it was confirmed that such higher mutation frequencies lasted for 6 weeks in total. The exceptionally high mutation frequency seemed to be related to the radioactive fallout which occurred in early to mid May of 1986, even in Japan, after the serious nuclear reactor accident at Chernobyl, and also to the biological concentrations of radioactive nuclides which subsequently occurred, although it was difficult to conclude this definitely. The mutation frequency in 1987 was second highest, and was also significantly higher than the lowest mutation frequency observed in 1990. PMID:8600356

  5. Yearly variation of spontaneous somatic mutation frequency in the stamen hairs of Tradescantia clone KU 9 grown outdoors, which showed a significant increase after the Chernobyl accident.

    PubMed

    Ichikawa, S; Nakano, A; Kenmochi, M; Yamamoto, I; Murai, M; Takahashi, E; Yamaguchi, A; Watanabe, K; Tomiyama, M; Sugiyama, K; Yogo, A; Yazaki, T; Okumura, M; Shima, N; Satoh, M; Yoshimoto, M; Xiao, L Z

    1996-02-01

    Scoring of spontaneous somatic pink mutation frequency in the stamen hairs of Tradescantia clone KU 9, a heterozygote for flower color (blue/pink; the blue color being dominant), was carried out for 11 years on plants grown outdoors, during the period of May 11-31 (for 3 weeks) in every year from 1982 to 1992. Weekly and yearly variations of the spontaneous mutation frequency were observed, and such variations could mostly be correlated to the difference in temperature. That is, the mutation frequency was generally higher in the weeks and years when the temperature was relatively low, showing the strongest negative correlation with the average minimum temperature. The variations were also correlated to the diurnal temperature difference, the mutation frequency being higher with larger diurnal temperature difference in general. However, the mutation frequency observed in 1986 was exceptionally higher than that expected from the temperature for this year, and was very significantly higher than for other years. The scoring of mutation frequency was thus continued in 1986 for an additional 4 weeks (June 1-28), and it was confirmed that such higher mutation frequencies lasted for 6 weeks in total. The exceptionally high mutation frequency seemed to be related to the radioactive fallout which occurred in early to mid May of 1986, even in Japan, after the serious nuclear reactor accident at Chernobyl, and also to the biological concentrations of radioactive nuclides which subsequently occurred, although it was difficult to conclude this definitely. The mutation frequency in 1987 was second highest, and was also significantly higher than the lowest mutation frequency observed in 1990.

  6. Frequency of the 677 C-->T mutation of the methylenetetrahydrofolate reductase gene among Kuwaiti sickle cell disease patients.

    PubMed

    Adekile, A D; Kutlar, F; Haider, M Z; Kutlar, A

    2001-04-01

    Sickle cell disease (SCD) is relatively mild among Kuwaiti Arabs. However, an atypical subset of patients exists with frequent, severe vaso-occlusive crisis and osteonecrosis. The thermolabile variant of MTHFR, resulting from a C-->T mutation at nucleotide 677, has been shown to be associated with hyperhomocysteinemia, which is an important risk factor for premature vascular disease. We have screened an unselected group of 41 Kuwaiti SCD patients (33 SS and 8 Sbeta(0)-thal) attending the Hematology Clinic of Kuwait University Teaching Hospital for the MTHFR mutation, using a PCR-RFLP method. The patients were aged 2-41 years (mean of 12.8 +/- 8.6). One (2.4%) individual was homozygous for the mutation while 15 (36.6%) were heterozygous, giving an allele frequency of 20.7%. Twenty-one patients (14 SS and 7 Sbeta(0)-thal) were screened for osteonecrosis using MRI of the hip (spin-echo T1- and T2-weighted images). Seven (33.3%) had varying degrees of osteonecrosis, among whom the frequency of the 677 C-->T allele was 21.4%. The frequency was identical among those without osteonecrosis. Although the allele frequency is higher among our patients compared to American SS patients, our results do not suggest an association with osteonecrosis. PMID:11279637

  7. [Monogenic form of diabetes mellitus due to HNF4α mutation (MODY-1) - the first case in Hungary].

    PubMed

    Jermendy, György; Balogh, István; Gaál, Zsolt

    2016-03-20

    The classification of diabetes mellitus in adolescents and young adults is often difficult. The diagnosis of the monogenic form of diabetes may have substantial influence on quality of life, prognosis and the choice of the appropriate treatment of affected patients. Among MODY (maturity-onset of diabetes in the young) MODY-1 is rarely detected, only 13 families were described in 2000, and 103 different mutations in 173 families were known in 2013 worldwide. The authors present the first Hungarian case of a monogenic form of diabetes due to HNF4α mutation (MODY-1). The diabetes of the index patient No. 1 (42-year-old woman with insulin treated diabetes) was diagnosed as gestational diabetes at age of 20 when she was treated with diet only. Later, insulin treatment has been initiated when marked hyperglycaemia was detected during an episode of acute pneumonia at age of 26. The diabetes of the index patient No. 2 (20-year-old daughter of the index patient No. 1, treated also with insulin) was diagnosed as type 2 diabetes at age of 13 and the patient was treated with diet only. Later the classification was modified to type 1 and insulin therapy was initiated at age of 14. The manifestation of diabetes, the familial occurrence and the low dose insulin requirement were suggestive for monogenic diabetes. Using molecular genetic method a mutation (c.869G>A, p.R290H) of HNF4α gene was found and MODY-1 was diagnosed in both cases. Insulin therapy was switched to treatment with low dose sulfanylurea and an excellent glycaemic control was achieved and sustained at follow-up of 1-year. No further positive cases were found during screening of other family members.

  8. Frequency dependence and intensity fluctuations due to shallow water internal waves.

    PubMed

    Badiey, Mohsen; Katsnelson, Boris G; Lynch, James F; Pereselkov, Serguey

    2007-08-01

    A theory and experimental results for sound propagation through an anisotropic shallow water environment are presented to examine the frequency dependence of the scintillation index in the presence of internal waves. The theory of horizontal rays and vertical modes is used to establish the azimutal and frequency behavior of the sound intensity fluctuations, specifically for shallow water broadband acoustic signals propagating through internal waves. This theory is then used to examine the frequency dependent, anisotropic acoustic field measured during the SWARM'95 experiment. The frequency dependent modal scintillation index is described for the frequency range of 30-200 Hz on the New Jersey continental shelf.

  9. Frequency and spectrum of c-Ki-ras mutations in human sporadic colon carcinoma, carcinomas arising in ulcerative colitis, and pancreatic adenocarcinoma

    SciTech Connect

    Burmer, G.C.; Rabinovitch, P.S.; Loeb, L.A. )

    1991-06-01

    Sporadic colon carcinomas, carcinomas arising in chronic ulcerative colitis, and pancreatic adenocarcinomas have been analyzed for the presence of c-Ki-ras mutations by a combination of histological enrichment, cell sorting, polymerase chain reaction, and direct sequencing. Although 60% (37/61) of sporadic colon carcinomas contained mutations in codon 12, only 1 of 17 specimens of dysplasia or carcinoma from ulcerative colitis patients contained c-Ki-ras mutations, despite a high frequency of aneuploid tumors. In contrast, a higher percentage (16/20 = 80%) of pancreatic adenocarcinomas contained mutations in c-Ki-ras 2, despite a lower frequency of DNA aneuploidy in these neoplasms. Moreover, the spectrum of mutations differed between sporadic colon carcinoma, where the predominant mutation was a G to A transition, and pancreatic carcinomas, which predominantly contained G to C or T transversions. These results suggest that the etiology of ras mutations is different in these three human neoplasms.

  10. Low-Frequency NNRTI-Resistant HIV-1 Variants and Relationship to Mutational Load in Antiretroviral-Naïve Subjects

    PubMed Central

    Gupta, Shaili; Lataillade, Max; Kyriakides, Tassos C.; Chiarella, Jennifer; St. John, Elizabeth P.; Webb, Suzin; Moreno, Elizabeth A.; Simen, Birgitte B.; Kozal, Michael J.

    2014-01-01

    Low-frequency HIV variants possessing resistance mutations against non‑nucleoside reverse transcriptase inhibitors (NNRTI), especially at HIV reverse transcriptase (RT) amino acid (aa) positions K103 and Y181, have been shown to adversely affect treatment response. Therapeutic failure correlates with both the mutant viral variant frequency and the mutational load. We determined the prevalence of NNRTI resistance mutations at several RT aa positions in viruses from 204 antiretroviral (ARV)-naïve HIV-infected individuals using deep sequencing, and examined the relationship between mutant variant frequency and mutational load for those variants. Deep sequencing to ≥0.4% levels found variants with major NNRTI-resistance mutations having a Stanford-HIVdb algorithm value ≥30 for efavirenz and/or nevirapine in 52/204 (25.5%) ARV-naïve HIV-infected persons. Eighteen different major NNRTI mutations were identified at 11 different positions, with the majority of variants being at frequency >1%. The frequency of these variants correlated strongly with the mutational load, but this correlation weakened at low frequencies. Deep sequencing detected additional major NNRTI-resistant viral variants in treatment-naïve HIV-infected individuals. Our study suggests the significance of screening for mutations at all RT aa positions (in addition to K103 and Y181) to estimate the true burden of pre-treatment NNRTI-resistance. An important finding was that variants at low frequency had a wide range of mutational loads (>100-fold) suggesting that frequency alone may underestimate the impact of specific NNRTI-resistant variants. We recommend further evaluation of all low-frequency NNRTI-drug resistant variants with special attention given to the impact of mutational loads of these variants on treatment outcomes. PMID:25256391

  11. The spectrum and frequency of self-inflicted and host gene mutations produced by the transposon Ac in maize.

    PubMed

    Huang, Jun T; Dooner, Hugo K

    2012-10-01

    The autonomous transposon Activator (Ac) is a powerful mutagen. Ac-induced mutations range from small footprints of host sequences to large rearrangements of transposon or host sequences. These mutations arise by different repair mechanisms of the double-strand break produced by Ac excision: footprints by nonhomologous end joining and rearrangements by various mechanisms, including DNA replication repair. Footprints greatly outnumber other mutations, masking them because they usually share a nonfunctional phenotype. To determine the spectrum and frequencies of host and self-mutations generated by Ac, we used an allele harboring Ac in the 5' untranslated region bronze (bz). In this system, simple excisions produce purple revertants, whereas deletions of host or transposon sequences produce stable bronze (bz-s) mutants. Internal and terminal deletions of Ac predominated among the 72 bz-s derivatives. Most internal deletions (52 of 54) behaved as nonautonomous Dissociation (Ds) elements. All nine terminal deletions or fractured Ac (fAc) elements had rearrangements of adjacent host sequences. Most Ds and fAc deletion junctions displayed microhomologies and contained filler DNA from nearby sequences, suggesting an origin by DNA repair synthesis followed by microhomology-mediated end joining. All mutations occurred more frequently in pollen, where one in 200 grains carried new Ds or fAc elements.

  12. Left ventricular non-compaction revealed by aortic regurgitation due to Kawasaki disease in a boy with LDB3 mutation.

    PubMed

    Hachiya, Akira; Motoki, Noriko; Akazawa, Yohei; Matsuzaki, Satoshi; Hirono, Keiichi; Hata, Yukiko; Nishida, Naoki; Ichida, Fukiko; Koike, Kenichi

    2016-08-01

    Kawasaki disease (KD) is an acute febrile illness of childhood characterized by systemic vasculitis, especially coronary arteritis. Aortic valve regurgitation (AVR) is a relatively common complication. There have been no reports to date of heart failure and left ventricular non-compaction (LVNC) after acute KD, although the precise etiology of this condition remains unclear. A 6-month-old boy with KD was admitted to hospital. Despite high-dose i.v. gammaglobulin for dilation of the coronary artery, moderate AVR appeared, and thereafter he developed heart failure. A rough, dense LV myocardium indicated LVNC. On genetic testing a heterogenous 163G > A substitution changing a valine to isoleucine in LIM domain binding protein 3 (LDB3) was identified. Additional cardiac stress, such as that caused by AVR and/or KD might have triggered cardiac failure in the form of LVNC due to LDB3 mutation.

  13. Increased frequencies of micronucleated reticulocytes and T-cell receptor mutation in Aldh2 knockout mice exposed to acetaldehyde.

    PubMed

    Kunugita, Naoki; Isse, Toyohi; Oyama, Tsunehiro; Kitagawa, Kyoko; Ogawa, Masanori; Yamaguchi, Tetsunosuke; Kinaga, Tsuyoshi; Kawamoto, Toshihiro

    2008-02-01

    Aldehyde dehydrogenase-2 (ALDH2) metabolizes acetaldehyde produced from ethanol into acetate and plays a major role in the oxidation of acetaldehyde in vivo. About half of all Japanese people have inactive ALDH2. We generated homozygous Aldh2 null (Aldh2-/-) mice by gene targeting knockout as a model of ALDH2-deficient humans. To investigate the mutagenicity of acetaldehyde, a micronucleus assay and a T-cell receptor (TCR) gene mutation assay were performed in Aldh2-/- mice and wild-type (Aldh2 +/+) mice exposed to acetaldehyde. The mice were continuously exposed to 125 and 500 ppm of acetaldehyde vapor for 2 weeks. Another group was orally administered 100 mg/kg once a day for 2 weeks continuously. The mice were killed after 2 weeks of exposure to acetaldehyde, and the frequency of micronucleated reticulocytes was measured by flow cytometry. We also observed the incidence of TCR gene mutations in T-lymphocytes by measuring the variant CD3(-CD4+) expression by flow cytometry. The frequency of micronucleated reticulocytes induced by acetaldehyde was significantly increased in Aldh2 -/- mice, but not in Aldh2 +/+ mice. TCR mutant frequency was also associated with acetaldehyde exposure in Aldh2-/ - mice, especially after oral administration; however, it was not associated with acetaldehyde exposure in Aldh2 +/+ mice. In conclusion, Aldh2 -/- mice showed high sensitivity in the micronuclei and TCR mutation assays compared with Aldh2 +/+ mice after exposure to acetaldehyde. PMID:18303182

  14. Increase in radiation-induced HPRT gene mutation frequency after nonthermal exposure to nonionizing 60 Hz electromagnetic fields.

    PubMed

    Walleczek, J; Shiu, E C; Hahn, G M

    1999-04-01

    It is widely accepted that moderate levels of nonionizing electric or magnetic fields, for example 50/60 Hz magnetic fields of about 1 mT, are not mutagenic. However, it is not known whether such fields can enhance the action of known mutagens. To explore this question, a stringent experimental protocol, which included blinding and systematic negative controls, was implemented, minimizing the possibility of observer bias or experimental artifacts. As a model system, we chose to measure mutation frequencies induced by 2 Gy gamma rays in the redox-sensitive hypoxanthine-guanine phosphoribosyl transferase (HPRT) gene in Chinese hamster ovary cells. We tested whether a 12-h exposure to a 60 Hz sinusoidally oscillating magnetic-flux density (Brms = 0.7 mT) could affect the mutagenic effects of ionizing radiation on the HPRT gene locus. We determined that the magnetic-field exposure induced an approximate 1.8-fold increase in HPRT mutation frequency. Additional experiments at Brms = 0.23 and 0.47 mT revealed that the effect was reduced at lower flux densities. The field exposure did not enhance radiation-induced cytotoxicity or mutation frequencies in cells not exposed to ionizing radiation. These results suggest that moderate-strength, oscillating magnetic fields may act as an enhancer of mutagenesis in mammalian cells.

  15. Nature and frequency of mutations in the argininosuccinate synthetase gene that cause classical citrullinemia.

    PubMed

    Kobayashi, K; Kakinoki, H; Fukushige, T; Shaheen, N; Terazono, H; Saheki, T

    1995-10-01

    Citrullinemia is an autosomal recessive disorder caused by a genetic deficiency of argininosuccinate synthetase (ASS). So far 20 mutations in ASS mRNA have been identified in human classical citrullinemia, including 14 single base changes causing missense mutations in the coding sequence of the enzyme, 4 mutations associated with an absence of exons 5, 6, 7, or 13 in mRNA, 1 mutation with a deletion of the first 7 bases in exon 16 (which is caused by abnormal splicing), and 1 mutation with an insertion of 37 bases between the exon 15 and 16 regions in mRNA. In order to identify the abnormality in the ASS gene causing the exon 7 and 13 deletion mutations and the 37-base insertion mutation between exons 15 and 16 in mRNA, and to establish a DNA diagnostic test, we isolated and sequenced the genomic DNA surrounding each exon. The absence of exon 7 or 13 in ASS mRNA resulted from abnormal splicing caused by a single base change in the intron region: IVS-6(-2) (a transition of A to G at the second nucleotide position within the 3' splice cleavage site of intron 6) and IVS-13(+5) (a transition of G to A at the fifth nucleotide position within the 5' splice cleavage site of intron 13), respectively. The IVS-6(-2) mutation resulted in the creation of an MspI restriction site. DNA diagnostic analysis of 33 Japanese alleles with classical citrullinemia showed that 19 alleles had the IVS-6(-2) mutation (over 50% of the mutated alleles in Japanese patients). It was thus confirmed that one mutation is predominant in Japan. This differs from the situation in the USA where there is far greater heterogeneity. The insertion mutation in mRNA on the other hand resulted from abnormal splicing caused by a 13-bp deletion at the splice-junction between exon 15 and intron 15. The deletion had a short direct repeat (CTCAGG) at the breakpoint junction and presumably resulted from slipped mispairing. PMID:7557970

  16. Antimicrobial Susceptibility and SOS-Dependent Increase in Mutation Frequency Are Impacted by Escherichia coli Topoisomerase I C-Terminal Point Mutation

    PubMed Central

    Yang, Jenny; Annamalai, Thirunavukkarasu; Cheng, Bokun; Banda, Srikanth; Tyagi, Rakhi

    2015-01-01

    Topoisomerase functions are required in all organisms for many vital cellular processes, including transcription elongation. The C terminus domains (CTD) of Escherichia coli topoisomerase I interact directly with RNA polymerase to remove transcription-driven negative supercoiling behind the RNA polymerase complex. This interaction prevents inhibition of transcription elongation from hypernegative supercoiling and R-loop accumulation. The physiological function of bacterial topoisomerase I in transcription is especially important for a rapid network response to an antibiotic challenge. In this study, Escherichia coli with a topA66 single nucleotide deletion mutation, which results in a frameshift in the TopA CTD, was shown to exhibit increased sensitivity to trimethoprim and quinolone antimicrobials. The topoisomerase I-RNA polymerase interaction and the SOS response to the antimicrobial agents were found to be significantly reduced by this topA66 mutation. Consequently, the mutation frequency measured by rifampin selection following SOS induction was diminished in the topA66 mutant. The increased antibiotic sensitivity for the topA66 mutant can be reversed by the expression of recombinant E. coli topoisomerase I but not by the expression of recombinant Mycobacterium tuberculosis topoisomerase I that has a nonhomologous CTD even though the recombinant M. tuberculosis topoisomerase I can restore most of the plasmid DNA linking number deficiency caused by the topA66 mutation. Direct interactions of E. coli topoisomerase I as part of transcription complexes are likely to be required for the rapid network response to an antibiotic challenge. Inhibitors of bacterial topoisomerase I functions and interactions may sensitize pathogens to antibiotic treatment and limit the mutagenic response. PMID:26248366

  17. Antimicrobial Susceptibility and SOS-Dependent Increase in Mutation Frequency Are Impacted by Escherichia coli Topoisomerase I C-Terminal Point Mutation.

    PubMed

    Yang, Jenny; Annamalai, Thirunavukkarasu; Cheng, Bokun; Banda, Srikanth; Tyagi, Rakhi; Tse-Dinh, Yuk-Ching

    2015-10-01

    Topoisomerase functions are required in all organisms for many vital cellular processes, including transcription elongation. The C terminus domains (CTD) of Escherichia coli topoisomerase I interact directly with RNA polymerase to remove transcription-driven negative supercoiling behind the RNA polymerase complex. This interaction prevents inhibition of transcription elongation from hypernegative supercoiling and R-loop accumulation. The physiological function of bacterial topoisomerase I in transcription is especially important for a rapid network response to an antibiotic challenge. In this study, Escherichia coli with a topA66 single nucleotide deletion mutation, which results in a frameshift in the TopA CTD, was shown to exhibit increased sensitivity to trimethoprim and quinolone antimicrobials. The topoisomerase I-RNA polymerase interaction and the SOS response to the antimicrobial agents were found to be significantly reduced by this topA66 mutation. Consequently, the mutation frequency measured by rifampin selection following SOS induction was diminished in the topA66 mutant. The increased antibiotic sensitivity for the topA66 mutant can be reversed by the expression of recombinant E. coli topoisomerase I but not by the expression of recombinant Mycobacterium tuberculosis topoisomerase I that has a nonhomologous CTD even though the recombinant M. tuberculosis topoisomerase I can restore most of the plasmid DNA linking number deficiency caused by the topA66 mutation. Direct interactions of E. coli topoisomerase I as part of transcription complexes are likely to be required for the rapid network response to an antibiotic challenge. Inhibitors of bacterial topoisomerase I functions and interactions may sensitize pathogens to antibiotic treatment and limit the mutagenic response.

  18. Gradual loss of ACTH due to a novel mutation in LHX4: comprehensive mutation screening in Japanese patients with congenital hypopituitarism.

    PubMed

    Takagi, Masaki; Ishii, Tomohiro; Inokuchi, Mikako; Amano, Naoko; Narumi, Satoshi; Asakura, Yumi; Muroya, Koji; Hasegawa, Yukihiro; Adachi, Masanori; Hasegawa, Tomonobu

    2012-01-01

    Mutations in transcription factors genes, which are well regulated spatially and temporally in the pituitary gland, result in congenital hypopituitarism (CH) in humans. The prevalence of CH attributable to transcription factor mutations appears to be rare and varies among populations.This study aimed to define the prevalence of CH in terms of nine CH-associated genes among Japanese patients. We enrolled 91 Japanese CH patients for DNA sequencing of POU1F1, PROP1, HESX1, LHX3, LHX4, SOX2, SOX3, OTX2, and GLI2. Additionally, gene copy numbers for POU1F1, PROP1, HESX1, LHX3, and LHX4 were examined by multiplex ligation-dependent probe amplification. The gene regulatory properties of mutant LHX4 proteins were characterized in vitro. We identified two novel heterozygous LHX4 mutations, namely c.249-1G>A, p.V75I, and one common POU1F1 mutation, p.R271W. The patient harboring the c.249-1G>A mutation exhibited isolated growth hormone deficiency at diagnosis and a gradual loss of ACTH, whereas the patient with the p.V75I mutation exhibited multiple pituitary hormone deficiency. In vitro experiments showed that both LHX4 mutations were associated with an impairment of the transactivation capacities of POU1F1 andαGSU, without any dominant-negative effects. The total mutation prevalence in Japanese CH patients was 3.3%. This study is the first to describe, a gradual loss of ACTH in a patient carrying an LHX4 mutation. Careful monitoring of hypothalamic-pituitary -adrenal function is recommended for CH patients with LHX4 mutations.

  19. Rich Medium Composition Affects Escherichia coli Survival, Glycation, and Mutation Frequency during Long-Term Batch Culture

    PubMed Central

    Kram, Karin E.

    2015-01-01

    Bacteria such as Escherichia coli are frequently grown to high density to produce biomolecules for study in the laboratory. To achieve this, cells can be incubated in extremely rich media that increase overall cell yield. In these various media, bacteria may have different metabolic profiles, leading to changes in the amounts of toxic metabolites produced. We have previously shown that stresses experienced during short-term growth can affect the survival of cells during the long-term stationary phase (LTSP). Here, we incubated cells in LB, 2× yeast extract-tryptone (YT), Terrific Broth, or Super Broth medium and monitored survival during the LTSP, as well as other reporters of genetic and physiological change. We observe differential cell yield and survival in all media studied. We propose that differences in long-term survival are the result of changes in the metabolism of components of the media that may lead to increased levels of protein and/or DNA damage. We also show that culture pH and levels of protein glycation, a covalent modification that causes protein damage, affect long-term survival. Further, we measured mutation frequency after overnight incubation and observed a correlation between high mutation frequencies at the end of the log phase and loss of viability after 4 days of LTSP incubation, indicating that mutation frequency is potentially predictive of long-term survival. Since glycation and mutation can be caused by oxidative stress, we measured expression of the oxyR oxidative stress regulator during log-phase growth and found that higher levels of oxyR expression during the log phase are consistent with high mutation frequency and lower cell density during the LTSP. Since these complex rich media are often used when producing large quantities of biomolecules in the laboratory, the observed increase in damage resulting in glycation or mutation may lead to production of a heterogeneous population of plasmids or proteins, which could affect the

  20. Estimation of Frequency Noise in Semiconductor Lasers Due to Mechanical Thermal Noise

    NASA Technical Reports Server (NTRS)

    Numata, Kenji; Camp, Jordan

    2012-01-01

    We evaluate mechanical thermal noise in semiconductor lasers, applying a methodology developed for fixed-spacer cavities for laser frequency stabilization. Our simple model determines an underlying fundamental limit for the frequency noise of free-running semiconductor laser, and provides a framework: where the noise may be potentially reduced with improved design.

  1. A second mutation associated with apparent [beta]-hexosaminidase A pseudodeficiency: Identification and frequency estimation

    SciTech Connect

    Cao, Z.; Chabot, T.; Triggs-Raine, B.L. ); Natowicz, M.R.; Prence, E.M. Harvard Medical School, Boston, MA ); Kaback, M.M.; Lim-Steele, S.T.; Brown, D. Univ. of California, San Diego, CA )

    1993-12-01

    Deficient activity of [beta]-hexosaminidase A (Hex A), resulting from mutations in the HEXA gene, typically causes Tay-Sachs disease. However, healthy individuals lacking Hex A activity against synthetic substrates (i.e., individuals who are pseudodeficient) have been described. Recently, an apparently benign C[sub 739]-to-T (Arg247Trp) mutation was found among individuals with Hex A levels indistinguishable from those of carriers of Tay-Sachs disease. This allele, when in compound heterozygosity with a second [open quotes]disease-causing[close quotes] allele, results in Hex A pseudodeficiency. The authors examined the HEXA gene of a healthy 42-year-old who was Hex A deficient but did not have the C[sub 739]-to-T mutation. The HEXA exons were PCR amplified, and the products were analyzed for mutations by using restriction-enzyme digestion or single-strand gel electrophoresis. A G[sub 805]-to-A (Gly269Ser) mutation associated with adult-onset G[sub m2] gangliosidosis was found on one chromosome. A new mutation, C[sub 745]-to-T (Arg 249Trp), was identified on the second chromosome. This mutation was detected in an additional 4/63 (6%) non-Jewish and 0/218 Ashkenazi Jewish enzyme-defined carriers. Although the Arg249Trp change may result in a late-onset form of G[sub M2] gangliosidosis, any phenotype must be very mild. This new mutation and the benign C[sub 739]-to-T mutation together account for [approximately]38% of non-Jewish enzyme-defined carriers. Because carriers of the C[sub 739]-to-T and C[sub 745]-to-T mutations cannot be differentiated from carriers of disease-causing alleles by using the classical biochemical screening approaches, DNA-based analyses for these mutations should be offered for non-Jewish enzyme-defined heterozygotes, before definitive counseling is provided. 46 refs., 5 figs., 2 tabs.

  2. Somatic mutational analysis of FAK in breast cancer: A novel gain-of-function mutation due to deletion of exon 33

    SciTech Connect

    Fang, Xu-Qian; Liu, Xiang-Fan; Yao, Ling; Chen, Chang-Qiang; Gu, Zhi-Dong; Ni, Pei-Hua; Zheng, Xin-Min; Fan, Qi-Shi

    2014-01-10

    Highlights: •A novel FAK splicing mutation identified in breast tumor. •FAK-Del33 mutation promotes cell migration and invasion. •FAK-Del33 mutation regulates FAK/Src signal pathway. -- Abstract: Focal adhesion kinase (FAK) regulates cell adhesion, migration, proliferation, and survival. We identified a novel splicing mutant, FAK-Del33 (exon 33 deletion, KF437463), in both breast and thyroid cancers through colony sequencing. Considering the low proportion of mutant transcripts in samples, this mutation was detected by TaqMan-MGB probes based qPCR. In total, three in 21 paired breast tissues were identified with the FAK-Del33 mutation, and no mutations were found in the corresponding normal tissues. When introduced into a breast cell line through lentivirus infection, FAK-Del33 regulated cell motility and migration based on a wound healing assay. We demonstrated that the expression of Tyr397 (main auto-phosphorylation of FAK) was strongly increased in FAK-Del33 overexpressed breast tumor cells compared to wild-type following FAK/Src RTK signaling activation. These results suggest a novel and unique role of the FAK-Del33 mutation in FAK/Src signaling in breast cancer with significant implications for metastatic potential.

  3. Different mosaicism frequencies for proximal and distal Duchenne muscular dystrophy (DMD) mutations indicate difference in etiology and recurrence risk.

    PubMed Central

    Passos-Bueno, M R; Bakker, E; Kneppers, A L; Takata, R I; Rapaport, D; den Dunnen, J T; Zatz, M; van Ommen, G J

    1992-01-01

    In about 65% of the cases of Duchenne muscular dystrophy (DMD) a partial gene deletion or duplication in the dystrophin gene can be detected. These mutations are clustered at two hot spots: 30% at the hot spot in the proximal part of the gene and about 70% at a more distal hot spot. Unexpectedly we observed a higher frequency of proximal gene rearrangements among proved "germ line" mosaic cases. Of the 24 mosaic cases we are aware of, 19 (79%) have a proximal mutation, while only 5 (21%) have a distal mutation. This finding indicates that the mutations at the two hot spots in the dystrophin gene differ in origin. Independent support for the different mosaicism frequency was found by comparing the mutation spectra observed in isolated cases of DMD and familial cases of DMD. In a large two-center study of 473 patients from Brazil and the Netherlands, we detected a significant difference in the deletion distribution of isolated (proximal:distal ratio 1:3) and familial cases (ratio 1:1). We conclude from these data that proximal deletions most likely occur early in embryonic development, causing them to have a higher chance of becoming familial, while distal deletions occur later and have a higher chance of causing only isolated cases. Finally, our findings have important consequences for the calculation of recurrence-risk estimates according to the site of the deletion: a "proximal" new mutant has an increased recurrence risk of approximately 30%, and a "distal" new mutant has a decreased recurrence risk of approximately 4%. PMID:1415256

  4. Fulminant neurological deterioration in a neonate with Leigh syndrome due to a maternally transmitted missense mutation in the mitochondrial ND3 gene

    SciTech Connect

    Leshinsky-Silver, E.; E-mail: leshinsky@wolfson.health.gov.il; Lev, D.; Tzofi-Berman, Z.; Cohen, S.; Saada, A.; Yanoov-Sharav, M.; Gilad, E.; Lerman-Sagie, T.

    2005-08-26

    Leigh syndrome can result from both nuclear and mitochondrial DNA defects. Mutations in complex V genes of the respiratory chain were considered until recently as the most frequent cause for mitochondrial inherited Leigh syndrome, while gene defects in complex I were related to recessive Leigh syndrome. Recently few reports of mutations in the mitochondrial-encoded complex I subunit genes causing Leigh syndrome have been reported. We describe a 1-month-old baby who acutely deteriorated, with abrupt onset of brainstem dysfunction, due to basal ganglia lesions extending to the brainstem. A muscle biopsy demonstrated complex I deficiency. Subsequent analysis of the mitochondrial genome revealed a homoplastic T10191C mutation in the ND3 gene (in blood and muscle), resulting in a substitution of serine to proline. Hair root analysis revealed a 50% mutant load, reflecting heteroplasmy in early embryonic stages. The mutation was also detected in his mother (5%). Western blot analysis revealed a decrease of the 20 kDa subunit (likely ND6) and of the 30 kDa subunit (NDUFA9), which is probably due to instability attributed to the inability to form subcomplexes with ND3. This is the first description of infantile Leigh syndrome due to a maternally transmitted T10191C substitution in ND3 and not due to a de novo mutation. This mutation is age and tissue dependent and therefore may not be amenable to prenatal testing.

  5. Conservation of CFTR codon frequency through primates suggests synonymous mutations could have a functional effect.

    PubMed

    Pizzo, Lucilla; Iriarte, Andrés; Alvarez-Valin, Fernando; Marín, Mónica

    2015-05-01

    Cystic fibrosis is an inherited chronic disease that affects the lungs and digestive system, with a prevalence of about 1:3000 people. Cystic fibrosis is caused by mutations in CFTR gene, which lead to a defective function of the chloride channel, the cystic fibrosis transmembrane conductance regulator (CFTR). Up-to-date, more than 1900 mutations have been reported in CFTR. However for an important proportion of them, their functional effects and the relation to disease are still not understood. Many of these mutations are silent (or synonymous), namely they do not alter the encoded amino acid. These synonymous mutations have been considered as neutral to protein function. However, more recent evidence in bacterial and human proteins has put this concept under revision. With the aim of understanding possible functional effects of synonymous mutations in CFTR, we analyzed human and primates CFTR codon usage and divergence patterns. We report the presence of regions enriched in rare and frequent codons. This spatial pattern of codon preferences is conserved in primates, but this cannot be explained by sequence conservation alone. In sum, the results presented herein suggest a functional implication of these regions of the gene that may be maintained by purifying selection acting to preserve a particular codon usage pattern along the sequence. Overall these results support the idea that several synonymous mutations in CFTR may have functional importance, and could be involved in the disease.

  6. FREQUENCY SHIFTS OF RESONANT MODES OF THE SUN DUE TO NEAR-SURFACE CONVECTIVE SCATTERING

    SciTech Connect

    Bhattacharya, J.; Hanasoge, S.; Antia, H. M.

    2015-06-20

    Measurements of oscillation frequencies of the Sun and stars can provide important independent constraints on their internal structure and dynamics. Seismic models of these oscillations are used to connect structure and rotation of the star to its resonant frequencies, which are then compared with observations, the goal being that of minimizing the difference between the two. Even in the case of the Sun, for which structure models are highly tuned, observed frequencies show systematic deviations from modeled frequencies, a phenomenon referred to as the “surface term.” The dominant source of this systematic effect is thought to be vigorous near-surface convection, which is not well accounted for in both stellar modeling and mode-oscillation physics. Here we bring to bear the method of homogenization, applicable in the asymptotic limit of large wavelengths (in comparison to the correlation scale of convection), to characterize the effect of small-scale surface convection on resonant-mode frequencies in the Sun. We show that the full oscillation equations, in the presence of temporally stationary three-dimensional (3D) flows, can be reduced to an effective “quiet-Sun” wave equation with altered sound speed, Brünt–Väisäla frequency, and Lamb frequency. We derive the modified equation and relations for the appropriate averaging of 3D flows and thermal quantities to obtain the properties of this effective medium. Using flows obtained from 3D numerical simulations of near-surface convection, we quantify their effect on solar oscillation frequencies and find that they are shifted systematically and substantially. We argue therefore that consistent interpretations of resonant frequencies must include modifications to the wave equation that effectively capture the impact of vigorous hydrodynamic convection.

  7. Theory of point-spread function artifacts due to structured mid-spatial frequency surface errors.

    PubMed

    Tamkin, John M; Dallas, William J; Milster, Tom D

    2010-09-01

    Optical design and tolerancing of aspheric or free-form surfaces require attention to surface form, structured surface errors, and nonstructured errors. We describe structured surface error profiles and effects on the image point-spread function using harmonic (Fourier) decomposition. Surface errors over the beam footprint map onto the pupil, where multiple structured surface frequencies mix to create sum and difference diffraction orders in the image plane at each field point. Difference frequencies widen the central lobe of the point-spread function and summation frequencies create ghost images.

  8. Nonuniform radio-frequency plasma potential due to edge asymmetry in large-area radio-frequency reactors

    SciTech Connect

    Howling, A.A.; Sansonnens, L.; Ballutaud, J.; Hollenstein, Ch.; Schmitt, J.P.M.

    2004-11-15

    In small area capacitive reactors, the rf and dc components of the plasma potential can be assumed to be uniform over all the plasma bulk because of the low plasma resistivity. In large area reactors, however, the rf plasma potential can vary over a long range across the reactor due to rf current flow and the nonzero plasma impedance. A perturbation in rf plasma potential, due to electrode edge asymmetry or the boundary of a dielectric substrate, propagates along the resistive plasma between capacitive sheaths. This is analogous to propagation along a lossy conductor in a transmission line and the damping length of the perturbation can be determined by the telegraph equation. Some consequences are the following: (i) The spatial variation in sheath rf amplitudes causes nonuniform rf power dissipation near to the reactor sidewalls. (ii) The surface charge and potential of a dielectric substrate can be negative and not only positive as for a uniform rf plasma potential. The variation of sheath dc potential across a dielectric substrate causes nonuniform ion energy bombardment. (iii) The self-bias voltage depends on the plasma parameters and on the reactor and substrate dimensions - not only on the ratio of electrode areas. (iv) The nonuniform rf plasma potential in presence of the uniform dc plasma potential leads to nonambipolar dc currents circulating along conducting surfaces and returning via the plasma. Electron current peaks can arise locally at the edge of electrodes and dielectric substrates. Perturbations to the plasma potential and currents due to the edge asymmetry of the electrodes are demonstrated by means of an analytical model and numerical simulations.

  9. Somatic Mutations Are Not Observed by Exome Sequencing of Lymphocyte DNA from Monozygotic Twins Discordant for Congenital Hypothyroidism due to Thyroid Dysgenesis

    PubMed Central

    Magne, Fabien; Serpa, Roman; Van Vliet, Guy; Samuels, Mark E.; Deladoëy, Johnny

    2016-01-01

    Background/Aims Congenital primary hypothyroidism (CH) is a rare pediatric disorder estimated to occur in about 1: 2,500 live births. Approximately half of these cases entail ectopic thyroid tissue, which is believed to result from a migration defect during embryogenesis. Approximately 3% of CH cases are explained by mutation(s) in known genes, most of which are transcription factors implicated in the embryology of the thyroid gland. Surprisingly, monozygotic (MZ) twins are usually discordant for CH due to thyroid dysgenesis, suggesting that most cases are not caused by transmitted genetic variation. One possible explanation is somatic mutation in genes involved in thyroid migration occurring after zygotic twinning. Such mutations should be observed only in the affected twin. Methods To test the hypothesis of somatic mutation, we performed whole exome sequencing of DNA from three pairs of MZ twins discordant for CH with ectopic glands. Results We found no somatic mutations exclusive to any of the three affected twins or in any of the unaffected twins. Conclusion Either somatic mutations are not significant for the etiology of CH or else such mutations lie outside regions of the genome accessible by exome sequencing technology. PMID:25277881

  10. Ultrasound (US) transducer of higher operating frequency detects photoacoustic (PA) signals due to the contrast in elastic property

    NASA Astrophysics Data System (ADS)

    Singh, Mayanglambam Suheshkumar; Jiang, Huabei

    2016-02-01

    We report our study that shows selection in operating frequency of US-transducer used for boundary detection of PA-signals, which result due to the contrast in elastic property distribution ( E ( r → ) ) in sample material other than that of optical absorption coefficient (μa). Studies were carried out, experimentally, in tissue-mimicking Agar phantoms employing acoustic resolution photoacoustic microscopy (AR-PAM) system as an imaging unit. In the experiments, various transducers having different operating frequencies, ranging from 1MHz to 50MHz, were employed for studying frequency response of the photoacoustic signals. The study shows that, for detecting photoacoustic signals due to the contrast in elastic property, ultrasound transducer with higher operating frequency (˜50MHz) is demanded.

  11. Rapid Frequency Chirps of TAE mode due to Finite Orbit Energetic Particles

    NASA Astrophysics Data System (ADS)

    Berk, Herb; Wang, Ge

    2013-10-01

    The tip model for the TAE mode in the large aspect ratio limit, conceived by Rosenbluth et al. in the frequency domain, together with an interaction term in the frequency domain based on a map model, has been extended into the time domain. We present the formal basis for the model, starting with the Lagrangian for the particle wave interaction. We shall discuss the formal nonlinear time domain problem and the procedure that needs to obtain solutions in the adiabatic limit.

  12. The adult polyglucosan body disease mutation GBE1 c.1076A>C occurs at high frequency in persons of Ashkenazi Jewish background.

    PubMed

    Hussain, Abrar; Armistead, Joy; Gushulak, Lara; Kruck, Christa; Pind, Steven; Triggs-Raine, Barbara; Natowicz, Marvin R

    2012-09-21

    Mutations of the glycogen branching enzyme gene, GBE1, result in glycogen storage disease (GSD) type IV, an autosomal recessive disorder having multiple clinical forms. One mutant allele of this gene, GBE1 c.1076A>C, has been reported in Ashkenazi Jewish cases of an adult-onset form of GSD type IV, adult polyglucosan body disease (APBD), but no epidemiological analyses of this mutation have been performed. We report here the first epidemiological study of this mutation in persons of Ashkenazi Jewish background and find that this mutation has a gene frequency of 1 in 34.5 (95% CI: 0.0145-0.0512), similar to the frequency of the common mutation causing Tay-Sachs disease among Ashkenazi Jews. This finding reveals APBD to be another monogenic disorder that occurs with increased frequency in persons of Ashkenazi Jewish ancestry. PMID:22943850

  13. Frequency shifts and modulation effects due to solenoidal magnetic field inhomogeneities in ion cyclotron mass spectrometry

    NASA Astrophysics Data System (ADS)

    Mitchell, Dale W.; Rockwood, Alan L.; Smith, Richard D.

    1995-02-01

    Solenoidal (i.e. axially symmetric) magnetic field inhomogeneities, which in addition have symmetry under the operation z --> -z are the most important to Fourier transform-ion cyclotron resonance (FT-ICR) mass spectrometry since they introduce frequency shifts at first-order in perturbation theory. Frequency shifts for all three fundamental modes are derived for the leading second-order and fourth-order solenoidal inhomogeneities without any restrictions on the initial conditions. The analytical frequency shifts agree very well with frequency shifts obtained from numerical trajectory calculations using the exact classical equations of motion. The effect of the inhomogeneity on the ion trajectory is solved analytically. For a strong magnetic bottle field, the cyclotron motion is frequency modulated at twice the z-oscillation frequency resulting in sidebands. However, the amplitude of these sidebands is negligibly small for typical inhomogeneity strengths. The effect of a magnetized ICR trap on the homogeneity of the magnetic field is studied by analytical methods. We find that the leading magnetic bottle field decreases as d-3, where d is the cylindrical ion trap diameter.

  14. The Increase in Thyroid Cancer Incidence During the Last Four Decades Is Accompanied by a High Frequency of BRAF Mutations and a Sharp Increase in RAS Mutations

    PubMed Central

    Jung, Chan Kwon; Little, Mark P.; Lubin, Jay H.; Brenner, Alina V.; Wells, Samuel A.; Sigurdson, Alice J.

    2014-01-01

    Context: Thyroid cancer incidence rates in the United States and globally have increased steadily over the last 40 years, primarily due to a tripling of the incidence of papillary thyroid carcinoma (PTC). Objective: The purpose of this study was to analyze trends in demographic, clinical, pathologic, and molecular characteristics of PTC from 1974 to 2009. Design and Setting: We identified and histologically reviewed 469 consecutive cases of PTC from one US institution from 4 preselected periods (1974 to 1985, 1990 to 1992, 2000, and 2009) and assessed BRAF and RAS point mutations and RET/PTC rearrangements among 341 tumors ≥0.3 cm in size. Changes over time were analyzed using polytomous and binary logistic regression; all analyses were adjusted for age and sex. Results: During this period, the median age of patients at diagnosis increased from 37 to 53 years (P < .001) and the percentage of microcarcinomas (≤1.0 cm) increased from 33% to 51% (P < .001), whereas extrathyroidal extension and advanced tumor stage decreased from 40% to 21% (P = .005) and from 43% to 28% (P = .036), respectively. Changes in tumor histopathology showed a decrease in classic PTC and an increase in the follicular variant (P < .001). The proportion of tumors with a BRAF mutation was stable (∼46%) but increased from 50% to 77% (P = .008) within classic papillary PTCs. The proportion of tumors with RAS mutations increased from 3% to 25% and within follicular pattern tumors from 18% to 44% (P < .001). The proportion of RET/PTC rearrangements decreased from 11% to 2% (P = .038). Conclusions: Similar to US national trends, we found an increasing age at diagnosis and greater detection of smaller-sized intrathyroidal PTCs. However, the overall proportion of BRAF mutations remained stable. Sharply rising percentages of the follicular variant histology and RAS mutations after 2000 suggest new and more recent etiologic factors. The increased incidence is not likely to be due to environmental

  15. Molecular spectrum of somatic EGFR and KRAS gene mutations in non small cell lung carcinoma: determination of frequency, distribution pattern and identification of novel variations in Indian patients.

    PubMed

    Das, Bibhu Ranjan; Bhaumik, Sangeet; Ahmad, Firoz; Mandsaurwala, Aziz; Satam, Heena

    2015-07-01

    Somatic mutations of EGFR and KRAS gene represent the most common alterations currently known in NSCLC patients. This study explored the frequency, distribution pattern of EGFR and KRAS mutations in Indian patients. The frequencies of EGFR and KRAS mutations were 29 % (116/400) and 4.5 % (6/132) respectively. Both EGFR and KRAS mutations were prevalent in females, and a trend towards higher mutation frequency was seen in patients under ≥ 60 years age. The presence of EGFR and KRAS mutations were higher in adenocarcinomas in comparison to other histological subtype. Sequencing analysis of EGFR exon 18 revealed Inframe deletion (G709_T710 > A) and missense mutation (K713R). Among exon 19 positive cases, 49.3 % (37/75) were in-frame deletions, of which E746_A750del was frequent. Similarly, ~47 % (35/75) cases showed complex mutation involving indel. Among mutations in exon 20 (N = 9), 8 were substitutions, one showed duplication, while all exon 21 mutations were of the missense types with L858R as the most recurrent type. Sequencing analysis of KRAS exon 1 revealed three different types codon 12 substitutions resulting in c34G > T (G12C) (n = 4), c.35G > A (G12D) (n = 1), and c.35G > T (G12V) (n = 1). In conclusion, the present study is an example of molecular diversity of EGFR and KRAS gene in Indian patients and further confirms that the frequency of EGFR and KRAS mutations varies considerably globally. To the best of our knowledge, this is the first Indian study to evaluate KRAS mutation. The current study also served to identify novel variations that added new insights into the genetic heterogeneity of NSCLC.

  16. Uniparental disomy as a cause of spinal muscular atrophy and progressive myoclonic epilepsy: phenotypic homogeneity due to the homozygous c.125C>T mutation in ASAH1.

    PubMed

    Giráldez, Beatriz G; Guerrero-López, Rosa; Ortega-Moreno, Laura; Verdú, Alfonso; Carrascosa-Romero, M Carmen; García-Campos, Óscar; García-Muñozguren, Susana; Pardal-Fernández, José Manuel; Serratosa, José M

    2015-03-01

    Spinal muscular atrophy and progressive myoclonic epilepsy (SMAPME, OMIM#159950) is a rare autosomal recessive disorder characterized by the combination of progressive myoclonic epilepsy and muscular weakness due to lower motor neuron disease. Mutations in ASAH1, previously associated only to Farber disease, have been recently described in seven patients with SMAPME. A homozygous c.125C>T mutation was initially found in six patients with a clinical homogeneous phenotype. A heterozygous compound mutation found in an additional patient has broadened the clinical and genetic spectrum of clinical SMAPME. We report a new case of a 13-year-old girl with SMAPME with the homozygous ASAH1 c.125C>T mutation, unique in that it is due to paternal uniparental disomy. She experienced muscle weakness from the age of three due to lower motor neuron involvement that lead to severe handicap and onset in late childhood of a progressive myoclonic epilepsy. This clinical picture fully overlaps with that of previously reported patients with this mutation and supports our view that the clinical phenotype associated with the homozygous c.125C>T mutation constitutes a clinically homogenous and recognizable disease. PMID:25578555

  17. Evaluations of effects due to low-frequency noise in a low demanding work situation

    NASA Astrophysics Data System (ADS)

    Bengtsson, J.; Persson Waye, K.; Kjellberg, A.

    2004-11-01

    Noise sources with a dominating content of low frequencies (20-200 Hz) are found in many occupational environments. This study aimed to evaluate effects of moderate levels of low-frequency noise on attention, tiredness and motivation in a low demanding work situation. Two ventilation noises at the same A-weighted sound pressure level of 45 dB were used: one of a low-frequency character and one of a flat frequency character (reference noise). Thirty-eight female subjects worked with six performance tasks for 4 h in the noises in a between-subject design. Most of the tasks were monotonous and routine in character. Subjective reports were collected using questionnaires and cortisol levels were measured in saliva. The major finding in this study was that low-frequency noise negatively influenced performance on two tasks sensitive to reduced attention and on a proof-reading task. Performances of tasks aimed at evaluating motivation were not significantly affected. The difference in work performance was not reflected by the subjective reports. No effect of noise was found on subjective stress or cortisol levels.

  18. The Near Naked Hairless (HrN) Mutation Disrupts Hair Formation but is not Due to a Mutation in the Hairless Coding Region

    SciTech Connect

    Liu, Yutao; Das, Suchita; Olszewski, Robert Edward; Culiat, Cymbeline T; Carpenter, D A; Sundberg, John P; Soteropoulos, Patricia; Liu, Xiaochen; Doktycz, Mitchel John; Michaud III, Edward J; Voy, Brynn H

    2007-01-01

    Near naked hairless (HrN) is a semi-dominant mutation that arose spontaneously and was suggested by allelism testing to be an allele of mouse Hairless (Hr). HrN mice differ from other Hr mutants in that hair loss appears as the postnatal coat begins to emerge, as opposed to failure to initiate the first postnatal hair cycle, and that the mutation displays semi-dominant inheritance. We sequenced the Hr cDNA in HrN/HrN mice and characterized the pathological and molecular phenotypes to identify the basis for hair loss in this model. HrN/HrN mice exhibit dystrophic hairs that are unable to consistently emerge from the hair follicle, while HrN/+ mice display a sparse coat of hair and a milder degree of follicular dystrophy than their homozygous littermates. DNA microarray analysis of cutaneous gene expression demonstrates that numerous genes are downregulated in HrN/HrN mice, primarily genes important for hair structure. By contrast, Hr expression is significantly increased. Sequencing the Hr coding region, intron-exon boundaries, 5'- and 3'- UTR and immediate upstream region did not reveal the underlying mutation. Therefore HrN does not appear to be an allele of Hr but may result from a mutation in a closely linked gene or from a regulatory mutation in Hr.

  19. Allele frequencies of BRAFV600 mutations in primary melanomas and matched metastases and their relevance for BRAF inhibitor therapy in metastatic melanoma

    PubMed Central

    Satzger, Imke; Marks, Lena; Kerick, Martin; Klages, Sven; Berking, Carola; Herbst, Rudolf; Völker, Bernward; Schacht, Vivien; Timmermann, Bernd; Gutzmer, Ralf

    2015-01-01

    Background The detection of BRAFV600 mutations in patients with metastatic melanoma is important because of the availability of BRAF inhibitor therapy. However, the clinical relevance of the frequency of BRAFV600 mutant alleles is unclear. Patients and Methods Allele frequencies of BRAFV600 mutations were analyzed by ultra-deep next-generation sequencing in formalin-fixed, paraffin-embedded melanoma tissue (75 primary melanomas and 88 matched metastases). In a second study, pretreatment specimens from 76 patients who received BRAF inhibitors were retrospectively analyzed, and BRAFV600 allele frequencies were correlated with therapeutic results. Results Thirty-five patients had concordantly BRAF-positive and 36 (48%) patients had concordantly BRAF-negative primary melanomas and matched metastases, and four patients had discordant samples with low allele frequencies (3.4–5.2%). Twenty-six of 35 patients with concordant samples had BRAFV600E mutations, three of whom had additional mutations (V600K in two patients and V600R in one) and nine patients had exclusively non-V600E mutations (V600K in eight patients and V600E -c.1799_1800TG > AA- in one patient). The frequency of mutated BRAFV600 alleles was similar in the primary melanoma and matched metastasis in 27/35 patients, but differed by >3-fold in 8/35 of samples. BRAFV600E allele frequencies in pretreatment tumor specimens were not significantly correlated with treatment outcomes in 76 patients with metastatic melanoma who were treated with BRAF inhibitors. Conclusions BRAFV600 mutation status and allele frequency is consistent in the majority of primary melanomas and matched metastases. A small subgroup of patients has double mutations. BRAFV600 allele frequencies are not correlated with the response to BRAF inhibitors. PMID:26498143

  20. Leigh syndrome associated with mitochondrial complex I deficiency due to novel mutations In NDUFV1 and NDUFS2.

    PubMed

    Marin, Samantha E; Mesterman, Ronit; Robinson, Brian; Rodenburg, Richard J; Smeitink, Jan; Tarnopolsky, Mark A

    2013-03-01

    Leigh syndrome (LS) is a progressive neurodegenerative disease caused by either mitochondrial or nuclear DNA mutations resulting in dysfunctional mitochondrial energy metabolism. Mutations in genes encoding for subunits of the respiratory chain or assembly factors of respiratory chain complexes are often documented in LS cases. Nicotinamide adenine dinucleotide (NADH):ubiquinone oxidoreductase (complex I) enzyme deficiencies account for a significant proportion of mitochondrial disorders, including LS. In an attempt to expand the repertoire of known mutations accounting for LS, we describe the clinical, radiological, biochemical and molecular data of six patients with LS found to have novel mutations in two complex I subunits (NDUFV1 and NDUFS2). Two siblings were homozygous for the previously undescribed R386C mutation in NDUFV1, one patient was a compound heterozygote for the R386C mutation in NDUFV1 and a frameshift mutation in the same gene, one patient was a compound heterozygote for the R88G and R199P mutations in NDUFV1, and two siblings were compound heterozygotes for an undescribed E104A mutation in NDUFS2. After the novel mutations were identified, we employed prediction models using protein conservation analysis (SIFT, PolyPhen and UCSC genome browser) to determine pathogenicity. The R386C, R88G, R199P, and E104A mutations were found to be likely pathogenic, and thus presumably account for the LS phenotype. This case series broadens our understanding of the etiology of LS by identifying new molecular defects that can result in complex I deficiency and may assist in targeted diagnostics and/or prenatal diagnosis of LS in the future.

  1. Macronodular Adrenal Hyperplasia due to Mutations in an Armadillo Repeat Containing 5 (ARMC5) Gene: A Clinical and Genetic Investigation

    PubMed Central

    Faucz, Fabio R.; Zilbermint, Mihail; Lodish, Maya B.; Szarek, Eva; Trivellin, Giampaolo; Sinaii, Ninet; Berthon, Annabel; Libé, Rossella; Assié, Guillaume; Espiard, Stéphanie; Drougat, Ludivine; Ragazzon, Bruno; Bertherat, Jerome

    2014-01-01

    Context: Inactivating germline mutations of the probable tumor suppressor gene, armadillo repeat containing 5 (ARMC5), have recently been identified as a genetic cause of macronodular adrenal hyperplasia (MAH). Objective: We searched for ARMC5 mutations in a large cohort of patients with MAH. The clinical phenotype of patients with and without ARMC5 mutations was compared. Methods: Blood DNA from 34 MAH patients was genotyped using Sanger sequencing. Diurnal serum cortisol measurements, plasma ACTH levels, urinary steroids, 6-day Liddle's test, adrenal computed tomography, and weight of adrenal glands at adrenalectomy were assessed. Results: Germline ARMC5 mutations were found in 15 of 34 patients (44.1%). In silico analysis of the mutations indicated that seven (20.6%) predicted major implications for gene function. Late-night cortisol levels were higher in patients with ARMC5-damaging mutations compared with those without and/or with nonpathogenic mutations (14.5 ± 5.6 vs 6.7 ± 4.3, P < .001). All patients carrying a pathogenic ARMC5 mutation had clinical Cushing's syndrome (seven of seven, 100%) compared with 14 of 27 (52%) of those without or with mutations that were predicted to be benign (P = .029). Repeated-measures analysis showed overall higher urinary 17-hydroxycorticosteroids and free cortisol values in the patients with ARMC5-damaging mutations during the 6-day Liddle's test (P = .0002). Conclusions: ARMC5 mutations are implicated in clinically severe Cushing's syndrome associated with MAH. Knowledge of a patient's ARMC5 status has important clinical implications for the diagnosis of Cushing's syndrome and genetic counseling of patients and their families. PMID:24601692

  2. A cluster of factor XI-deficient patients due to a new mutation (Ile 436 Lys) in northeastern Italy.

    PubMed

    Girolami, Antonio; Scarparo, Pamela; Bonamigo, Emanuela; Santarossa, Liliana; Cristiani, Andrea; Moro, Stefano; Lombardi, Anna Maria

    2012-03-01

    A new mutation (Ile 436 Lys) was found in a cluster of patients in northeastern Italy. The mutation was present in five patients at the homozygote level and in one patient as a compound heterozygote with an already known mutation namely Glu 117 stop. All these patients showed a mild bleeding tendency mainly associated with deliveries or surgery. The first two patients were two sisters, and their parents were consanguineous. The third patient was the only homozygote in the family, and parents apparently were not consanguineous. The fourth and fifth patients were a brother and a sister, and in this case too, parents were not consanguineous. The sixth patient, a compound heterozygote, negated also the existence of consanguinity between his parents. There were also seven heterozygotes among the family members of the patients homozygous for this new mutation (Ile 436 Lys). Finally, there were two heterozygotes for the Glu 117 stop mutation in the family of the sixth patient. The heterozygotes, regardless of the mutation, were asymptomatic. The Ile436Lys mutation is characterized by low factor XI activity and antigen, namely is a cross-reaction material negative form. Molecular modeling indicates that the Ile436Lys mutation causes a large conformational change within the 432-442 loop. No relation could be traced among the different families; however, all their ancestors were autochthonous of the same two small towns. Furthermore, no Jewish ancestry could be found. The close geographical area in which all these patients were found and the absence of the same mutation in the general population of the area strongly suggests a founder effect and that the mutation is responsible for the defect. The compound heterozygosis with the Glu 117 stop mutation, common among Jews, was not surprising because of the past strict ties of the Republic of Venice with the Middle East. PMID:21999818

  3. A laser-cooled cesium fountain frequency standard and a measurement of the frequency shift due to ultra-cold collisions

    NASA Technical Reports Server (NTRS)

    Gibble, Kurt; Kasapi, Steven; Chu, Steven

    1993-01-01

    A frequency standard based on an atomic fountain of cesium atoms may have an accuracy of 10(exp -16) due to longer interaction times and smaller anticipated systematic errors. All of the known systematic effects that now limit the accuracy of the Cs frequency standard increase either linearly or as some higher power of the atom's velocity. The one systematic frequency shift which is dramatically different is the frequency shift due to the collisions between the laser cooled atoms. At a temperature of a few micro-K, the de Broglie wavelength (lambda(sub deB) = h/p, where h is Planck's constant and p is the momentum of the atom) is much larger than the scale of the interatomic potential. Under these conditions the collision cross sections can be as large as (lambda(sub deB)(sup 2))/Pi and the frequency shift due to these collisions was recently calculated. In our Cs atomic fountain, we laser cooled and trapped 10(exp 10) Cs atoms in 0.4 s. By shifting the frequencies of the laser beams, the atoms were launched upwards at 2.5 m/s and a fraction of the atoms were optically pumped into the F=3 ground state. The unwanted atoms in the F=4 ground state were removed from the fountain with radiation pressure from a laser beam tuned to excite only those atoms. The Cs atoms in the F=3 state traveled ballistically upwards, were excited by the microwave cavity, and then returned back through the same cavity in the atomic fountain configuration. By varying the cold atom density, a density dependent shift of -12.9 +/- 0.7 mHz or -1.4 x 10-12 for an average fountain density of (2.7 +/- 1.5) 10(exp 9) atoms/cm(sup 3) was measured.

  4. Evaluation the frequency of factor V Leiden mutation in pregnant women with preeclampsia syndrome in an Iranian population

    PubMed Central

    Karimi, Samieh; Yavarian, Majid; Azinfar, Azadeh; Rajaei, Minoo; Azizi Kootenaee, Maryam

    2012-01-01

    Background: Role of genetic factors in etiology of preeclampsia is not confirmed yet. Objective: Gene defect frequency varies in different geographic areas as well as ethnic groups. In this study, the role of factor V Leiden mutation in the pathogenesis of preeclampsia syndrome among the pregnant population of northern shore of Persian Gulf in Iran, were considered. Materials and Methods: Between Jan. 2008 and Dec. 2009, in a nested case control study, pregnant women with preeclampsia (N=198) as cases and healthy (N=201) as controls were enrolled in the study. DNA were extracted from 10 CC peripheral blood and analyzed for presence of factor V Leiden mutation in these subjects. The maternal and neonatal outcomes of pregnancy according to the distribution of factor V Leiden were also compared among cases. Results: In total, 17(8.6%) of cases and 2(1%) of controls showed the factor V Leiden mutation. The incidence of factor V Leiden was typically higher in preeclamptic women than control group (OR: 9.34 %95 CI: 2.12-41.01). There was no difference in incidence rate of preterm delivery< 37 weeks (OR: 1.23 %95 CI: 0.38-4.02), very early preterm delivery<32 weeks (OR: 1.00 %95 CI: 0.12-8.46), intra uterine fetal growth restriction (IUGR) (OR: 1.32 %95 CI: 0.15-11.30 ),and the rate of cesarean section (OR: 0.88 %95 CI: 0.29-2.62 ) among cases based on the prevalence of factor V Leiden mutation. Conclusion: The pregnant women with factor V Leiden mutation are prone for preeclampsia syndrome during pregnancy, but this risk factor was not correlated to pregnancy complications in the studied women. PMID:25242976

  5. Screening the Expression of ABCB6 in Erythrocytes Reveals an Unexpectedly High Frequency of Lan Mutations in Healthy Individuals

    PubMed Central

    Kiss, Katalin; Varady, Gyorgy; Gera, Melinda; Antalffy, Geza; Andrikovics, Hajnalka; Tordai, Attila; Studzian, Maciej; Strapagiel, Dominik; Pulaski, Lukasz; Tani, Yoshihiko; Sarkadi, Balazs; Szakacs, Gergely

    2014-01-01

    Lan is a high-incidence blood group antigen expressed in more than 99.9% of the population. Identification of the human ABC transporter ABCB6 as the molecular basis of Lan has opened the way for studies assessing the relation of ABCB6 function and expression to health and disease. To date, 34 ABCB6 sequence variants have been described in association with reduced ABCB6 expression based on the genotyping of stored blood showing weak or no reactivity with anti-Lan antibodies. In the present study we examined the red blood cell (RBC) surface expression of ABCB6 by quantitative flow cytometry in a cohort of 47 healthy individuals. Sequencing of the entire coding region of the ABCB6 gene in low RBC ABCB6 expressors identified a new allele (IVS9+1G>A, affecting a putative splice site at the boundary of exon 9) and two nonsynonymous SNPs listed in the SNP database (R192Q (rs150221689) and G588 S (rs145526996)). The R192Q mutation showed co-segregation with reduced RBC ABCB6 expression in a family, and we found the G588 S mutation in a compound heterozygous individual with undetectable ABCB6 expression, suggesting that both mutations result in weak or no expression of ABCB6 on RBCs. Analysis of the intracellular expression pattern in HeLa cells by confocal microscopy indicated that these mutations do not compromise overall expression or the endolysosomal localization of ABCB6. Genotyping of two large cohorts, containing 235 and 1039 unrelated volunteers, confirmed the high allele frequency of Lan-mutations. Our results suggest that genetic variants linked to lower or absent cell surface expression of ABCB6/Langereis may be more common than previously thought. PMID:25360778

  6. Predictable allele frequency changes due to habitat fragmentation in the Glanville fritillary butterfly.

    PubMed

    Fountain, Toby; Nieminen, Marko; Sirén, Jukka; Wong, Swee Chong; Hanski, Ilkka

    2016-03-01

    Describing the evolutionary dynamics of now extinct populations is challenging, as their genetic composition before extinction is generally unknown. The Glanville fritillary butterfly has a large extant metapopulation in the Åland Islands in Finland, but declined to extinction in the nearby fragmented southwestern (SW) Finnish archipelago in the 20th century. We genotyped museum samples for 222 SNPs across the genome, including SNPs from candidate genes and neutral regions. SW Finnish populations had significantly reduced genetic diversity before extinction, and their allele frequencies gradually diverged from those in contemporary Åland populations over 80 y. We identified 15 outlier loci among candidate SNPs, mostly related to flight, in which allele frequencies have changed more than the neutral expectation. At outlier loci, allele frequencies in SW Finland shifted in the same direction as newly established populations deviated from old local populations in contemporary Åland. Moreover, outlier allele frequencies in SW Finland resemble those in fragmented landscapes as opposed to continuous landscapes in the Baltic region. These results indicate selection for genotypes associated with good colonization capacity in the highly fragmented landscape before the extinction of the populations. Evolutionary response to habitat fragmentation may have enhanced the viability of the populations, but it did not save the species from regional extinction in the face of severe habitat loss and fragmentation. These results highlight a potentially common situation in changing environments: evolutionary changes are not strong enough to fully compensate for the direct adverse effects of environmental change and thereby rescue populations from extinction.

  7. Subfraction analysis of circulating lipoproteins in a patient with Tangier disease due to a novel ABCA1 mutation.

    PubMed

    Murano, Takeyoshi; Yamaguchi, Takashi; Tatsuno, Ichiro; Suzuki, Masayo; Noike, Hirofumi; Takanami, Tarou; Yoshida, Tomoe; Suzuki, Mitsuya; Hashimoto, Ryuya; Maeno, Takatoshi; Terai, Kensuke; Tokuyama, Wataru; Hiruta, Nobuyuki; Schneider, Wolfgang J; Bujo, Hideaki

    2016-01-15

    Tangier disease, characterized by low or absent high-density lipoprotein (HDL), is a rare hereditary lipid storage disorder associated with frequent, but not obligatory, severe premature atherosclerosis due to disturbed reverse cholesterol transport from tissues. The reasons for the heterogeneity in atherogenicity in certain dyslipidemias have not been fully elucidated. Here, using high-performance liquid chromatography with a gel filtration column (HPLC-GFC), we have studied the lipoprotein profile of a 17-year old male patient with Tangier disease who to date has not developed manifest coronary atherosclerosis. The patient was shown to be homozygous for a novel mutation (Leu1097Pro) in the central cytoplasmic region of ATP-binding cassette transporter A1 (ABCA1). Serum total and HDL-cholesterol levels were 59mg/dl and 2mg/dl, respectively. Lipoprotein electrophoretic analyses on agarose and polyacrylamide gels showed the presence of massively abnormal lipoproteins. Further analysis by HPLC-GFC identified significant amounts of lipoproteins in low-density lipoprotein (LDL) subfractions. The lipoprotein particles found in the peak subfraction were smaller than normal LDL, were rich in triglycerides, but poor in cholesterol and phospholipids. These findings in an adolescent Tangier patient suggest that patients in whom these triglyceride-rich, cholesterol- and phospholipid-poor LDL-type particles accumulate over time, would experience an increased propensity for developing atherosclerosis. PMID:26616730

  8. L712V mutation in the androgen receptor gene causes complete androgen insensitivity syndrome due to severe loss of androgen function.

    PubMed

    Rajender, Singh; Gupta, Nalini J; Chakrabarty, Baidyanath; Singh, Lalji; Thangaraj, Kumarasamy

    2013-12-11

    Inability to respond to the circulating androgens is named as androgen insensitivity syndrome (AIS). Mutations in the androgen receptor (AR) gene are the most common cause of AIS. A cause and effect relationship between some of these mutations and the AIS phenotype has been proven by in vitro studies. Several other mutations have been identified, but need to be functionally validated for pathogenicity. Screening of the AR mutations upon presumptive diagnosis of AIS is recommended. We analyzed a case of complete androgen insensitivity syndrome (CAIS) for mutations in the AR gene. Sequencing of the entire coding region revealed C>G mutation (CTT-GTT) at codon 712 (position according to the NCBI database) in exon 4 of the gene, resulting in replacement of leucine with valine in the ligand-binding domain of the AR protein. No incidence of this mutation was observed in 230 normal male individuals analyzed for comparison. In vitro androgen binding and transactivation assays using mutant clone showed approximately 71% loss of ligand binding and about 76% loss of transactivation function. We conclude that CAIS in this individual was due to L712V substitution in the androgen receptor protein.

  9. Optic atrophy and a Leigh-like syndrome due to mutations in the c12orf65 gene: report of a novel mutation and review of the literature.

    PubMed

    Heidary, Gena; Calderwood, Laurel; Cox, Gerald F; Robson, Caroline D; Teot, Lisa A; Mullon, Jennifer; Anselm, Irina

    2014-03-01

    Combined oxidative phosphorylation deficiency type 7 (COXPD7) is a rare disorder of mitochondrial metabolism that results in optic atrophy and Leigh syndrome-like disease. We describe 2 siblings with compound heterozygous mutations in the recently identified C12orf65 gene who presented with optic atrophy and mild developmental delays and subsequently developed bilateral, symmetric lesions in the brainstem reminiscent of Leigh syndrome. Repeat neuroimaging demonstrated reversibility of the findings in 1 sibling and persistent metabolic stroke in the other. This article highlights the phenotypic manifestations from a novel mutation in the C12orf65 gene and reviews the clinical presentation of the 5 other individuals reported to date who carry mutations in this gene. PMID:24284555

  10. The Splicing Efficiency of Activating HRAS Mutations Can Determine Costello Syndrome Phenotype and Frequency in Cancer.

    PubMed

    Hartung, Anne-Mette; Swensen, Jeff; Uriz, Inaki E; Lapin, Morten; Kristjansdottir, Karen; Petersen, Ulrika S S; Bang, Jeanne Mari V; Guerra, Barbara; Andersen, Henriette Skovgaard; Dobrowolski, Steven F; Carey, John C; Yu, Ping; Vaughn, Cecily; Calhoun, Amy; Larsen, Martin R; Dyrskjøt, Lars; Stevenson, David A; Andresen, Brage S

    2016-05-01

    Costello syndrome (CS) may be caused by activating mutations in codon 12/13 of the HRAS proto-oncogene. HRAS p.Gly12Val mutations have the highest transforming activity, are very frequent in cancers, but very rare in CS, where they are reported to cause a severe, early lethal, phenotype. We identified an unusual, new germline p.Gly12Val mutation, c.35_36GC>TG, in a 12-year-old boy with attenuated CS. Analysis of his HRAS cDNA showed high levels of exon 2 skipping. Using wild type and mutant HRAS minigenes, we confirmed that c.35_36GC>TG results in exon 2 skipping by simultaneously disrupting the function of a critical Exonic Splicing Enhancer (ESE) and creation of an Exonic Splicing Silencer (ESS). We show that this vulnerability of HRAS exon 2 is caused by a weak 3' splice site, which makes exon 2 inclusion dependent on binding of splicing stimulatory proteins, like SRSF2, to the critical ESE. Because the majority of cancer- and CS- causing mutations are located here, they affect splicing differently. Therefore, our results also demonstrate that the phenotype in CS and somatic cancers is not only determined by the different transforming potentials of mutant HRAS proteins, but also by the efficiency of exon 2 inclusion resulting from the different HRAS mutations. Finally, we show that a splice switching oligonucleotide (SSO) that blocks access to the critical ESE causes exon 2 skipping and halts proliferation of cancer cells. This unravels a potential for development of new anti-cancer therapies based on SSO-mediated HRAS exon 2 skipping.

  11. The Splicing Efficiency of Activating HRAS Mutations Can Determine Costello Syndrome Phenotype and Frequency in Cancer

    PubMed Central

    Kristjansdottir, Karen; Petersen, Ulrika S. S.; Bang, Jeanne Mari V.; Guerra, Barbara; Andersen, Henriette Skovgaard; Dobrowolski, Steven F.; Carey, John C.; Yu, Ping; Calhoun, Amy; Larsen, Martin R.; Dyrskjøt, Lars; Stevenson, David A.; Andresen, Brage S.

    2016-01-01

    Costello syndrome (CS) may be caused by activating mutations in codon 12/13 of the HRAS proto-oncogene. HRAS p.Gly12Val mutations have the highest transforming activity, are very frequent in cancers, but very rare in CS, where they are reported to cause a severe, early lethal, phenotype. We identified an unusual, new germline p.Gly12Val mutation, c.35_36GC>TG, in a 12-year-old boy with attenuated CS. Analysis of his HRAS cDNA showed high levels of exon 2 skipping. Using wild type and mutant HRAS minigenes, we confirmed that c.35_36GC>TG results in exon 2 skipping by simultaneously disrupting the function of a critical Exonic Splicing Enhancer (ESE) and creation of an Exonic Splicing Silencer (ESS). We show that this vulnerability of HRAS exon 2 is caused by a weak 3’ splice site, which makes exon 2 inclusion dependent on binding of splicing stimulatory proteins, like SRSF2, to the critical ESE. Because the majority of cancer- and CS- causing mutations are located here, they affect splicing differently. Therefore, our results also demonstrate that the phenotype in CS and somatic cancers is not only determined by the different transforming potentials of mutant HRAS proteins, but also by the efficiency of exon 2 inclusion resulting from the different HRAS mutations. Finally, we show that a splice switching oligonucleotide (SSO) that blocks access to the critical ESE causes exon 2 skipping and halts proliferation of cancer cells. This unravels a potential for development of new anti-cancer therapies based on SSO-mediated HRAS exon 2 skipping. PMID:27195699

  12. An evolutionary approach to the high frequency of the Delta F508 CFTR mutation in European populations.

    PubMed

    Alfonso-Sánchez, Miguel A; Pérez-Miranda, Ana M; García-Obregón, Susana; Peña, José A

    2010-06-01

    The diffusion of the cattle pastoralism across Europe during the Neolithic period was probably accompanied by the emergence and spread of diverse contagious diseases that were unknown in the Paleolithic and that would have affected the frequency of genes directly or indirectly associated with differential susceptibility and/or resistance to infectious pathogens. We therefore propose that the high frequency of the CFTR gene, and in particular, the common Delta F508 allele mutation in current European and European-derived populations might be a consequence of the impact of selective pressures generated by the transmission of pathogenic agents from domesticated animals, mainly bovine cattle, to the man. Intestinal infectious diseases were probably a major health problem for Neolithic peoples. In such a context, a gene mutation that conferred an increased resistance to the diseases caused by pathogens transmitted by dairy cattle would have constituted a definite selective advantage, particularly in those human groups where cow's milk became an essential component of the diet. This selective advantage would be determined by an increased resistance to Cl(-)-secreting diarrheas of those individuals carrying a single copy of the Delta F508 CFTR mutation (heterozygote resistance). This hypothesis is supported by the strong association between the geography of the diffusion of cattle pastoralism (assessed indirectly by the lactase persistence distribution), the geographic distribution of a sizeable number of HLA alleles (as indicative of potential selective pressures generated by epidemic mortality) and the geographic distribution of the most common mutation causing cystic fibrosis (Delta F508). The systematic interaction of humans with infectious pathogens would have begun in northern Europe, among the carriers of the Funnel Beaker Culture, the first farmers of the North European plain, moving progressively to the south with the dissemination of the cattle pastoralism. This

  13. Spectrum and frequency of GJB2, GJB6 and SLC26A4 gene mutations among nonsyndromic hearing loss patients in eastern part of India.

    PubMed

    Adhikary, Bidisha; Ghosh, Sudakshina; Paul, Silpita; Bankura, Biswabandhu; Pattanayak, Arup Kumar; Biswas, Subhradev; Maity, Biswanath; Das, Madhusudan

    2015-12-01

    Genetically caused nonsyndromic hearing loss is highly heterogeneous. Inspite of this large heterogeneity, mutations in the genes GJB2, GJB6 and SLC26A4 are major contributors. The mutation spectrum of these genes varies among different ethnic groups. Only a handful of studies focused on the altered genetic signature of these genes in different demographic regions of India but never focused on the eastern part of the country. Our study for the first time aimed to characterize the mutation profile of these genes in hearing loss patients of West Bengal state, India. Mutations in GJB2, GJB6 and SLC26A4 genes were screened by bidirectional sequencing from 215 congenital nonsyndromic hearing loss patients. Radiological diagnosis was performed in patients with SLC26A4 mutations by temporal bone CT scan. The study revealed that 4.65% and 6.97% patients had monoallelic and biallelic GJB2 mutations respectively. Six mutations were identified, p.W24X being the most frequent one accounting for 71.05% of the mutated alleles. Mutations in GJB6 including the previously identified deletion mutation (GJB6-D13S1830) were not identified in our study. Further, no patients harbored biallelic mutations in the SLC26A4 gene or the common inner ear malformation Enlarged Vestibular Aqueduct (EVA). The mutation profile of GJB2 in our study is distinct from other parts of India, suggesting that the mutation spectrum of this gene varies with ethnicity and geographical origin. The absence of GJB6 mutations and low frequency of SLC26A4 mutations suggest that additional genetic factors may also contribute to this disease.

  14. Mitigating Oscillator Pulling Due To Magnetic Coupling in Monolithic Mixed-Signal Radio-Frequency Integrated Circuits

    SciTech Connect

    Sobering, Ian David

    2014-01-01

    An analysis of frequency pulling in a varactor-tuned LC VCO under coupling from an on-chip PA is presented. The large-signal behavior of the VCO's inversion-mode MOS varactors is outlined, and the susceptibility of the VCO to frequency pulling from PA aggressor signals with various modulation schemes is discussed. We show that if the aggressor signal is aperiodic, band-limited, or amplitude-modulated, the varactor-tuned LC VCO will experience frequency pulling due to time-modulation of the varactor capacitance. However, if the aggressor signal has constant-envelope phase modulation, VCO pulling can be eliminated, even in the presence of coupling, through careful choice of VCO frequency and divider ratio. Additional mitigation strategies, including new inductor topologies and system-level architectural choices, are also examined.

  15. Predictable allele frequency changes due to habitat fragmentation in the Glanville fritillary butterfly

    PubMed Central

    Fountain, Toby; Nieminen, Marko; Sirén, Jukka; Wong, Swee Chong; Lehtonen, Rainer; Hanski, Ilkka

    2016-01-01

    Describing the evolutionary dynamics of now extinct populations is challenging, as their genetic composition before extinction is generally unknown. The Glanville fritillary butterfly has a large extant metapopulation in the Åland Islands in Finland, but declined to extinction in the nearby fragmented southwestern (SW) Finnish archipelago in the 20th century. We genotyped museum samples for 222 SNPs across the genome, including SNPs from candidate genes and neutral regions. SW Finnish populations had significantly reduced genetic diversity before extinction, and their allele frequencies gradually diverged from those in contemporary Åland populations over 80 y. We identified 15 outlier loci among candidate SNPs, mostly related to flight, in which allele frequencies have changed more than the neutral expectation. At outlier loci, allele frequencies in SW Finland shifted in the same direction as newly established populations deviated from old local populations in contemporary Åland. Moreover, outlier allele frequencies in SW Finland resemble those in fragmented landscapes as opposed to continuous landscapes in the Baltic region. These results indicate selection for genotypes associated with good colonization capacity in the highly fragmented landscape before the extinction of the populations. Evolutionary response to habitat fragmentation may have enhanced the viability of the populations, but it did not save the species from regional extinction in the face of severe habitat loss and fragmentation. These results highlight a potentially common situation in changing environments: evolutionary changes are not strong enough to fully compensate for the direct adverse effects of environmental change and thereby rescue populations from extinction. PMID:26903642

  16. Predictable allele frequency changes due to habitat fragmentation in the Glanville fritillary butterfly.

    PubMed

    Fountain, Toby; Nieminen, Marko; Sirén, Jukka; Wong, Swee Chong; Hanski, Ilkka

    2016-03-01

    Describing the evolutionary dynamics of now extinct populations is challenging, as their genetic composition before extinction is generally unknown. The Glanville fritillary butterfly has a large extant metapopulation in the Åland Islands in Finland, but declined to extinction in the nearby fragmented southwestern (SW) Finnish archipelago in the 20th century. We genotyped museum samples for 222 SNPs across the genome, including SNPs from candidate genes and neutral regions. SW Finnish populations had significantly reduced genetic diversity before extinction, and their allele frequencies gradually diverged from those in contemporary Åland populations over 80 y. We identified 15 outlier loci among candidate SNPs, mostly related to flight, in which allele frequencies have changed more than the neutral expectation. At outlier loci, allele frequencies in SW Finland shifted in the same direction as newly established populations deviated from old local populations in contemporary Åland. Moreover, outlier allele frequencies in SW Finland resemble those in fragmented landscapes as opposed to continuous landscapes in the Baltic region. These results indicate selection for genotypes associated with good colonization capacity in the highly fragmented landscape before the extinction of the populations. Evolutionary response to habitat fragmentation may have enhanced the viability of the populations, but it did not save the species from regional extinction in the face of severe habitat loss and fragmentation. These results highlight a potentially common situation in changing environments: evolutionary changes are not strong enough to fully compensate for the direct adverse effects of environmental change and thereby rescue populations from extinction. PMID:26903642

  17. Evidence that in xeroderma pigmentosum variant cells, which lack DNA polymerase eta, DNA polymerase iota causes the very high frequency and unique spectrum of UV-induced mutations.

    PubMed

    Wang, Yun; Woodgate, Roger; McManus, Terrence P; Mead, Samantha; McCormick, J Justin; Maher, Veronica M

    2007-04-01

    Xeroderma pigmentosum variant (XPV) patients have normal DNA excision repair, yet are predisposed to develop sunlight-induced cancer. They exhibit a 25-fold higher than normal frequency of UV-induced mutations and very unusual kinds (spectrum), mainly transversions. The primary defect in XPV cells is the lack of functional DNA polymerase (Pol) eta, the translesion synthesis DNA polymerase that readily inserts adenine nucleotides opposite photoproducts involving thymine. The high frequency and striking difference in kinds of UV-induced mutations in XPV cells strongly suggest that, in the absence of Pol eta, an abnormally error-prone polymerase substitutes. In vitro replication studies of Pol iota show that it replicates past 5'T-T3' and 5'T-U3' cyclobutane pyrimidine dimers, incorporating G or T nucleotides opposite the 3' nucleotide. To test the hypothesis that Pol iota causes the high frequency and abnormal spectrum of UV-induced mutations in XPV cells, we identified an unlimited lifespan XPV cell line expressing two forms of Pol iota, whose frequency of UV-induced mutations is twice that of XPV cells expressing one form. We eliminated expression of one form and compared the parental cells and derivatives for the frequency and kinds of UV-induced mutations. All exhibited similar sensitivity to the cytotoxicity of UV((254 nm)), and the kinds of mutations induced were identical, but the frequency of mutations induced in the derivatives was reduced to frequency and abnormal spectrum of UV-induced mutations, and ultimately their malignant transformation.

  18. [Reliability of the Search for 19 Common Mutations in the CFTR Gene in Russian Cystic Fibrosis Patients and the Calculated Frequency of the Disease in Russian Federation].

    PubMed

    Stepanova, A A; Krasovsky, S A; Polyakov, A V

    2016-02-01

    A study of Russian cystic fibrosis (CF) patient DNA was conducted to assess the incidence frequency of 19 mutations, namely CFTRdele2,3(21kb), F508del, I507del, 1677delTA, 2143delT, 2184insA, 394delTT, 3821delT, L138ins, 604insA, 3944delGT, G542X, W128X, N1303K, R334W, and 3849+10kbC>T, S1196X, 621+1g>t, and E92K of the CFTR gene. We also sought to determine the estimated CF frequency in Russian Federation. In addition, we determined the total information content of the approach for 19 common mutations registration in the CFTR gene, 84.6%, and the allelic frequencies of the examined mutations: three mutations were observed with a frequency exceeding 5% (F508del, 53.98%, E92K, 6.47%, CFTRdele2,3(21kb), 5.35%); other mutations were observed with frequencies ranging from 0.13% to 3.0%. The CF population carrier frequency was 1 in 38 subjects, while the predicted CF frequency was 1 in 5776 newborns. PMID:27215038

  19. [Reliability of the Search for 19 Common Mutations in the CFTR Gene in Russian Cystic Fibrosis Patients and the Calculated Frequency of the Disease in Russian Federation].

    PubMed

    Stepanova, A A; Krasovsky, S A; Polyakov, A V

    2016-02-01

    A study of Russian cystic fibrosis (CF) patient DNA was conducted to assess the incidence frequency of 19 mutations, namely CFTRdele2,3(21kb), F508del, I507del, 1677delTA, 2143delT, 2184insA, 394delTT, 3821delT, L138ins, 604insA, 3944delGT, G542X, W128X, N1303K, R334W, and 3849+10kbC>T, S1196X, 621+1g>t, and E92K of the CFTR gene. We also sought to determine the estimated CF frequency in Russian Federation. In addition, we determined the total information content of the approach for 19 common mutations registration in the CFTR gene, 84.6%, and the allelic frequencies of the examined mutations: three mutations were observed with a frequency exceeding 5% (F508del, 53.98%, E92K, 6.47%, CFTRdele2,3(21kb), 5.35%); other mutations were observed with frequencies ranging from 0.13% to 3.0%. The CF population carrier frequency was 1 in 38 subjects, while the predicted CF frequency was 1 in 5776 newborns.

  20. Development of primary early-onset colorectal cancers due to biallelic mutations of the FANCD1/BRCA2 gene

    PubMed Central

    Degrolard-Courcet, Emilie; Sokolowska, Joanna; Padeano, Marie-Martine; Guiu, Séverine; Bronner, Myriam; Chery, Carole; Coron, Fanny; Lepage, Côme; Chapusot, Caroline; Loustalot, Catherine; Jouve, Jean-Louis; Hatem, Cyril; Ferrant, Emmanuelle; Martin, Laurent; Coutant, Charles; Baurand, Amandine; Couillault, Gérard; Delignette, Alexandra; El Chehadeh, Salima; Lizard, Sarab; Arnould, Laurent; Fumoleau, Pierre; Callier, Patrick; Mugneret, Francine; Philippe, Christophe; Frebourg, Thierry; Jonveaux, Philippe; Faivre, Laurence

    2014-01-01

    Fanconi anaemia (FA) is characterized by progressive bone marrow failure, congenital anomalies, and predisposition to malignancy. In a minority of cases, FA results from biallelic FANCD1/BRCA2 mutations that are associated with early-onset leukaemia and solid tumours. Here, we describe the clinical and molecular features of a remarkable family presenting with multiple primary colorectal cancers (CRCs) without detectable mutations in genes involved in the Mendelian predisposition to CRCs. We unexpectedly identified, despite the absence of clinical cardinal features of FA, a biallelic mutation of the FANCD1/BRCA2 corresponding to a frameshift alteration (c.1845_1846delCT, p.Asn615Lysfs*6) and a missense mutation (c.7802A>G, p.Tyr2601Cys). The diagnosis of FA was confirmed by the chromosomal analysis of lymphocytes. Reverse transcriptase (RT)-PCR analysis revealed that the c.7802A>G BRCA2 variation was in fact a splicing mutation that creates an aberrant splicing donor site and results partly into an aberrant transcript encoding a truncated protein (p.Tyr2601Trpfs*46). The atypical FA phenotype observed within this family was probably explained by the residual amount of BRCA2 with the point mutation c.7802A>G in the patients harbouring the biallelic FANCD1/BRCA2 mutations. Although this report is based in a single family, it suggests that CRCs may be part of the tumour spectrum associated with FANCD1/BRCA2 biallelic mutations and that the presence of such mutations should be considered in families with CRCs, even in the absence of cardinal features of FA. PMID:24301060

  1. Primary open angle glaucoma due to T377M MYOC: Population mapping of a Greek founder mutation in Northwestern Greece

    PubMed Central

    Kitsos, George; Petrou, Zacharias; Grigoriadou, Maria; Samples, John R; Hewitt, Alex W; Kokotas, Haris; Giannoulia-Karantana, Aglaia; Mackey, David A; Wirtz, Mary K; Moschou, Marilita; Ioannidis, John PA; Petersen, Michael B

    2010-01-01

    Background: Mutations in the MYOC gene have been shown to explain 5% of unrelated primary open angle glaucoma (POAG) in different populations. In particular, the T377M MYOC mutation has arisen at least three separate times in history, in Great Britain, India, and Greece. The purpose of this study is to investigate the distribution of the mutation among different population groups in the northwestern region of Greece. Materials and methods: We explored the distribution of the “Greek” T377M founder mutation in the Epirus region in Northwestern Greece, which could be its origin. Genotyping was performed in POAG cases and controls by PCR amplification of the MYOC gene, followed by digestion with restriction enzyme. Statistical analyses were performed by an exact test, the Kaplan–Meier method and the t-test. Results: In the isolated Chrysovitsa village in the Pindus Mountains, a large POAG family demonstrated the T377M mutation in 20 of 66 family members while no controls from the Epirus region (n = 124) carried this mutation (P < 0.001). Among other POAG cases from Epirus, 2 out of 14 familial cases and 1 out of 80 sporadic cases showed the mutation (P = 0.057). The probability of POAG diagnosis with advancing age among mutation carriers was 23% at age 40, and reached 100% at age 75. POAG patients with the T377M mutation were diagnosed at a mean age of 51 years (SD ± 13.9), which is younger than the sporadic or familial POAG cases: 63.1 (SD ± 11) and 66.8 (SD ± 9.8) years, respectively. Conclusions: The T377M mutation was found in high proportion in members of the Chrysovitsa family (30.3%), in lower proportion in familial POAG cases (14.2%) and seems rare in sporadic POAG cases (1.2%), while no controls (0%) from the Epirus region carried the mutation. Historical and geographical data may explain the distribution of this mutation within Greece and worldwide. PMID:20390039

  2. Frequency of Births Due to Assisted Reproductive Technology (ART) in Prader-Willi Syndrome

    PubMed Central

    Gold, June-Anne; Ruth, Chelsey; Osann, Kathryn; Flodman, Pamela; McManus, Barbara; Lee, Hye-Seung; Donkervoort, Sandra; Khare, Manaswitha; Roof, Elizabeth; Dykens, Elizabeth; Driscoll, Daniel J.; Butler, Merlin G.; Heinemann, Janalee; Cassidy, Suzanne; Kimonis, Virginia

    2014-01-01

    Purpose Prader-Willi syndrome (PWS) is an imprinting disorder characterized by typical facial, physical and cognitive/behavioral features, resulting from lack of paternally-expressed genes on chromosome 15q11.2-q13. Studies have suggested an increased risk of other imprinting disorders in children conceived by assisted reproductive techniques (ART). This study was designed to determine the association between ART and PWS. Methods Data on individuals with PWS were collected from three distinct sources and the proportion of ART-births analyzed. Results The proportion of ART-births in the Prader-Willi Syndrome Association [PWSA (USA)], Rare Diseases Clinical Research Network (RDCRN), and University of California, Irvine Medical Center (UCIMC) populations was 1.0% (18/1,736), 1.0% (1/98), and 2.0% (1/50), respectively (overall 1.1%; population frequency for the U.S was 1.0%). Interestingly, 2.4% (45/1,898) of participants were co-twins (eleven born after ART procedures); U.S. twin frequency is 1.6% (p=0.007). The proportion of individuals with maternal disomy 15/imprinting defects born after ART was higher than in the total sample, 55.6% (10/18) and 34.5% (431/1,250), respectively. Conclusion This study found no association between ART and PWS. There was an increased frequency of twinning. The number of individuals with maternal disomy 15/imprinting defect was nearly double in the ART group compared to the total PWS participants. PMID:23928912

  3. KRAS and PIK3CA mutation frequencies in patient-derived xenograft models of pancreatic and colorectal cancer are reflective of patient tumors and stable across passages.

    PubMed

    Tignanelli, Christopher J; Herrera Loeza, Silvia G; Yeh, Jen Jen

    2014-09-01

    One obstacle in the translation of advances in cancer research into the clinic is a deficiency of adequate preclinical models that recapitulate human disease. Patient-derived xenograft (PDX) models are established by engrafting patient tumor tissue into mice and are advantageous because they capture tumor heterogeneity. One concern with these models is that selective pressure could lead to mutational drift and thus be an inaccurate reflection of patient tumors. Therefore, we evaluated if mutational frequency in PDX models is reflective of patient populations and if crucial mutations are stable across passages. We examined KRAS and PIK3CA gene mutations from pancreatic ductal adenocarcinoma (PDAC) (n = 30) and colorectal cancer (CRC) (n = 37) PDXs for as many as eight passages. DNA was isolated from tumors and target sequences were amplified by polymerase chain reaction. KRAS codons 12/13 and PIK3CA codons 542/545/1047 were examined using pyrosequencing. Twenty-three of 30 (77%) PDAC PDXs had KRAS mutations and one of 30 (3%) had PIK3CA mutations. Fifteen of 37 (41%) CRC PDXs had KRAS mutations and three of 37 (8%) had PIK3CA mutations. Mutations were 100 per cent preserved across passages. We found that the frequency of KRAS (77%) and PIK3CA (3%) mutations in PDAC PDX was similar to frequencies in patient tumors (71 to 100% KRAS, 0 to 11% PIK3CA). Similarly, KRAS (41%) and PIK3CA (8%) mutations in CRC PDX closely paralleled patient tumors (35 to 51% KRAS, 12 to 21% PIK3CA). The accurate mirroring and stability of genetic changes in PDX models compared with patient tumors suggest that these models are good preclinical surrogates for patient tumors.

  4. Anomalous Electron Transport Due to Multiple High Frequency Beam Ion Driven Alfven Eigenmode

    SciTech Connect

    Gorelenkov, N. N.; Stutman, D.; Tritz, K.; Boozer, A.; Delgardo-Aparicio, L.; Fredrickson, E.; Kaye, S.; White, R.

    2010-07-13

    We report on the simulations of recently observed correlations of the core electron transport with the sub-thermal ion cyclotron frequency instabilities in low aspect ratio plasmas of the National Spherical Torus Experiment (NSTX). In order to model the electron transport of the guiding center code ORBIT is employed. A spectrum of test functions of multiple core localized Global shear Alfven Eigenmode (GAE) instabilities based on a previously developed theory and experimental observations is used to examine the electron transport properties. The simulations exhibit thermal electron transport induced by electron drift orbit stochasticity in the presence of multiple core localized GAE.

  5. Analysis of the transverse kick to beams in low-frequency photoinjectors due to wakefield effects

    NASA Astrophysics Data System (ADS)

    Salah, Wa'el; Jones, Roger M.; Coacolo, J.-L.

    2009-04-01

    A time domain analysis of the normal modes in a cavity is used to obtain an analytical expression for the transverse momentum imparted to particles within an accelerated electron beam in a low frequency photoinjector. These analytical expressions form the basis of detailed simulations on the transverse momentum imparted to an accelerated beam. This analysis of the wakefields employs a modified form of the Panofsky-Wenzel theorem in which additional velocity dependent effects are taken into account. Simulations are presented for parameters of the ELSA photocathode.

  6. Greater variation in BCL-2 mutation frequency among lymphocytes of heavy smokers than among those of controls

    SciTech Connect

    Cortopassi, G.A.; Liu, Y.; Bell, D.A.

    1994-12-31

    It is possible that the risk for tumors in specific human individuals might be most usefully estimated by determining the frequency of (rare) somatic mutations at oncogenic loci in their tissue. Using a sensitive nested PCR assay, we have investigated the frequency of rare t(14;18) (q32;q21) translocations at the bcl-2 proto-oncogene locus in peripheral blood lymphocytes of 85 smokers and 36 control non-smokers. The variation in translocation frequencies (plus or minus the variation at the 95% confidence interval) were 1.4 {+-} -0.37 per million lymphocytes among smokers, versus 0.53 {+-} -0.20 among non-smokers, a 2.6-fold excess of such oncogenic translocations among lymphocytes of smokers. Logistic regression analysis including age, race, sex, years of smoking and pack-years indicated that only current smoking was significantly associated with increased frequency of the translocation of bcl-2 occur in 85% of follicular lymphoma tumors, and about 50% of all Non-Hodgkin`s Lymphoma, and are thought to be the result of errors of the V(D)J recombinase. Epidemiological studies by others have shown that there is about a two-fold higher relative risk of Non-Hodgkin`s Lymphoma for heavy smokers vs. non-smokers. We speculate that one reason for excess NHL tumors among heavy smokers may be their increased average burden of t(14;18) mutations, and that smoke-derived substances may induce errors of the V(D)J recombinase by mutagenic or antigenic mechanisms.

  7. Dravet syndrome with favourable cognitive and behavioral development due to a novel SCN1A frameshift mutation.

    PubMed

    Jiang, Peifang; Shen, Jue; Yu, Yonglin; Jiang, Lihua; Xu, Jialu; Xu, Lu; Yu, Huimin; Gao, Feng

    2016-07-01

    Children with Dravet syndrome (DS) often have severe cognitive, behaviour and motor impairments. Patients with truncating mutations would logically have the more severe phenotype. Here we present a case of DS with an unusually favourable cognitive and behavioral development with a novel SCN1A frameshift mutation (c.4233-4234insAT). Under regular following up for ten years, the patient had normal expressive language and mild motor clumsiness. It is suggested that besides the type of SCN1A mutation, other mechanisms may be existed to influence the SCN1A phenotype, such as modifier genes, developmental variability, accumulation of somatic mutation in lifetime and environmental insults can all contribute to the cognitive and behavioral outcome.

  8. Isolated case of mental retardation and ataxia due to a de novo mitochondrial T8993G mutation

    SciTech Connect

    De Coo, I.F.M.; Smeets, H.J.M.; Oost, B.A. van

    1996-03-01

    Neurogenic muscle weakness, ataxia, and retinitis pigmentosa (NARP) and subacute necrotizing encephalomyelopathy (Leigh disease) are both associated with an alteration of nt 8993 in the mitochondrial ATPase 6 gene. In NARP, the T-to-G transversion at that position changes leucine into arginine. In Leigh syndrome, the same mutation can be found, as can a T-to-C transition, which changes this leucine into proline. Clinical manifestations occur for NARP when {approximately}60%-90% mutated mtDNA is present. In case of Leigh, these percentages usually exceed 95%. It is known that this mutation can segregate very rapidly within pedigrees. Here we report on a sporadic case with mental retardation and ataxia without retinitis pigmentosa in which the T8993G mutation was found. 13 refs., 1 fig.

  9. Congenital adrenal hyperplasia due to 11-beta-hydroxylase deficiency: functional consequences of four CYP11B1 mutations

    PubMed Central

    Menabò, Soara; Polat, Seher; Baldazzi, Lilia; Kulle, Alexandra E; Holterhus, Paul-Martin; Grötzinger, Joachim; Fanelli, Flaminia; Balsamo, Antonio; Riepe, Felix G

    2014-01-01

    Congenital adrenal hyperplasia (CAH) is one of the most common autosomal recessive inherited endocrine disease. Steroid 11β-hydroxylase deficiency (11β-OHD) is the second most common form of CAH. The aim of the study was to study the functional consequences of three novel and one previously described CYP11B1 gene mutations (p.(Arg143Trp), p.(Ala306Val), p.(Glu310Lys) and p.(Arg332Gln)) detected in patients suffering from classical and non-classical 11β-OHD. Functional analyses were performed by using a HEK293 cell in vitro expression system comparing wild type (WT) with mutant 11β-hydroxylase activity. Mutant proteins were examined in silico to study their effect on the three-dimensional structure of the protein. Two mutations (p.(Ala306Val) and p.(Glu310Lys)) detected in patients with classical 11β-OHD showed a nearly complete loss of 11β-hydroxylase activity. The mutations p.(Arg143Trp) and p.(Arg332Gln) detected in patients with non-classical 11β-OHD showed a partial functional impairment with approximately 8% and 6% of WT activity, respectively. Functional mutation analysis allows the classification of novel CYP11B1 mutations as causes of classical and non-classical 11β-OHD. The detection of patients with non-classical phenotypes underscores the importance to screen patients with a phenotype comparable to non-classical 21-hydroxylase deficiency for mutations in the CYP11B1 gene in case of a negative analysis of the CYP21A2 gene. As CYP11B1 mutations are most often individual for a family, the in vitro analysis of novel mutations is essential for clinical and genetic counselling. PMID:24022297

  10. Linkage Study Revealed Complex Haplotypes in a Multifamily due to Different Mutations in CAPN3 Gene in an Iranian Ethnic Group.

    PubMed

    Mojbafan, Marzieh; Tonekaboni, Seyed Hassan; Abiri, Maryam; Kianfar, Soudeh; Sarhadi, Ameneh; Nilipour, Yalda; Tavakkoly-Bazzaz, Javad; Zeinali, Sirous

    2016-07-01

    Calpainopathy is an autosomal recessive form of limb girdle muscular dystrophies which is caused by mutation in CAPN3 gene. In the present study, co-segregation of this disorder was analyzed with four short tandem repeat markers linked to the CAPN3 gene. Three apparently unrelated Iranian families with same ethnicity were investigated. Haplotype analysis and sequencing of the CAPN3 gene were performed. DNA sample from one of the patients was simultaneously sent for next-generation sequencing. DNA sequencing identified two mutations. It was seen as a homozygous c.2105C>T in exon 19 in one family, a homozygous novel mutation c.380G>A in exon 3 in another family, and a compound heterozygote form of these two mutations in the third family. Next-generation sequencing also confirmed our results. It was expected that, due to the rare nature of limb girdle muscular dystrophies, affected individuals from the same ethnic group share similar mutations. Haplotype analysis showed two different homozygote patterns in two families, yet a compound heterozygote pattern in the third family as seen in the mutation analysis. This study shows that haplotype analysis would help in determining presence of different founders. PMID:27262448

  11. Heat generation in an elastic binder system with embedded discrete energetic particles due to high-frequency, periodic mechanical excitation

    NASA Astrophysics Data System (ADS)

    Mares, J. O.; Miller, J. K.; Gunduz, I. E.; Rhoads, J. F.; Son, S. F.

    2014-11-01

    High-frequency mechanical excitation can induce heating within energetic materials and may lead to advances in explosives detection and defeat. In order to examine the nature of this mechanically induced heating, samples of an elastic binder (Sylgard 184) were embedded with inert and energetic particles placed in a fixed spatial pattern and were subsequently excited with an ultrasonic transducer at discrete frequencies from 100 kHz to 20 MHz. The temperature and velocity responses of the sample surfaces suggest that heating due to frictional effects occurred near the particles at excitation frequencies near the transducer resonance of 215 kHz. An analytical solution involving a heat point source was used to estimate heating rates and temperatures at the particle locations in this frequency region. Heating located near the sample surface at frequencies near and above 1 MHz was attributed to viscoelastic effects related to the surface motion of the samples. At elevated excitation parameters near the transducer resonance frequency, embedded particles of ammonium perchlorate and cyclotetramethylene-tetranitramine were driven to chemical decomposition.

  12. Molecular diagnosis of congenital adrenal hyperplasia due to 21-hydroxylase deficiency: an update of new CYP21A2 mutations.

    PubMed

    Concolino, Paola; Mello, Enrica; Zuppi, Cecilia; Capoluongo, Ettore

    2010-08-01

    Steroid 21-hydroxylase deficiency is present in more than 90% of patients with congenital adrenal hyperplasia, an inherited metabolic disorder of adrenal steroidogenesis. Impaired enzymatic activity leads to the accumulation of metabolic intermediates (progesterone and 17-hydroxyprogesterone), which results in excessive androgen production and varied signs of virilisation. CYP21A2 is an active gene and encodes for the steroid 21-hydroxylase enzyme, whereas CYP21A1P is an inactive pseudogene that contains a series of deleterious mutations. The major part of disease-causing mutations in CYP21A2 alleles are CYP21A1P-derived sequence transferred to the active gene by macro or microconversion events. Approximately 5% of all disease-causing CYP21A2 alleles harbour rare mutations that do not originate from the pseudogene. A list of all reported CYP21A2 mutations can be found in the CYP21A2 database created by the Human Cytochrome P450 (CYP) Allele Nomenclature Committee (http:www.imm.Ki.se/CYPalleles/cyp21.htm). Unfortunately, the last update of this database was in 2006. However, over the last 4 years many other novel CYP21A2 mutations have been reported in PubMed. The aim of this review is to provide a focus on the molecular and genetic aspects of the diagnosis of 21-hydroxylase deficiency. In addition, an updated list of the last new CYP21A2 mutations is included.

  13. Sinusoidal Siemens star spatial frequency response measurement errors due to misidentified target centers

    SciTech Connect

    Birch, Gabriel Carisle; Griffin, John Clark

    2015-07-23

    Numerous methods are available to measure the spatial frequency response (SFR) of an optical system. A recent change to the ISO 12233 photography resolution standard includes a sinusoidal Siemens star test target. We take the sinusoidal Siemens star proposed by the ISO 12233 standard, measure system SFR, and perform an analysis of errors induced by incorrectly identifying the center of a test target. We show a closed-form solution for the radial profile intensity measurement given an incorrectly determined center and describe how this error reduces the measured SFR of the system. As a result, using the closed-form solution, we propose a two-step process by which test target centers are corrected and the measured SFR is restored to the nominal, correctly centered values.

  14. Sinusoidal Siemens star spatial frequency response measurement errors due to misidentified target centers

    DOE PAGESBeta

    Birch, Gabriel Carisle; Griffin, John Clark

    2015-07-23

    Numerous methods are available to measure the spatial frequency response (SFR) of an optical system. A recent change to the ISO 12233 photography resolution standard includes a sinusoidal Siemens star test target. We take the sinusoidal Siemens star proposed by the ISO 12233 standard, measure system SFR, and perform an analysis of errors induced by incorrectly identifying the center of a test target. We show a closed-form solution for the radial profile intensity measurement given an incorrectly determined center and describe how this error reduces the measured SFR of the system. As a result, using the closed-form solution, we proposemore » a two-step process by which test target centers are corrected and the measured SFR is restored to the nominal, correctly centered values.« less

  15. Amplification of radiation near cyclotron frequency due to electron population inversion

    NASA Technical Reports Server (NTRS)

    Lee, L. C.; Wu, C. S.

    1980-01-01

    Amplification of electromagnetic waves via the cyclotron maser mechanism by a population of weakly relativistic electrons is studied. The effect of a tenuous population of low energy background plasma is included. It is found that both the ordinary and extraordinary modes can be excited by the weakly relativistic electrons with a loss-cone distribution. The growth rate for the extraordinary mode is much higher than that for the ordinary mode. Velocity spread in the energetic electron distribution function may reduce the growth rate by a factor of approximately 10 from that in the monoenergetic case. The maximum growth rate for the fast extraordinary mode (X mode) occurs near the upper hybrid cutoff frequency. Numerical results are obtained and discussed.

  16. Potential damage to DC superconducting magnets due to the high frequency electromagnetic waves

    NASA Technical Reports Server (NTRS)

    Gabriel, G. J.

    1977-01-01

    Experimental data are presented in support of the hypothesis that a dc superconducting magnet coil does not behave strictly as an inductor, but as a complicated electrodynamic device capable of supporting electromagnetic waves. Travel times of nanosecond pulses and evidence of sinusoidal standing waves were observed on a prototype four-layer solenoidal coil at room temperature. Ringing observed during switching transients appears as a sequence of multiple reflected square pulses whose durations are related to the layer lengths. With sinusoidal excitation of the coil, the voltage amplitude between a pair of points on the coil exhibits maxima at those frequencies such that the distance between these points is an odd multiple of half wavelength in free space. Evidence indicates that any disturbance, such as that resulting from switching or sudden fault, initiates multiple reflections between layers, thus raising the possibility for sufficiently high voltages to cause breakdown.

  17. Increased frequency of extreme Indian Ocean Dipole events due to greenhouse warming.

    PubMed

    Cai, Wenju; Santoso, Agus; Wang, Guojian; Weller, Evan; Wu, Lixin; Ashok, Karumuri; Masumoto, Yukio; Yamagata, Toshio

    2014-06-12

    The Indian Ocean dipole is a prominent mode of coupled ocean-atmosphere variability, affecting the lives of millions of people in Indian Ocean rim countries. In its positive phase, sea surface temperatures are lower than normal off the Sumatra-Java coast, but higher in the western tropical Indian Ocean. During the extreme positive-IOD (pIOD) events of 1961, 1994 and 1997, the eastern cooling strengthened and extended westward along the equatorial Indian Ocean through strong reversal of both the mean westerly winds and the associated eastward-flowing upper ocean currents. This created anomalously dry conditions from the eastern to the central Indian Ocean along the Equator and atmospheric convergence farther west, leading to catastrophic floods in eastern tropical African countries but devastating droughts in eastern Indian Ocean rim countries. Despite these serious consequences, the response of pIOD events to greenhouse warming is unknown. Here, using an ensemble of climate models forced by a scenario of high greenhouse gas emissions (Representative Concentration Pathway 8.5), we project that the frequency of extreme pIOD events will increase by almost a factor of three, from one event every 17.3 years over the twentieth century to one event every 6.3 years over the twenty-first century. We find that a mean state change--with weakening of both equatorial westerly winds and eastward oceanic currents in association with a faster warming in the western than the eastern equatorial Indian Ocean--facilitates more frequent occurrences of wind and oceanic current reversal. This leads to more frequent extreme pIOD events, suggesting an increasing frequency of extreme climate and weather events in regions affected by the pIOD.

  18. Increased frequency of extreme Indian Ocean Dipole events due to greenhouse warming.

    PubMed

    Cai, Wenju; Santoso, Agus; Wang, Guojian; Weller, Evan; Wu, Lixin; Ashok, Karumuri; Masumoto, Yukio; Yamagata, Toshio

    2014-06-12

    The Indian Ocean dipole is a prominent mode of coupled ocean-atmosphere variability, affecting the lives of millions of people in Indian Ocean rim countries. In its positive phase, sea surface temperatures are lower than normal off the Sumatra-Java coast, but higher in the western tropical Indian Ocean. During the extreme positive-IOD (pIOD) events of 1961, 1994 and 1997, the eastern cooling strengthened and extended westward along the equatorial Indian Ocean through strong reversal of both the mean westerly winds and the associated eastward-flowing upper ocean currents. This created anomalously dry conditions from the eastern to the central Indian Ocean along the Equator and atmospheric convergence farther west, leading to catastrophic floods in eastern tropical African countries but devastating droughts in eastern Indian Ocean rim countries. Despite these serious consequences, the response of pIOD events to greenhouse warming is unknown. Here, using an ensemble of climate models forced by a scenario of high greenhouse gas emissions (Representative Concentration Pathway 8.5), we project that the frequency of extreme pIOD events will increase by almost a factor of three, from one event every 17.3 years over the twentieth century to one event every 6.3 years over the twenty-first century. We find that a mean state change--with weakening of both equatorial westerly winds and eastward oceanic currents in association with a faster warming in the western than the eastern equatorial Indian Ocean--facilitates more frequent occurrences of wind and oceanic current reversal. This leads to more frequent extreme pIOD events, suggesting an increasing frequency of extreme climate and weather events in regions affected by the pIOD. PMID:24919920

  19. Thermoacoustic contrast of prostate cancer due to heating by very high frequency irradiation

    NASA Astrophysics Data System (ADS)

    Patch, S. K.; Hull, D.; Thomas, M.; Griep, SK; Jacobsohn, K.; See, WA

    2015-01-01

    Applying the thermoacoustic (TA) effect to diagnostic imaging was first proposed in the 1980s. The object under test is irradiated by high-power pulses of electromagnetic energy, which heat tissue and cause thermal expansion. Outgoing TA pressure pulses are detected by ultrasound transducers and reconstructed to provide images of the object. The TA contrast mechanism is strongly dependent upon the frequency of the irradiating electromagnetic pulse. When very high frequency (VHF) electromagnetic irradiation is utilized, TA signal production is driven by ionic content. Prostatic fluids contain high levels of ionic metabolites, including citrate, zinc, calcium, and magnesium. Healthy prostate glands produce more ionic metabolites than diseased glands. VHF pulses are therefore expected to generate stronger TA signal in healthy prostate glands than in diseased glands. A benchtop system for performing ex vivo TA computed tomography with VHF energy is described and images are presented. The system utilizes irradiation pulses of 700 ns duration exceeding 20 kW power. Reconstructions frequently visualize anatomic landmarks such as the urethra and verumontanum. TA reconstructions from three freshly excised human prostate glands with little, moderate, and severe cancerous involvement are compared with histology. TA signal strength is negatively correlated with percent cancerous involvement in this small sample size. For the 45 regions of interest analyzed, a reconstruction value of 0.4 mV provides 100% sensitivity but only 29% specificity. This sample size is far too small to draw sweeping conclusions, but the results warrant a larger volume study including comparison of TA images to the gold standard, histology.

  20. Thermoacoustic contrast of prostate cancer due to heating by very high frequency irradiation.

    PubMed

    Patch, S K; Hull, D; Thomas, M; Griep, S K; Jacobsohn, K; See, W A

    2015-01-21

    Applying the thermoacoustic (TA) effect to diagnostic imaging was first proposed in the 1980s. The object under test is irradiated by high-power pulses of electromagnetic energy, which heat tissue and cause thermal expansion. Outgoing TA pressure pulses are detected by ultrasound transducers and reconstructed to provide images of the object. The TA contrast mechanism is strongly dependent upon the frequency of the irradiating electromagnetic pulse. When very high frequency (VHF) electromagnetic irradiation is utilized, TA signal production is driven by ionic content. Prostatic fluids contain high levels of ionic metabolites, including citrate, zinc, calcium, and magnesium. Healthy prostate glands produce more ionic metabolites than diseased glands. VHF pulses are therefore expected to generate stronger TA signal in healthy prostate glands than in diseased glands. A benchtop system for performing ex vivo TA computed tomography with VHF energy is described and images are presented. The system utilizes irradiation pulses of 700 ns duration exceeding 20 kW power. Reconstructions frequently visualize anatomic landmarks such as the urethra and verumontanum. TA reconstructions from three freshly excised human prostate glands with little, moderate, and severe cancerous involvement are compared with histology. TA signal strength is negatively correlated with percent cancerous involvement in this small sample size. For the 45 regions of interest analyzed, a reconstruction value of 0.4 mV provides 100% sensitivity but only 29% specificity. This sample size is far too small to draw sweeping conclusions, but the results warrant a larger volume study including comparison of TA images to the gold standard, histology.

  1. Molecular characterization of twelve patients affected by homocystinuria due to cystathionine beta-synthase deficiency: Report of two novel mutations

    SciTech Connect

    Sebastio, G.; Sperandeo, M.P.; Panico, M.

    1994-09-01

    Cystathionine beta-synthase (CBS) deficiency, an autosomal recessive disorder of sulfur amino acid metabolism (MIM 236200), causes homocystinuria and a clinical presentation involving eye, skeleton, central nervous and vascular systems. Less that 20 mutations of CBS gene have been characterized so far, G919A and T833C being the most commonly reported (36 and 9 out of 62 identified alleles, respectively). We have investigated 12 patients (10 Italians, 1 Jewish-French, 1 Italian-Spanish) and one allele of each patient has been characterized at least. T833C has been found in 7 independent alleles (6 in heterozygosity and 1 in homozygosity); G9191A, the most common mutation in Irish and North-European patients, has never been detected in the present survey. C341T (previously reported in 1 Irish-German patient only) has been found in 3 patients in heterozygosity. Besides the two new mutations previously described, i.e. G374A and C770T, we have identified two additional new missense mutations: C869T, a transition in exon 8, causing a P290L amino acid substitution, and C262T, a transition in exon 2, causing a P88S amino acid change. In 4 additional Italian patients, none of the known mutations have been detected; in one of them, a 50 bp deletion has been found in intron 11. The deletion involves the entire sequence of the second element of a tandem repeat. Conclusions: T833C is the most common panethnic mutation; C341T is relatively widespread, while G919A appears to be restricted to North-European patients. Exons 3 and 8 of the CBS gene are the hot-spots of mutational events leading to CBS deficiency.

  2. Frequency of mitochondrial mutations in non-syndromic hearing loss as well as possibly responsible variants found by whole mitochondrial genome screening

    PubMed Central

    Yano, Takuya; Nishio, Shin-ya; Usami, Shin-ichi

    2014-01-01

    Mutations in mitochondrial DNA (mtDNA) are reported to be responsible for the pathogenesis of maternally inherited hearing loss. Complete mtDNA sequencing may detect pathogenic mutations, but whether they are indeed pathogenic can be difficult to interpret because of normal ethnic-associated haplogroup variation and other rare variations existing among control populations. In this study, we performed systemic mutational analysis of mtDNA in 394 Japanese patients with hearing loss. Two different cohorts were analyzed in this study: Cohort 1, 254 maternally inherited patients; and Cohort 2, 140 patients with various inheritance modes. After screening of the entire mtDNA genome with direct sequencing, we evaluated the frequency of previously reported mutations and the frequency and pathogenicity of the novel variants. As a result, the ‘Confirmed' mitochondrial mutations were found predominantly in Cohort 1 rather than in Cohort 2 (14.6 vs 0.7%). 1555A>G (n=23) is the most common mutation, followed by the 3243A>G (n=11) mutations. On the basis of prediction analysis, we detected 10 novel homoplasmic mitochondrial variants. After further classification, the 3595A>G and 6204A>G variants were found to be new candidate mutations possibly associated with hearing loss. PMID:24401907

  3. Somatic mutation analysis of KRAS, BRAF, HER2 and PTEN in EGFR mutation-negative non-small cell lung carcinoma: determination of frequency, distribution pattern and identification of novel deletion in HER2 gene from Indian patients.

    PubMed

    Bhaumik, Sangeet; Ahmad, Firoz; Das, Bibhu Ranjan

    2016-10-01

    Somatic mutations of KRAS, BRAF, HER2, PTEN genes are the most important molecular markers after the EGFR gene mutation. The current study evaluated the frequency and distribution pattern of KRAS, BRAF, HER2, PTEN mutation in Indian non-small cell lung carcinoma patients. The frequency of KRAS, BRAF, HER2, PTEN mutations was 6.4 % (14/204), 1.5 % (3/204), 1.5 % (3/204), 0 % (0/204), respectively. KRAS, BRAF, HER2 mutations were more prevalent in males than in females. KRAS and HER2 showed a trend of a higher frequency of mutation in the age group of <60 years, whereas BRAF mutations were more frequent in the age group of ≥60 years. Sequencing analysis of KRAS gene revealed c.34G>T (G12C) (n = 8), c.35G>A (G12D) (n = 3), c.35G>T (G12 V) (n = 1) and c.34G>T (G12C)/c.41T>C (V14A) (n = 2) mutations. Three different BRAF mutations (L584P: n = 1, V600E: n = 1, K601E: n = 1) were detected. Two cases harboured c.2324_2325ins12 (ATACGTGATGGC duplication) in HER2 gene, and one case was positive for NG_007503.2 (NM_001005862.2):c.2218-4del. It is less certain, but still quite possible that this mutation will affect splicing as the deletion of one C actually brings in one additional purine into the region. In conclusion, the present study demonstrates an instance of diverse nature of KRAS, BRAF, HER2 and PTEN gene in Indian patients and confirms that the frequency of these gene mutations varies globally. To the best of our knowledge, this is the first Indian study to evaluate KRAS, BRAF, HER2 and PTEN gene mutations.

  4. Somatic mutation analysis of KRAS, BRAF, HER2 and PTEN in EGFR mutation-negative non-small cell lung carcinoma: determination of frequency, distribution pattern and identification of novel deletion in HER2 gene from Indian patients.

    PubMed

    Bhaumik, Sangeet; Ahmad, Firoz; Das, Bibhu Ranjan

    2016-10-01

    Somatic mutations of KRAS, BRAF, HER2, PTEN genes are the most important molecular markers after the EGFR gene mutation. The current study evaluated the frequency and distribution pattern of KRAS, BRAF, HER2, PTEN mutation in Indian non-small cell lung carcinoma patients. The frequency of KRAS, BRAF, HER2, PTEN mutations was 6.4 % (14/204), 1.5 % (3/204), 1.5 % (3/204), 0 % (0/204), respectively. KRAS, BRAF, HER2 mutations were more prevalent in males than in females. KRAS and HER2 showed a trend of a higher frequency of mutation in the age group of <60 years, whereas BRAF mutations were more frequent in the age group of ≥60 years. Sequencing analysis of KRAS gene revealed c.34G>T (G12C) (n = 8), c.35G>A (G12D) (n = 3), c.35G>T (G12 V) (n = 1) and c.34G>T (G12C)/c.41T>C (V14A) (n = 2) mutations. Three different BRAF mutations (L584P: n = 1, V600E: n = 1, K601E: n = 1) were detected. Two cases harboured c.2324_2325ins12 (ATACGTGATGGC duplication) in HER2 gene, and one case was positive for NG_007503.2 (NM_001005862.2):c.2218-4del. It is less certain, but still quite possible that this mutation will affect splicing as the deletion of one C actually brings in one additional purine into the region. In conclusion, the present study demonstrates an instance of diverse nature of KRAS, BRAF, HER2 and PTEN gene in Indian patients and confirms that the frequency of these gene mutations varies globally. To the best of our knowledge, this is the first Indian study to evaluate KRAS, BRAF, HER2 and PTEN gene mutations. PMID:27637917

  5. Frequencies of organophosphate resistance-associated mutations in the acetylcholinesterase gene of field collected olive fly (Bactrocera oleae) populations under different insecticide regimes.

    PubMed

    Başkurt, S Ibel; Doğaç, E; Taşkın, V; Taşkın, Belg In Göçmen

    2011-03-01

    In the present study, the frequencies of three organophosphate (OP) resistance-associated mutations in acetylcholinesterase gene of Bactrocera oleae (BoAce) populations collected from 8 different important olivegrowing areas in the west part of Turkey were determined. Populations were sampled from the areas that have been treated with only the pyrethroid α-cypermethrin; pyrethroids plus OPs; deltamethrin with pheromone eco-traps, and no insecticide treatment applied areas for many years. For Ile214Val and Gly488Ser point mutations PCR-RFLP and for Δ3Q deletion mutation PCR diagnostic tests were carried out. Seventy-two percent of the total individuals analyzed in the study were exhibited heterozygous genotype (RS) for both Ile214Val and Gly488Ser point and homozygous susceptible genotype (SS) for Δ3Q deletion mutations. This RS/RS/SS combination together with RS/RR/SS with the frequency of 13% were the most common two combinations observed in all of the populations under different insecticide regimes, even in the populations under no insecticide pressure for many years. Independent evaluation of the three mutations resulted in 0.450, 0.534 and 0.037 frequency values for the resistant alleles of 214Val, 488Ser and Δ3Q mutations, respectively. Among the studied populations, the frequencies of resistant alleles for the positions of 214 and 488 were not differed from each other. However, in 3 of the populations the frequency of the R allele of Δ3Q was zero and it changed between 0.025 and 0.100 in the remaining five populations. Results of this study contributed to the distribution pattern of the two point mutations in Europe and a pattern for Δ3Q mutation was determined for the first time in the field collected olive fly samples.

  6. The Frequency and Significance of Silent Myocardial Ischemia Due to Hyoscine Butylbromide Use in Peripheral Angiography

    SciTech Connect

    Maher, Richard; Phillips-Hughes, Jane; Banning, Adrian; Boardman, Philip

    1999-09-15

    Purpose: Hyoscine-N-butylbromide (HB) is an anticholinergic drug used in digital subtraction angiography of the aortoiliac region because it decreases bowel gas movement artifact. HB also causes an increase in heart rate. We investigated whether this could cause silent myocardial ischemia (SMI) in susceptible patients during peripheral angiography. Methods: Thirty-six patients undergoing peripheral angiography were randomized into two groups, with 17 patients receiving 20 mg HB intraarterially during the angiogram and 19 patients receiving no drug. All patients were fitted with a Holter monitor that recorded the electrocardiogram before, during, and after the angiogram. Heart rate trends and ST segments were then analyzed. Results: Patients given HB had a statistically significant rise in heart rate compared with the control group. Although the difference was not statistically significant, two (12%) patients receiving HB had procedural ST depression compared with none in the control group. Pre- and postprocedural episodes of ST depression were common, occurring in 41% of patients receiving HB and 37% of patients receiving no drug, and were associated with an increase in heart rate. Conclusion: The infrequent episodes of procedural SMI, potentially caused by the positive chronotropic effects of HB, are probably insignificant when compared with the high frequency of SMI episodes occurring outside the procedure.

  7. Sudden cardiac arrest due to a single sodium channel mutation producing a mixed phenotype of Brugada and Long QT3 syndromes.

    PubMed

    Lakshmanadoss, U; Mertens, A; Gallagher, M; Kutinsky, I; Williamson, B

    2016-01-01

    Inherited arrhythmia syndromes are a known, albeit rare, cause of sudden cardiac arrest which may present with characteristic electrocardiogram changes in patients with structurally normal heart. There are a variety of distinct arrhythmogenic syndromes that arise from mutations in voltage gated sodium channels, resulting in either gain or loss of function. We describe a patient with a primary inherited arrhythmia syndrome which presented as sudden cardiac arrest. Further workup revealed that her arrest was due to a combination of Brugada syndrome and Long QT3 syndrome secondary to a deleterious mutation of voltage-gated, sodium channel, type V alpha subunit (SCN5A Thr1709Met). PMID:27676163

  8. Ataxia and myoclonic epilepsy due to a heterozygous new mutation in KCNA2: proposal for a new channelopathy.

    PubMed

    Pena, S D J; Coimbra, R L M

    2015-02-01

    We have recently performed exome analysis in a 7 year boy who presented in infancy with an encephalopathy characterized by ataxia and myoclonic epilepsy. Parents were not consanguineous and there was no family history of the disease. Exome analysis did not show any pathogenic variants in genes known to be associated with seizures and/or ataxia in children, including all known human channelopathies. However, we have identified a mutation in KCNA2 that we believe to be responsible for the disease in our patient. This gene, which encodes a member of the potassium channel, voltage-gated, shaker-related subfamily, has not been previously described as a cause of disease in humans, but mutations of the orthologous gene in mice (Kcna2) are known to cause both ataxia and convulsions. The mutation is c.890C>A, leading to the amino acid substitution p.Arg297Gln, which involves the second of the critical arginines in the S4 voltage sensor. This mutation is characterized as pathogenic by five different prediction programs. RFLP analysis and Sanger sequencing confirmed the presence of the mutation in the patient, but not in his parents, characterizing it as de novo. We believe that this discovery characterizes a new channelopathy.

  9. Resonance frequency shifts due to quantized electronic states in atomically thin NEMS

    NASA Astrophysics Data System (ADS)

    Chen, Changyao; Deshpande, Vikram; Koshino, Mikito; Lee, Sunwoo; Gondarenko, Alexander; MacDonald, Allan; Kim, Philip; Hone, James

    The classic picture of the force exerted on a parallel plate capacitor assumes infinite density of states (DOS), which implies identical electrochemical and electrostatic potential. However, such assumption can breakdown in low-dimensional devices where the DOS is finite or quantized. Here we consider the mechanical resonance shift of a nanoelectromechanical (NEMS) resonator with small DOS, actuated and detected capacitively at fixed electrochemical potential. We found three leading correction terms to the classical picture: the first term leads to the modulation of static force due to the variation in chemical potential, and the second and third terms are related to the static and dynamic changes in spring constants, caused by quantum capacitance. The theory agrees well with recent experimental findings from graphene resonator in quantum Hall regimes, where the chemical potential and quantum capacitance are tuned by magnetic field, while the gate voltage is kept constant.

  10. Fitness cost due to mutations in the 16S rRNA associated with spectinomycin resistance in Chlamydia psittaci 6BC.

    PubMed

    Binet, Rachel; Maurelli, Anthony T

    2005-11-01

    The fitness cost of a resistance determinant is the primary parameter that determines its frequency in vivo. As a model for analysis of the impact of drug resistance mutations on the intracellular life cycle of Chlamydia spp., we studied the growth of four genetically defined spectinomycin-resistant (Spc(r)) clonal variants of Chlamydia psittaci 6BC isolated in the plaque assay. The development of each variant was monitored over 46 h postinfection in the absence of drug, either in pure culture or in 1:1 competition with the parent strain. Spc(r) mutations in the 16S rRNA gene at positions 1191 and 1193 were associated with a marked impairment of C.psittaci biological fitness, and the bacteria were severely out-competed by the wild-type parent. In contrast, mutations at position 1192 had minor effects on the bacterial life cycle, allowing the resistant isolates to compete more efficiently with the wild-type strain. Thus, mutations with a wide range of fitness costs can be selected in the plaque assay, providing a new strategy for prediction and monitoring of the emergence of antibiotic resistance in chlamydiae. So far, drug resistance has not been a serious threat for the treatment of chlamydial infections. Tetracycline is an effective antichlamydial drug that targets 16S rRNA. Attempts to isolate spontaneous tetracycline-resistant mutants of C. psittaci 6BC revealed a frequency <3 x 10(-9). We suggest that the rarity of genotypic antibiotic resistance among chlamydial clinical isolates reflects the deleterious effects of such mutations on the fitness of these obligate intracellular bacteria in the host.

  11. Apolipoprotein A-I deficiency due to a codon 84 nonsense mutation of the apolipoprotein A-I gene

    SciTech Connect

    Matsunaga, Tomoyuki; Yanagi, Hisako; Hattori, Naoko; Yamakawa, Kimiko; Yamanouchi, Yasuko; Hamaguchi, Hideo ); Hiasa, Yoshikazu; Maeda, Toshihiro ); Tanaka, Isao; Obara, Takashi )

    1991-04-01

    The molecular genetic defect of a female patient with apolipoprotein A-I (apoA-I) deficiency and premature atherosclerosis was examined. Her parents were first cousins. Her plasma density fraction from 1.063 to 1.21 g/ml contained no apoA-I on SDS/PAGE and no measurable high density lipoprotein cholesterol. Southern blot hybridization showed no gross abnormality to be present in the patient's apoA-I gene and homozygosity for a haplotype of restriction fragment length polymorphisms in the apoA-I gene region. Sequencing after amplification by PCR revealed a codon 84 nonsense mutation (CAG {r arrow} TAG, Gln {r arrow} stop) of exon 4 and a codon 37 missense mutation (GCC{r arrow} ACC, Ala {r arrow} Thr) of exon 3 in the patient's apoA-I gene. The data from dot-blot hybridization with allele-specific oligonucleotide probes indicated that she was homozygous for the apoA-I gene with regard to the two mutations. The codon 37 missense mutation was also detected in the apoA-I gene of 6 out of 60 controls, who all had normal levels of apoA-I and high density lipoprotein cholesterol, suggesting that the missense mutation is polymorphic and not associated with apoA-I deficiency. These finding indicate that homozygosity for the apoA-I gene with codon 84 nonsense mutation causes the deficiency of apoA-I and of high density lipoprotein cholesterol in the patient.

  12. A frameshift mutation in MC1R and a high frequency of somatic reversions cause black spotting in pigs.

    PubMed Central

    Kijas, J M; Moller, M; Plastow, G; Andersson, L

    2001-01-01

    Black spotting on a red or white background in pigs is determined by the E(P) allele at the MC1R/Extension locus. A previous comparison of partial MC1R sequences revealed that E(P) shares a missense mutation (D121N) with the E(D2) allele for dominant black color. Sequence analysis of the entire coding region now reveals a second mutation in the form of a 2-bp insertion at codon 23 (nt67insCC). This mutation expands a tract of six C nucleotides to eight and introduces a premature stop codon at position 56. This frameshift mutation is expected to cause a recessive red color, which was in fact observed in some breeds with the E(P) allele present (Tamworth and Hereford). RT-PCR analyses were conducted using skin samples taken from both spotted and background areas of spotted pigs. The background red area had transcript only from the mutant nt67insCC MC1R allele, whereas the black spot also contained a transcript without the 2-bp insertion. This indicates that black spots are due to somatic reversion events that restore the frame and MC1R function. The phenotypic expression of the E(P) allele is highly variable and the associated coat color ranges from red, red with black spots, white with black spots, to almost completely solid black. In several breeds of pigs the phenotypic manifestation of this allele has been modified by selection for or against black spots. PMID:11404341

  13. Slowly Progressive Encephalopathy with Hearing Loss Due to a Mutation in the mtDNA tRNALeu(CUN) Gene

    PubMed Central

    Çoku, Jorida; Shanske, Sara; Mehrazin, Mahsa; Tanji, Kurenai; Naini, Ali; Emmanuele, Valentina; Patterson, Marc; Hirano, Michio; DiMauro, Salvatore

    2014-01-01

    Pathogenic mutations in the tRNALeu(UCN) gene of mitochondrial DNA (mtDNA) have been invariably accompanied by skeletal myopathy with or without chronic progressive external ophthalmoplegia (CPEO). We report a young woman with a heteroplasmic m.12276G>A mutation in tRNALeu(UCN), who had childhood-onset and slowly progressive encephalopathy with ataxia, cognitive impairment, and hearing loss. Sequencing of the 22 tRNA mitochondrial genes is indicated in all unusual neurological syndromes, even in the absence of maternal inheritance. PMID:20022607

  14. Familial corticosteroid-binding globulin deficiency due to a novel null mutation: association with fatigue and relative hypotension.

    PubMed

    Torpy, D J; Bachmann, A W; Grice, J E; Fitzgerald, S P; Phillips, P J; Whitworth, J A; Jackson, R V

    2001-08-01

    Corticosteroid-binding globulin is a 383-amino acid glycoprotein that serves a hormone transport role and may have functions related to the stress response and inflammation. We describe a 39-member Italian-Australian family with a novel complete loss of function (null) mutation of the corticosteroid-binding globulin gene. A second, previously described, mutation (Lyon) segregated independently in the same kindred. The novel exon 2 mutation led to a premature termination codon corresponding to residue -12 of the procorticosteroid-binding globulin molecule (c.121G-->A). Among 32 family members there were 3 null homozygotes, 19 null heterozygotes, 2 compound heterozygotes, 3 Lyon heterozygotes, and 5 individuals without corticosteroid-binding globulin mutations. Plasma immunoreactive corticosteroid-binding globulin was undetectable in null homozygotes, and mean corticosteroid-binding globulin levels were reduced by approximately 50% at 18.7 +/- 1.3 microg/ml (reference range, 30-52 microg/ml) in null heterozygotes. Morning total plasma cortisol levels were less than 1.8 microg/dl in homozygotes and were positively correlated to the plasma corticosteroid-binding globulin level in heterozygotes. Homozygotes and heterozygote null mutation subjects had a high prevalence of hypotension and fatigue. Among 19 adults with the null mutation, the systolic blood pressure z-score was 12.1 +/- 3.5; 11 of 19 subjects (54%) had a systolic blood pressure below the third percentile. The mean diastolic blood pressure z-score was 18.1 +/- 3.4; 8 of 19 subjects (42%) had a diastolic blood pressure z-score below 10. Idiopathic chronic fatigue was present in 12 of 14 adult null heterozygote subjects (86%) and in 2 of 3 null homozygotes. Five cases met the Centers for Disease Control criteria for chronic fatigue syndrome. Fatigue questionnaires revealed scores of 25.1 +/- 2.5 in 18 adults with the mutation vs. 4.2 +/- 1.5 in 23 healthy controls (P < 0.0001). Compound heterozygosity for both

  15. Distribution and Frequency of kdr Mutations within Anopheles gambiae s.l. Populations and First Report of the Ace.1G119S Mutation in Anopheles arabiensis from Burkina Faso (West Africa)

    PubMed Central

    Dabiré, Roch K.; Namountougou, Moussa; Diabaté, Abdoulaye; Soma, Dieudonné D.; Bado, Joseph; Toé, Hyacinthe K.; Bass, Chris; Combary, Patrice

    2014-01-01

    An entomological survey was carried out at 15 sites dispersed throughout the three eco-climatic regions of Burkina Faso (West Africa) in order to assess the current distribution and frequency of mutations that confer resistance to insecticides in An. gambiae s.l. populations in the country. Both knockdown (kdr) resistance mutation variants (L1014F and L1014S), that confer resistance to pyrethroid insecticides, were identified concomitant with the ace-1 G119S mutation confirming the presence of multiple resistance mechanisms in the An. gambiae complex in Burkina Faso. Compared to the last survey, the frequency of the L1014F kdr mutation appears to have remained largely stable and relatively high in all species. In contrast, the distribution and frequency of the L1014S mutation has increased significantly in An. gambiae s.l. across much of the country. Furthermore we report, for the first time, the identification of the ace.1 G116S mutation in An. arabiensis populations collected at 8 sites. This mutation, which confers resistance to organophosphate and carbamate insecticides, has been reported previously only in the An. gambiae S and M molecular forms. This finding is significant as organophosphates and carbamates are used in indoor residual sprays (IRS) to control malaria vectors as complementary strategies to the use of pyrethroid impregnated bednets. The occurrence of the three target-site resistance mutations in both An. gambiae molecular forms and now An. arabiensis has significant implications for the control of malaria vector populations in Burkina Faso and for resistance management strategies based on the rotation of insecticides with different modes of action. PMID:25077792

  16. U1 small nuclear ribonucleoproteins (snRNPs) aggregate in Alzheimer’s disease due to autosomal dominant genetic mutations and trisomy 21

    PubMed Central

    2014-01-01

    Background We recently identified U1 small nuclear ribonucleoprotein (snRNP) tangle-like aggregates and RNA splicing abnormalities in sporadic Alzheimer’s disease (AD). However little is known about snRNP biology in early onset AD due to autosomal dominant genetic mutations or trisomy 21 in Down syndrome. Therefore we investigated snRNP biochemical and pathologic features in these disorders. Findings We performed quantitative proteomics and immunohistochemistry in postmortem brain from genetic AD cases. Electron microscopy was used to characterize ultrastructural features of pathologic aggregates. U1-70k and other snRNPs were biochemically enriched in the insoluble fraction of human brain from subjects with presenilin 1 (PS1) mutations. Aggregates of U1 snRNP-immunoreactivity formed cytoplasmic tangle-like structures in cortex of AD subjects with PS1 and amyloid precursor protein (APP) mutations as well as trisomy 21. Ultrastructural analysis with electron microscopy in an APP mutation case demonstrated snRNP immunogold labeling of paired helical filaments (PHF). Conclusions These studies identify U1 snRNP pathologic changes in brain of early onset genetic forms of AD. Since dominant genetic mutations and trisomy 21 result in dysfunctional amyloid processing, the findings suggest that aberrant β-amyloid processing may influence U1 snRNP aggregate formation. PMID:24773620

  17. Carrier frequency of a nonsense mutation in the adenosine deaminase (ADA) gene implies a high incidence of ADA-deficient severe combined immunodeficiency (SCID) in Somalia and a single, common haplotype indicates common ancestry.

    PubMed

    Sanchez, Juan J; Monaghan, Gemma; Børsting, Claus; Norbury, Gail; Morling, Niels; Gaspar, H Bobby

    2007-05-01

    Inherited adenosine deaminase (ADA) deficiency is a rare metabolic disorder that causes immunodeficiency, varying from severe combined immunodeficiency (SCID) in the majority of cases to a less severe form in a small minority of patients. Five patients of Somali origin from four unrelated families, with severe ADA-SCID, were registered in the Greater London area. Patients and their parents were investigated for the nonsense mutation Q3X (ADA c7C>T), two missense mutations K80R (ADA c239A>G) and R142Q (ADA c425G>A), and a TAAA repeat located at the 3' end of an Alu element (AluVpA) positioned 1.1 kb upstream of the ADA transcription start site. All patients were homozygous for the haplotype ADA-7T/ADA-239G/ADA-425G/AluVpA7. Among 207 Somali immigrants to Denmark, the frequency of ADA c7C>T and the maximum likelihood estimate of the frequency of the haplotype ADA-7T/ADA-239G/ADA-425G/AluVpA7 were both 0.012 (carrier frequency 2.4%). Based on the analysis of AluVpA alleles, the ADA c7C/T mutation was estimated to be approximately 7,100 years old. Approximately 1 out of 5 - 10000 Somali children will be born with ADA deficiency due to an ADA c7C/T mutation, although within certain clans the frequency may be significantly higher. ADA-SCID may be a frequent immunodeficiency disorder in Somalia, but will be underdiagnosed due to the prevailing socioeconomic and nutritional deprivation.

  18. Recurrent Muscle Weakness with Rhabdomyolysis, Metabolic Crises, and Cardiac Arrhythmia Due to Bi-allelic TANGO2 Mutations

    PubMed Central

    Lalani, Seema R.; Liu, Pengfei; Rosenfeld, Jill A.; Watkin, Levi B.; Chiang, Theodore; Leduc, Magalie S.; Zhu, Wenmiao; Ding, Yan; Pan, Shujuan; Vetrini, Francesco; Miyake, Christina Y.; Shinawi, Marwan; Gambin, Tomasz; Eldomery, Mohammad K.; Akdemir, Zeynep Hande Coban; Emrick, Lisa; Wilnai, Yael; Schelley, Susan; Koenig, Mary Kay; Memon, Nada; Farach, Laura S.; Coe, Bradley P.; Azamian, Mahshid; Hernandez, Patricia; Zapata, Gladys; Jhangiani, Shalini N.; Muzny, Donna M.; Lotze, Timothy; Clark, Gary; Wilfong, Angus; Northrup, Hope; Adesina, Adekunle; Bacino, Carlos A.; Scaglia, Fernando; Bonnen, Penelope E.; Crosson, Jane; Duis, Jessica; Maegawa, Gustavo H.B.; Coman, David; Inwood, Anita; McGill, Jim; Boerwinkle, Eric; Graham, Brett; Beaudet, Art; Eng, Christine M.; Hanchard, Neil A.; Xia, Fan; Orange, Jordan S.; Gibbs, Richard A.; Lupski, James R.; Yang, Yaping

    2016-01-01

    The underlying genetic etiology of rhabdomyolysis remains elusive in a significant fraction of individuals presenting with recurrent metabolic crises and muscle weakness. Using exome sequencing, we identified bi-allelic mutations in TANGO2 encoding transport and Golgi organization 2 homolog (Drosophila) in 12 subjects with episodic rhabdomyolysis, hypoglycemia, hyperammonemia, and susceptibility to life-threatening cardiac tachyarrhythmias. A recurrent homozygous c.460G>A (p.Gly154Arg) mutation was found in four unrelated individuals of Hispanic/Latino origin, and a homozygous ∼34 kb deletion affecting exons 3–9 was observed in two families of European ancestry. One individual of mixed Hispanic/European descent was found to be compound heterozygous for c.460G>A (p.Gly154Arg) and the deletion of exons 3–9. Additionally, a homozygous exons 4–6 deletion was identified in a consanguineous Middle Eastern Arab family. No homozygotes have been reported for these changes in control databases. Fibroblasts derived from a subject with the recurrent c.460G>A (p.Gly154Arg) mutation showed evidence of increased endoplasmic reticulum stress and a reduction in Golgi volume density in comparison to control. Our results show that the c.460G>A (p.Gly154Arg) mutation and the exons 3–9 heterozygous deletion in TANGO2 are recurrent pathogenic alleles present in the Latino/Hispanic and European populations, respectively, causing considerable morbidity in the homozygotes in these populations. PMID:26805781

  19. SIMPLE estimate of the free energy change due to aliphatic mutations: superior predictions based on first principles.

    PubMed

    Bueno, Marta; Camacho, Carlos J; Sancho, Javier

    2007-09-01

    The bioinformatics revolution of the last decade has been instrumental in the development of empirical potentials to quantitatively estimate protein interactions for modeling and design. Although computationally efficient, these potentials hide most of the relevant thermodynamics in 5-to-40 parameters that are fitted against a large experimental database. Here, we revisit this longstanding problem and show that a careful consideration of the change in hydrophobicity, electrostatics, and configurational entropy between the folded and unfolded state of aliphatic point mutations predicts 20-30% less false positives and yields more accurate predictions than any published empirical energy function. This significant improvement is achieved with essentially no free parameters, validating past theoretical and experimental efforts to understand the thermodynamics of protein folding. Our first principle analysis strongly suggests that both the solute-solute van der Waals interactions in the folded state and the electrostatics free energy change of exposed aliphatic mutations are almost completely compensated by similar interactions operating in the unfolded ensemble. Not surprisingly, the problem of properly accounting for the solvent contribution to the free energy of polar and charged group mutations, as well as of mutations that disrupt the protein backbone remains open.

  20. Auditory and verbal working memory deficits in a child with congenital aniridia due to a PAX6 mutation.

    PubMed

    Bamiou, Doris-Eva; Campbell, Nicole G; Musiek, Frank E; Taylor, Rachael; Chong, W K; Moore, Anthony; van Heyningen, Veronica; Free, Samantha; Sisodiya, Sanjay; Luxon, Linda M

    2007-04-01

    PAX6 encodes a transcriptional regulator that is essential for brain morphogenesis. Heterozygous PAX6 mutation is associated with aniridia and abnormalities of the interhemispheric pathway in humans. We present the case of a 12 year old boy with a known mutation of the PAX6 gene. There were parental concerns regarding his hearing, but repeated pure-tone audiograms were normal. He had a battery of standard central auditory tests, which gave abnormal results in tests which required auditory interhemispheric transfer (dichotic digits and pattern tests). A speech and language assessment, which yielded age-appropriate scores for speech, receptive and expressive language, revealed impaired verbal working memory. These test results were interpreted as indicating impaired auditory sensory and higher order interhemispheric transfer, consistent with reported findings in adults with mutations in PAX6, and correlated with his parent-reported hearing difficulties. This is the first report of central auditory and verbal working memory deficits in a child with a PAX6 mutation. Further research is needed to assess how these deficits impact on academic performance particularly in childhood. PMID:17454233

  1. Mutations in pregnancy-associated plasma protein A2 cause short stature due to low IGF-I availability.

    PubMed

    Dauber, Andrew; Muñoz-Calvo, María T; Barrios, Vicente; Domené, Horacio M; Kloverpris, Soren; Serra-Juhé, Clara; Desikan, Vardhini; Pozo, Jesús; Muzumdar, Radhika; Martos-Moreno, Gabriel Á; Hawkins, Federico; Jasper, Héctor G; Conover, Cheryl A; Frystyk, Jan; Yakar, Shoshana; Hwa, Vivian; Chowen, Julie A; Oxvig, Claus; Rosenfeld, Ron G; Pérez-Jurado, Luis A; Argente, Jesús

    2016-01-01

    Mutations in multiple genes of the growth hormone/IGF-I axis have been identified in syndromes marked by growth failure. However, no pathogenic human mutations have been reported in the six high-affinity IGF-binding proteins (IGFBPs) or their regulators, such as the metalloproteinase pregnancy-associated plasma protein A2 (PAPP-A2) that is hypothesized to increase IGF-I bioactivity by specific proteolytic cleavage of IGFBP-3 and -5. Multiple members of two unrelated families presented with progressive growth failure, moderate microcephaly, thin long bones, mildly decreased bone density and elevated circulating total IGF-I, IGFBP-3, and -5, acid labile subunit, and IGF-II concentrations. Two different homozygous mutations in PAPPA2, p.D643fs25* and p.Ala1033Val, were associated with this novel syndrome of growth failure. In vitro analysis of IGFBP cleavage demonstrated that both mutations cause a complete absence of PAPP-A2 proteolytic activity. Size-exclusion chromatography showed a significant increase in IGF-I bound in its ternary complex. Free IGF-I concentrations were decreased. These patients provide important insights into the regulation of longitudinal growth in humans, documenting the critical role of PAPP-A2 in releasing IGF-I from its BPs. PMID:26902202

  2. Recurrent Muscle Weakness with Rhabdomyolysis, Metabolic Crises, and Cardiac Arrhythmia Due to Bi-allelic TANGO2 Mutations.

    PubMed

    Lalani, Seema R; Liu, Pengfei; Rosenfeld, Jill A; Watkin, Levi B; Chiang, Theodore; Leduc, Magalie S; Zhu, Wenmiao; Ding, Yan; Pan, Shujuan; Vetrini, Francesco; Miyake, Christina Y; Shinawi, Marwan; Gambin, Tomasz; Eldomery, Mohammad K; Akdemir, Zeynep Hande Coban; Emrick, Lisa; Wilnai, Yael; Schelley, Susan; Koenig, Mary Kay; Memon, Nada; Farach, Laura S; Coe, Bradley P; Azamian, Mahshid; Hernandez, Patricia; Zapata, Gladys; Jhangiani, Shalini N; Muzny, Donna M; Lotze, Timothy; Clark, Gary; Wilfong, Angus; Northrup, Hope; Adesina, Adekunle; Bacino, Carlos A; Scaglia, Fernando; Bonnen, Penelope E; Crosson, Jane; Duis, Jessica; Maegawa, Gustavo H B; Coman, David; Inwood, Anita; McGill, Jim; Boerwinkle, Eric; Graham, Brett; Beaudet, Art; Eng, Christine M; Hanchard, Neil A; Xia, Fan; Orange, Jordan S; Gibbs, Richard A; Lupski, James R; Yang, Yaping

    2016-02-01

    The underlying genetic etiology of rhabdomyolysis remains elusive in a significant fraction of individuals presenting with recurrent metabolic crises and muscle weakness. Using exome sequencing, we identified bi-allelic mutations in TANGO2 encoding transport and Golgi organization 2 homolog (Drosophila) in 12 subjects with episodic rhabdomyolysis, hypoglycemia, hyperammonemia, and susceptibility to life-threatening cardiac tachyarrhythmias. A recurrent homozygous c.460G>A (p.Gly154Arg) mutation was found in four unrelated individuals of Hispanic/Latino origin, and a homozygous ∼34 kb deletion affecting exons 3-9 was observed in two families of European ancestry. One individual of mixed Hispanic/European descent was found to be compound heterozygous for c.460G>A (p.Gly154Arg) and the deletion of exons 3-9. Additionally, a homozygous exons 4-6 deletion was identified in a consanguineous Middle Eastern Arab family. No homozygotes have been reported for these changes in control databases. Fibroblasts derived from a subject with the recurrent c.460G>A (p.Gly154Arg) mutation showed evidence of increased endoplasmic reticulum stress and a reduction in Golgi volume density in comparison to control. Our results show that the c.460G>A (p.Gly154Arg) mutation and the exons 3-9 heterozygous deletion in TANGO2 are recurrent pathogenic alleles present in the Latino/Hispanic and European populations, respectively, causing considerable morbidity in the homozygotes in these populations.

  3. THE ANTIMUTAGENIC EFFECT OF VANILLIN AND CINNAMALDEHYDE ON SPONTANEOUS MUTATION IN SALMONELLA TA104 IS DUE TO A REDUCTION IN MUTATIONS AT GC BUT NOT AT SITES

    EPA Science Inventory

    Abstract
    Vanillin (VAN) and cinnamaldehyde (CIN) are dietary antimutagens that, when added to assay plates, reduced the spontaneous mutant frequency in Salmonella typhimurium strain TA104 (hisG428, rfa, uvrB, pKM101) by 50%. To date, no study has demonstrated whether or not...

  4. Screening for five mutations detects 97% of cystic fibrosis (CF) chromosomes and predicts a carrier frequency of 1:29 in the Jewish Ashkenazi population

    SciTech Connect

    Abeliovich, D.; Lavon, I.P.; Lerer, I.; Cohen, T. ); Cutting, G.R. ); Springer, C.; Avital, A.

    1992-11-01

    To determine the distribution and frequency of cystic fibrosis (CF) mutations in the Israeli population, the authors have screened 96 patients for 11 relatively common mutations. Five mutations - [Delta]F508, G542X, W1282X, N1303K, and 3849 + 10kb C[yields]T-were found to account for 97% of the CF alleles in the Ashkenazi Jews. In contrast, of the 11 mutations tested, only [Delta]F508 was detected in Jewish patients of Sephardic or Oriental origin, accounting for 43% of the CF alleles. Four mutations - [Delta]F508, G542X, W1282X, and N1303K- accounted for 55% of the CF alleles in Arab patients. In a pilot screening study, a random sample of 424 Ashkenazi individuals was analyzed for three mutations - [Delta]F508, W128X, and G542X. Thirteen individuals were detected as heterozygotes (six for [Delta]F508 and seven for W1282X), predicting a heterozygote frequency of 1:29. This is similar to the frequency of carriers in the Caucasian population of northern European ancestry. On the basis of these data, the Ashkenazi populations is considered to be a candidate for CF heterozygote screening. 32 refs., 2 tabs.

  5. Case control study of the factor V Leiden and factor II G20210A mutation frequency in women with recurrent pregnancy loss

    PubMed Central

    Teremmahi Ardestani, Majid; Nodushan, Hossein Hadi; Aflatoonian, Abbas; Ghasemi, Nasrin; Sheikhha, Mohammad Hasan

    2013-01-01

    Background: Recurrent pregnancy loss (RPL) caused by various genetic and non-genetic factors. After chromosome abnormality, thrombophilia is one of the most important genetic factors that could cause RPL. Factor V Leiden and factor II G20210A mutation were the most common mutations cause thrombophilia in the world. Objective: The purpose of this study was to determine the frequency of factor V Leiden and prothrombine gene mutations in women with RPL compared with women who had uneventful pregnancies. Materials and Methods: This case control study evaluates the frequency of factor V-Leiden and factor II G20210 genotypes in 80 women with two or more pregnancy losses, compared with 80 women without adverse pregnancy outcome. The mutations were assessed by PCR-RFLP. Results: Frequency of the factor V Leiden among cases was 2.5%, which was higher than controls (1.25%), but the difference was not significant. No factor II G20210 mutation was found among cases and controls. Conclusion: These data did not confirm that factor V Leiden and factor II G20210 mutation might play a role in recurrent pregnancy loss in Iranian women. PMID:24639694

  6. Milder clinical course of Type IV 3-methylglutaconic aciduria due to a novel mutation in TMEM70.

    PubMed

    Shchelochkov, Oleg A; Li, Fang-Yuan; Wang, Jing; Zhan, Hongli; Towbin, Jeffrey A; Jefferies, John Lynn; Wong, Lee-Jun; Scaglia, Fernando

    2010-01-01

    Mitochondrial disorders are a large and genetically heterogeneous group of disorders posing a significant diagnostic challenge. Only approximately 10-20% of patients have identifiable alterations in their mitochondrial DNA (mtDNA). The remaining ~80-90% of affected patients likely harbor mutations in nuclear genes, most of which are still poorly characterized, and therefore not amenable to efficient screening using currently available molecular methods. Here we present a patient, who has been followed since birth after presenting with neonatal hyperammonemia, lactic acidosis, Reye-like syndrome episodes, and ventricular tachyarrhythmia. Initial biochemical work-up revealed hyperalaninemia, normal plasma glutamine, mild orotic aciduria and significant amounts of urinary 3-methylglutaconic (3-MGC) and 3-methylglutaric (3-MGA) acids. Muscle biopsy demonstrated the presence of ragged-red fibers and non-specific structural abnormalities of mitochondria. The activities of respiratory chain enzymes (complexes I-IV) showed no deficiency. Mutational analysis of the entire mitochondrial genome did not reveal deleterious point mutations or large deletions. Long-term follow-up was significant for a later-onset hypertrophic cardiomyopathy, muscle weakness, and exercise intolerance. Although she had frequent episodes of Reye-like episodes in infancy and early childhood, mostly triggered by illnesses, these symptoms improved significantly with the onset of puberty. In the light of recent reports linking cases of type IV 3-methylglutaconic aciduria (3-MGCA) and hypertrophic cardiomyopathy to mutations in TMEM70, we proceeded with sequencing analysis of this gene. We identified one previously reported splice site mutation, c.317-2A>G and a novel mutation c.494G>A (p.G165D) in an evolutionarily conserved region predicted to be deleterious. This variant was not identified in 100 chromosomes of healthy control subjects and 200 chromosomes of patients with cardiomyopathies. Western

  7. Incipient allochronic speciation due to non-selective assortative mating by flowering time, mutation and genetic drift

    PubMed Central

    Devaux, Céline; Lande, Russell

    2008-01-01

    We model the evolution of flowering time using a multilocus quantitative genetic model with non-selective assortative mating and mutation to investigate incipient allochronic speciation in a finite population. For quantitative characters with evolutionary parameters satisfying empirical observations and two approximate inequalities that we derived, disjunct clusters in the population flowering phenology originated within a few thousand generations in the absence of disruptive natural or sexual selection. Our simulations and the conditions we derived showed that cluster formation was promoted by limited population size, high mutational variance of flowering time, short individual flowering phenology and a long flowering season. By contrast, cluster formation was hindered by inbreeding depression, stabilizing selection and pollinator limitation. Our results suggest that incipient allochronic speciation in populations of limited size (satisfying two inequalities) could be a common phenomenon. PMID:18700202

  8. BRCA Mutation Frequency and Patterns of Treatment Response in BRCA Mutation–Positive Women With Ovarian Cancer: A Report From the Australian Ovarian Cancer Study Group

    PubMed Central

    Alsop, Kathryn; Fereday, Sian; Meldrum, Cliff; deFazio, Anna; Emmanuel, Catherine; George, Joshy; Dobrovic, Alexander; Birrer, Michael J.; Webb, Penelope M.; Stewart, Colin; Friedlander, Michael; Fox, Stephen; Bowtell, David; Mitchell, Gillian

    2012-01-01

    Purpose The frequency of BRCA1 and BRCA2 germ-line mutations in women with ovarian cancer is unclear; reports vary from 3% to 27%. The impact of germ-line mutation on response requires further investigation to understand its impact on treatment planning and clinical trial design. Patients and Methods Women with nonmucinous ovarian carcinoma (n = 1,001) enrolled onto a population-based, case-control study were screened for point mutations and large deletions in both genes. Survival outcomes and responses to multiple lines of chemotherapy were assessed. Results Germ-line mutations were found in 14.1% of patients overall, including 16.6% of serous cancer patients (high-grade serous, 22.6%); 44% had no reported family history of breast or ovarian cancer. Patients carrying germ-line mutations had improved rates of progression-free and overall survival. In the relapse setting, patients carrying mutations more frequently responded to both platin- and nonplatin-based regimens than mutation-negative patients, even in patients with early relapse after primary treatment. Mutation-negative patients who responded to multiple cycles of platin-based treatment were more likely to carry somatic BRCA1/2 mutations. Conclusion BRCA mutation status has a major influence on survival in ovarian cancer patients and should be an additional stratification factor in clinical trials. Treatment outcomes in BRCA1/2 carriers challenge conventional definitions of platin resistance, and mutation status may be able to contribute to decision making and systemic therapy selection in the relapse setting. Our data, together with the advent of poly(ADP-ribose) polymerase inhibitor trials, supports the recommendation that germ-line BRCA1/2 testing should be offered to all women diagnosed with nonmucinous, ovarian carcinoma, regardless of family history. PMID:22711857

  9. High frequency of copy number imbalances in Rubinstein–Taybi patients negative to CREBBP mutational analysis

    PubMed Central

    Gervasini, Cristina; Mottadelli, Federica; Ciccone, Roberto; Castronovo, Paola; Milani, Donatella; Scarano, Gioacchino; Bedeschi, Maria Francesca; Belli, Serena; Pilotta, Alba; Selicorni, Angelo; Zuffardi, Orsetta; Larizza, Lidia

    2010-01-01

    Rubinstein–Taybi syndrome (RSTS) is a rare autosomal dominant disorder characterised by facial dysmorphisms, growth and psychomotor development delay, and skeletal defects. The known genetic causes are point mutations or deletions of the CREBBP (50–60%) and EP300 (5%) genes. To detect chromosomal rearrangements indicating novel positional candidate RSTS genes, we used a-CGH to study 26 patients fulfilling the diagnostic criteria for RSTS who were negative at fluorescence in situ hybridisation analyses of the CREBBP and EP300 regions, and direct sequencing analyses of the CREBBP gene. We found seven imbalances (27%): four de novo and three inherited rearrangements not reported among the copy number variants. A de novo 7p21.1 deletion of 500 kb included the TWIST1 gene, a suggested candidate for RSTS that is responsible for the Saethre–Chotzen syndrome, an entity that enters in differential diagnosis with RSTS. A similar issue of differential diagnosis was raised by a large 4.3 Mb 2q22.3q23.1 deletion encompassing ZEB2, the gene responsible for the Mowat–Wilson syndrome, whose signs may overlap with RSTS. Positional candidate genes could not be sought in the remaining pathogenetic imbalances, because of the size of the involved region (a 9 Mb 2q24.3q31.1 deletion) and/or the relative paucity of suitable genes (a 5 Mb 3p13p12.3 duplication). One of the inherited rearrangements, the 17q11.2 379Kb duplication, represents the reciprocal event of the deletion underlying an overgrowth syndrome, both being mediated by the NF1-REP-P1 and REP-P2 sub-duplicons. The contribution of this and the other detected CNVs to the clinical RSTS phenotype is difficult to assess. PMID:20125191

  10. Börjeson-Forssman-Lehmann Syndrome due to a novel plant homeodomain zinc finger mutation in the PHF6 gene.

    PubMed

    Mangelsdorf, Marie; Chevrier, Evelyne; Mustonen, Aki; Picketts, David J

    2009-05-01

    The Börjeson-Forssman-Lehmann syndrome is an X-linked mental retardation disorder caused by mutations in the PHF6 gene. The PHF6 gene contains 2 plant homeodomain zinc fingers, suggesting a role for the protein in chromatin remodeling. In this study, the authors report on a Finnish family with a classical Börjeson-Forssman-Lehmann syndrome phenotype caused by a G to T nucleotide substitution at position 266 within exon 4 within the PHF6 gene (c.266G>T). The resulting glycine to valine (p.G89V) change corresponds to a highly conserved residue within the first plant homeodomain zinc finger domain. This is a novel change that adds to the number of plant homeodomain zinc finger mutations identified, such that 23% of all Börjeson-Forssman-Lehmann syndrome mutations lie within this motif. Moreover, it highlights the functional importance of plant homeodomain zinc finger motifs to human disease and more specifically to PHF6 function.

  11. Vascular and connective tissue anomalies associated with X-linked periventricular heterotopia due to mutations in Filamin A

    PubMed Central

    Reinstein, Eyal; Frentz, Sophia; Morgan, Tim; García-Miñaúr, Sixto; Leventer, Richard J; McGillivray, George; Pariani, Mitchel; van der Steen, Anthony; Pope, Michael; Holder-Espinasse, Muriel; Scott, Richard; Thompson, Elizabeth M; Robertson, Terry; Coppin, Brian; Siegel, Robert; Bret Zurita, Montserrat; Rodríguez, Jose I; Morales, Carmen; Rodrigues, Yuri; Arcas, Joaquín; Saggar, Anand; Horton, Margaret; Zackai, Elaine; Graham, John M; Rimoin, David L; Robertson, Stephen P

    2013-01-01

    Mutations conferring loss of function at the FLNA (encoding filamin A) locus lead to X-linked periventricular nodular heterotopia (XL-PH), with seizures constituting the most common clinical manifestation of this disorder in female heterozygotes. Vascular dilatation (mainly the aorta), joint hypermobility and variable skin findings are also associated anomalies, with some reports suggesting that this might represents a separate syndrome allelic to XL-PH, termed as Ehlers-Danlos syndrome-periventricular heterotopia variant (EDS-PH). Here, we report a cohort of 11 males and females with both hypomorphic and null mutations in FLNA that manifest a wide spectrum of connective tissue and vascular anomalies. The spectrum of cutaneous defects was broader than previously described and is inconsistent with a specific type of EDS. We also extend the range of vascular anomalies associated with XL-PH to included peripheral arterial dilatation and atresia. Based on these observations, we suggest that there is little molecular or clinical justification for considering EDS-PH as a separate entity from XL-PH, but instead propose that there is a spectrum of vascular and connective tissues anomalies associated with this condition for which all individuals with loss-of-function mutations in FLNA should be evaluated. In addition, since some patients with XL-PH can present primarily with a joint hypermobility syndrome, we propose that screening for cardiovascular manifestations should be offered to those patients when there are associated seizures or an X-linked pattern of inheritance. PMID:23032111

  12. Resistance to oxyimino beta-lactams due to a mutation of chromosomal beta-lactamase in Citrobacter freundii.

    PubMed

    Haruta, S; Nukaga, M; Taniguchi, K; Sawai, T

    1998-01-01

    The duplicative mutation of an Ala-Val-Arg sequence at positions 208 to 210 in the loop structure of Enterobacter cloacae class C beta-lactamase caused substrate specificity extension to oxyimino beta-lactam antibiotics and this chromosomal mutation provided bacterial cells with high resistance to the beta-lactams (M. Nukaga et al, 1995, J. Biol. Chem. 270, 5729-5735). In order to confirm the universality of this phenomenon among other class C beta-lactamases, the duplicative mutation was applied to a class C beta-lactamase of Citrobacter freundii, which has 74% homology to the E. cloacae beta-lactamase amino acid sequence. The counterpart sequence to the Ala-Val-Arg of the E. cloacae enzyme in C. freundii beta-lactamase was identified to be Pro-Val-His. A Pro-Val-His sequence was inserted just after the native Pro-Val-His sequence at positions 208 to 210 in the C. freundii beta-lactamase. The resulting mutant of C. freundii beta-lactamase obtained a striking characteristic that we expected, showing substrate specificity extension to oxyimino beta-lactams. Nearly the same result was obtained with the insertion of an Ala-Val-Arg sequence after the native Pro-Val-His sequence. These results indicate that structural modification of this locus commonly induces modification of the substrate specificity to unfavorable substrates for many chromosomal class C beta-lactamases produced by gram-negative bacteria.

  13. Omenn syndrome associated with a functional reversion due to a somatic second-site mutation in CARD11 deficiency

    PubMed Central

    Fuchs, Sebastian; Rensing-Ehl, Anne; Pannicke, Ulrich; Lorenz, Myriam R.; Fisch, Paul; Jeelall, Yogesh; Rohr, Jan; Speckmann, Carsten; Vraetz, Thomas; Farmand, Susan; Schmitt-Graeff, Annette; Krüger, Marcus; Strahm, Brigitte; Henneke, Philipp; Enders, Anselm; Horikawa, Keisuke; Goodnow, Christopher; Schwarz, Klaus

    2015-01-01

    Omenn syndrome (OS) is a severe immunodeficiency associated with erythroderma, lymphoproliferation, elevated IgE, and hyperactive oligoclonal T cells. A restricted T-cell repertoire caused by defective thymic T-cell development and selection, lymphopenia with homeostatic proliferation, and lack of regulatory T cells are considered key factors in OS pathogenesis. We report 2 siblings presenting with cytomegalovirus (CMV) and Pneumocystis jirovecii infections and recurrent sepsis; one developed all clinical features of OS. Both carried homozygous germline mutations in CARD11 (p.Cys150*), impairing NF-κB signaling and IL-2 production. A somatic second-site mutation reverting the stop codon to a missense mutation (p.Cys150Leu) was detected in tissue-infiltrating T cells of the OS patient. Expression of p.Cys150Leu in CARD11-deficient T cells largely reconstituted NF-κB signaling. The reversion likely occurred in a prethymic T-cell precursor, leading to a chimeric T-cell repertoire. We speculate that in our patient the functional advantage of the revertant T cells in the context of persistent CMV infection, combined with lack of regulatory T cells, may have been sufficient to favor OS. This first observation of OS in a patient with a T-cell activation defect suggests that severely defective T-cell development or homeostatic proliferation in a lymphopenic environment are not required for this severe immunopathology. PMID:26289640

  14. Congenital hypomyelinating neuropathy due to the association of a truncating mutation in PMP22 with the classical HNPP deletion.

    PubMed

    Jouaud, Maxime; Gonnaud, Pierre-Marie; Richard, Laurence; Latour, Philippe; Ollagnon-Roman, Elisabeth; Sturtz, Franck; Mathis, Stéphane; Magy, Laurent; Vallat, Jean-Michel

    2016-01-01

    Congenital hypomyelinating neuropathy appears early in life, resulting in a delay of motor and sensory development. Mutations involve genes such as myelin protein zero (MPZ), peripheral myelin protein 22 (PMP22), and early growth response 2 (EGR2). We present a patient with two compound mutations in PMP22: a point mutation causing a premature STOP codon in exon 3 was inherited from the mother on the first allele, and the "typical" PMP22 deletion in the 17p11.2-p12 region was inherited from the father on the other allele. A sural biopsy was performed at age four. The patient has been followed from 28 months to 21 years of age; he presented significant sensory disturbances, with a slight motor deficit. PMP22 mRNA quantitation showed a severe decrease of PMP22 protein. No myelin sheaths were observed in the biopsy; mesaxons failed to form. The absence of PMP22 provides new insights into the role of this protein. PMID:27067623

  15. Modified structural and frequency dependent impedance formalism of nanoscale BaTiO3 due to Tb inclusion

    NASA Astrophysics Data System (ADS)

    Borah, Manjit; Mohanta, Dambarudhar

    2016-05-01

    We report the effect of Tb-doping on the structural and high frequency impedance response of the nanoscale BaTiO3 (BT) systems. While exhibiting a mixed phase crystal structure, the nano-BT systems are found to evolve with edges, and facets. The interplanar spacing of crystal lattice fringes is ~0.25 nm. The Cole-Cole plots, in the impedance formalism, have demonstrated semicircles which are the characteristic feature of grain boundary resistance of several MΩ. A lowering of ac conductivity with doping was believed to be due to the manifestation of oxygen vacancies and vacancy ordering.

  16. Electron density changes in the nighttime D region due to heating by very-low-frequency transmitters

    NASA Technical Reports Server (NTRS)

    Rodriguez, Juan V.; Inan, Umran S.

    1994-01-01

    Modification of the nighttime D region electron density (N(sub e)) due to heating by very-low-frequency (VLF) transmitters is investigated theoretically using a four-species model of the ion chemistry. The effects of a 100 kW, a 265 kW, and a 1000 kW VLF transmitter are calculated for three ambient N(sub e) profiles. Results indicate that N(sub e) is reduced by up to 26% at approximately 80 km altitude over a 1000 kW transmitter.

  17. Heterozygous splice mutation in PIK3R1 causes human immunodeficiency with lymphoproliferation due to dominant activation of PI3K

    PubMed Central

    Lucas, Carrie L.; Zhang, Yu; Venida, Anthony; Wang, Ying; Hughes, Jason; McElwee, Joshua; Butrick, Morgan; Matthews, Helen; Price, Susan; Biancalana, Matthew; Wang, Xiaochuan; Richards, Michael; Pozos, Tamara; Barlan, Isil; Ozen, Ahmet; Rao, V. Koneti; Su, Helen C.

    2014-01-01

    Class IA phosphatidylinositol 3-kinases (PI3K), which generate PIP3 as a signal for cell growth and proliferation, exist as an intracellular complex of a catalytic subunit bound to a regulatory subunit. We and others have previously reported that heterozygous mutations in PIK3CD encoding the p110δ catalytic PI3K subunit cause a unique disorder termed p110δ-activating mutations causing senescent T cells, lymphadenopathy, and immunodeficiency (PASLI) disease. We report four patients from three families with a similar disease who harbor a recently reported heterozygous splice site mutation in PIK3R1, which encodes the p85α, p55α, and p50α regulatory PI3K subunits. These patients suffer from recurrent sinopulmonary infections and lymphoproliferation, exhibit hyperactive PI3K signaling, and have prominent expansion and skewing of peripheral blood CD8+ T cells toward terminally differentiated senescent effector cells with short telomeres. The PIK3R1 splice site mutation causes skipping of an exon, corresponding to loss of amino acid residues 434–475 in the inter-SH2 domain. The mutant p85α protein is expressed at low levels in patient cells and activates PI3K signaling when overexpressed in T cells from healthy subjects due to qualitative and quantitative binding changes in the p85α–p110δ complex and failure of the C-terminal region to properly inhibit p110δ catalytic activity. PMID:25488983

  18. Neonatal multiorgan failure due to ACAD9 mutation and complex I deficiency with mitochondrial hyperplasia in liver, cardiac myocytes, skeletal muscle, and renal tubules.

    PubMed

    Leslie, Nancy; Wang, Xinjian; Peng, Yanyan; Valencia, C Alexander; Khuchua, Zaza; Hata, Jessica; Witte, David; Huang, Taosheng; Bove, Kevin E

    2016-03-01

    Complex I deficiency causes Leigh syndrome, fatal infant lactic acidosis, and neonatal cardiomyopathy. Mutations in more than 100 nuclear DNA and mitochondrial DNA genes miscode for complex I subunits or assembly factors. ACAD9 is an acyl-CoA dehydrogenase with a novel function in assembly of complex I; biallelic mutations cause progressive encephalomyopathy, recurrent Reye syndrome, and fatal cardiomyopathy. We describe the first autopsy in fatal neonatal lethal lactic acidosis due to mutations in ACAD9 that reduced complex I activity. We identified mitochondrial hyperplasia in cardiac myocytes, diaphragm muscle, and liver and renal tubules in formalin-fixed, paraffin-embedded tissue using immunohistochemistry for mitochondrial antigens. Whole-exome sequencing revealed compound heterozygous variants in the ACAD9 gene: c.187G>T (p.E63*) and c.941T>C (p.L314P). The nonsense mutation causes late infantile lethality; the missense variant is novel. Autopsy-derived fibroblasts had reduced complex I activity (53% of control) with normal activity in complexes II to IV, similar to reported cases of ACAD9 deficiency.

  19. Acute abdomen due to group A streptococcus bacteremia caused by an isolate with a mutation in the csrS gene.

    PubMed

    Kaneko, Masahiko; Maruta, Masaki; Shikata, Hisaharu; Hanayama, Masakazu; Ikebe, Tadayoshi

    2015-11-01

    Streptococcus pyogenes (group A streptococcus) is an aerobic gram-positive coccus that causes infections ranging from non-invasive pharyngitis to severely invasive necrotizing fasciitis. Mutations in csrS/csrR and rgg, negative regulator genes of group A streptococcus, are crucial factors in the pathogenesis of streptococcal toxic shock syndrome, which is a severe, invasive infection characterized by sudden onset of shock and multiorgan failure, resulting in a high mortality rate. Here we present a case of group A streptococcal bacteremia in a 28-year-old Japanese woman with no relevant previous medical history. The patient developed progressive abdominal symptoms that may have been due to spontaneous bacterial peritonitis, followed by a state of shock, which did not fulfill the proposed criteria for streptococcal toxic shock. The isolate was found to harbor a mutation in the negative regulator csrS gene, whereas the csrR and rgg genes were intact. It was noteworthy that this strain carrying a csrS mutation had caused group A streptococcal bacteremia characterized by acute abdomen as the presenting symptom in a young individual who had been previously healthy. This case indicates that group A streptococcus with csrS mutations has potential virulence factors that are associated with the onset of group A streptococcal bacteremia that does not meet the diagnostic criteria for streptococcal toxic shock syndrome.

  20. Systematic biases in low frequency radio interferometric data due to calibration: the LOFAR EoR case

    NASA Astrophysics Data System (ADS)

    Patil, Ajinkya H.; Yatawatta, Sarod; Zaroubi, Saleem; Koopmans, Léon V. E.; de Bruyn, A. G.; Jelić, Vibor; Ciardi, Benedetta; Iliev, Ilian T.; Mevius, Maaijke; Pandey, Vishambhar N.; Gehlot, Bharat K.

    2016-09-01

    The redshifted 21 cm line of neutral hydrogen is a promising probe of the Epoch of Reionization (EoR). However, its detection requires a thorough understanding and control of the systematic errors. We study two systematic biases observed in the LOFAR-EoR residual data after calibration and subtraction of bright discrete foreground sources. The first effect is a suppression in the diffuse foregrounds, which could potentially mean a suppression of the 21 cm signal. The second effect is an excess of noise beyond the thermal noise. The excess noise shows fluctuations on small frequency scales, and hence it can not be easily removed by foreground removal or avoidance methods. Our analysis suggests that sidelobes of residual sources due to the chromatic point spread function and ionospheric scintillation can not be the dominant causes of the excess noise. Rather, both the suppression of diffuse foregrounds and the excess noise can occur due to calibration with an incomplete sky model containing predominantly bright discrete sources. The levels of the suppression and excess noise depend on the relative flux of sources which are not included in the model with respect to the flux of modeled sources. We predict that the excess noise will reduce with more observation time in the same way as the thermal noise does. We also discuss possible solutions such as using only long baselines to calibrate the interferometric gain solutions as well as simultaneous multi-frequency calibration along with their benefits and shortcomings.

  1. A mouse model for spondyloepiphyseal dysplasia congenita with secondary osteoarthritis due to a Col2a1 mutation.

    PubMed

    Esapa, Christopher T; Hough, Tertius A; Testori, Sarah; Head, Rosie A; Crane, Elizabeth A; Chan, Carol P S; Evans, Holly; Bassett, J H Duncan; Tylzanowski, Przemko; McNally, Eugene G; Carr, Andrew J; Boyde, Alan; Howell, Peter G T; Clark, Anne; Williams, Graham R; Brown, Matthew A; Croucher, Peter I; Nesbit, M Andrew; Brown, Steve D M; Cox, Roger D; Cheeseman, Michael T; Thakker, Rajesh V

    2012-02-01

    Progeny of mice treated with the mutagen N-ethyl-N-nitrosourea (ENU) revealed a mouse, designated Longpockets (Lpk), with short humeri, abnormal vertebrae, and disorganized growth plates, features consistent with spondyloepiphyseal dysplasia congenita (SEDC). The Lpk phenotype was inherited as an autosomal dominant trait. Lpk/+ mice were viable and fertile and Lpk/Lpk mice died perinatally. Lpk was mapped to chromosome 15 and mutational analysis of likely candidates from the interval revealed a Col2a1 missense Ser1386Pro mutation. Transient transfection of wild-type and Ser1386Pro mutant Col2a1 c-Myc constructs in COS-7 cells and CH8 chondrocytes demonstrated abnormal processing and endoplasmic reticulum retention of the mutant protein. Histology revealed growth plate disorganization in 14-day-old Lpk/+ mice and embryonic cartilage from Lpk/+ and Lpk/Lpk mice had reduced safranin-O and type-II collagen staining in the extracellular matrix. The wild-type and Lpk/+ embryos had vertical columns of proliferating chondrocytes, whereas those in Lpk/Lpk mice were perpendicular to the direction of bone growth. Electron microscopy of cartilage from 18.5 dpc wild-type, Lpk/+, and Lpk/Lpk embryos revealed fewer and less elaborate collagen fibrils in the mutants, with enlarged vacuoles in the endoplasmic reticulum that contained amorphous inclusions. Micro-computed tomography (CT) scans of 12-week-old Lpk/+ mice revealed them to have decreased bone mineral density, and total bone volume, with erosions and osteophytes at the joints. Thus, an ENU mouse model with a Ser1386Pro mutation of the Col2a1 C-propeptide domain that results in abnormal collagen processing and phenotypic features consistent with SEDC and secondary osteoarthritis has been established.

  2. Compound Heterozygosity of Low-Frequency Promoter Deletions and Rare Loss-of-Function Mutations in TXNL4A Causes Burn-McKeown Syndrome

    PubMed Central

    Wieczorek, Dagmar; Newman, William G.; Wieland, Thomas; Berulava, Tea; Kaffe, Maria; Falkenstein, Daniela; Beetz, Christian; Graf, Elisabeth; Schwarzmayr, Thomas; Douzgou, Sofia; Clayton-Smith, Jill; Daly, Sarah B.; Williams, Simon G.; Bhaskar, Sanjeev S.; Urquhart, Jill E.; Anderson, Beverley; O’Sullivan, James; Boute, Odile; Gundlach, Jasmin; Czeschik, Johanna Christina; van Essen, Anthonie J.; Hazan, Filiz; Park, Sarah; Hing, Anne; Kuechler, Alma; Lohmann, Dietmar R.; Ludwig, Kerstin U.; Mangold, Elisabeth; Steenpaß, Laura; Zeschnigk, Michael; Lemke, Johannes R.; Lourenco, Charles Marques; Hehr, Ute; Prott, Eva-Christina; Waldenberger, Melanie; Böhmer, Anne C.; Horsthemke, Bernhard; O’Keefe, Raymond T.; Meitinger, Thomas; Burn, John; Lüdecke, Hermann-Josef; Strom, Tim M.

    2014-01-01

    Mutations in components of the major spliceosome have been described in disorders with craniofacial anomalies, e.g., Nager syndrome and mandibulofacial dysostosis type Guion-Almeida. The U5 spliceosomal complex of eight highly conserved proteins is critical for pre-mRNA splicing. We identified biallelic mutations in TXNL4A, a member of this complex, in individuals with Burn-McKeown syndrome (BMKS). This rare condition is characterized by bilateral choanal atresia, hearing loss, cleft lip and/or palate, and other craniofacial dysmorphisms. Mutations were found in 9 of 11 affected families. In 8 families, affected individuals carried a rare loss-of-function mutation (nonsense, frameshift, or microdeletion) on one allele and a low-frequency 34 bp deletion (allele frequency 0.76%) in the core promoter region on the other allele. In a single highly consanguineous family, formerly diagnosed as oculo-oto-facial dysplasia, the four affected individuals were homozygous for a 34 bp promoter deletion, which differed from the promoter deletion in the other families. Reporter gene and in vivo assays showed that the promoter deletions led to reduced expression of TXNL4A. Depletion of TXNL4A (Dib1) in yeast demonstrated reduced assembly of the tri-snRNP complex. Our results indicate that BMKS is an autosomal-recessive condition, which is frequently caused by compound heterozygosity of low-frequency promoter deletions in combination with very rare loss-of-function mutations. PMID:25434003

  3. A young-onset frontal dementia with dramatic calcifications due to a novel CSF1R mutation.

    PubMed

    Gore, Ethan; Manley, Andrew; Dees, Daniel; Appleby, Brian S; Lerner, Alan J

    2016-06-01

    Neuroimaging and genomic analysis greatly aid in the identification of young-onset dementia antemortem. We present the case of a 33-year-old female with a 2-year rapid decline to dementia and immobility marked by personality change, executive deficits including compulsions, attention deficit, apraxia, Parkinsonism, and pyramidal signs. She had unique and dramatic calcifications and confluent white matter changes on imaging and was found to have a novel mutation in the colony stimulating factor 1 receptor gene causing adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP). Here, we review ALSP and briefly discuss differential diagnoses. PMID:27092868

  4. Familial congenital hypothyroidism due to inactivating mutation of the thyrotropin receptor causing profound hypoplasia of the thyroid gland.

    PubMed Central

    Abramowicz, M J; Duprez, L; Parma, J; Vassart, G; Heinrichs, C

    1997-01-01

    Thyroid gland agenesis is the most common cause of congenital hypothyroidism and is usually sporadic. We investigated a brother and sister from consanguineous parents, ascertained through systematic newborn screening, and initially diagnosed with thyroid agenesis. Careful cervical ultrasonography in both patients revealed a very hypoplastic thyroid gland. By direct sequencing of the thyrotropin receptor gene, we identified the substitution of threonine in place of a highly conserved alanine at position 553, in the fourth predicted transmembrane domain. The mutation was found homozygous in the affected siblings, and heterozygous in both parents and two unaffected siblings. Functional analysis in transfected COS-7 cells showed that it resulted in extremely low expression at the cell surface as compared with the wild-type receptor, in spite of an apparently normal intracellular synthesis. The small amount of mutated receptor expressed at the surface of transfected cells bound thyrotropin with normal affinity and responded in terms of cAMP production, but the in vivo significance of these data from overexpressed receptor in transfected cells is unclear. Of note, blood thyroglobulin was unexpectedly elevated in the patients at the time of diagnosis, a finding that might prove useful in refining etiologies of congenital hypothyroidism. PMID:9185526

  5. Novel Insights into 46,XY Disorders of Sex Development due to NR5A1 Gene Mutation.

    PubMed

    Werner, Ralf; Mönig, Isabel; August, Julia; Freiberg, Clemens; Lünstedt, Ralf; Reiz, Benedikt; Wünsch, Lutz; Holterhus, Paul-Martin; Kulle, Alexandra; Döhnert, Ulla; Wudy, Stefan A; Richter-Unruh, Annette; Thorns, Christoph; Hiort, Olaf

    2015-01-01

    The differential diagnosis of 46,XY disorders of sex development (DSD) is based on the distinction between forms of gonadal dysgenesis and disorders of androgen biosynthesis and action. However, clinical and endocrine evaluations are often not conclusive. Here, we describe an adolescent female with hirsutism and hyperandrogenization at puberty. Her karyotype was 46,XY, and clinical investigation demonstrated clitoromegaly, but no uterine remnants were detected. Histology of the gonads revealed a testicular structure with a Sertoli-cell-only pattern. Endocrine evaluation showed hypergonadotropic hypogonadism, and the Sertoli cell markers inhibin B and anti-Müllerian hormone were also low. Several molecular genetic studies were initiated. While analyses of the androgen receptor gene, the SRD5A2 gene and HSD17B3 gene were uninformative, a novel p.L230R mutation was found in the NR5A1 gene. A mutant construct proved a severe dysfunction of this variant in functional analysis after recreation and transfection into HeLa cells. We conclude that the NR5A1 p.L230R mutation most likely leads to a spatial and time-dependent Leydig cell and Sertoli cell dysfunction during development not causing the classical gonadal dysgenesis phenotype. This case demonstrates that the current classification should be updated to encompass the overlapping phenotypes of some genetic conditions within 46,XY DSD. PMID:26681172

  6. Successful sulfonylurea treatment of an insulin-naïve neonate with diabetes mellitus due to a KCNJ11 mutation.

    PubMed

    Wambach, Jennifer A; Marshall, Bess A; Koster, Joseph C; White, Neil H; Nichols, Colin G

    2010-06-01

    Activating mutations in the K(ATP)-channel cause neonatal diabetes mellitus (NDM), and patients have been safely transitioned from insulin to sulfonylureas. We report a male infant with permanent NDM (PNDM), born to a PNDM mother. Blood glucose began to rise on day of life (DOL) 2, and sulfonylurea (glyburide) therapy was initiated on DOL 5. Glucose was subsequently well controlled and normal at 3 months. A K(ATP) mutation (R201H; KCNJ11) was detected in the infant, the mother, and 6-yr-old sister with PNDM; both were also subsequently transitioned off insulin onto glyburide. To our knowledge, this is the youngest NDM patient to receive oral glyburide and, importantly, the only one deliberately initiated on sulfonylureas. Strikingly, the current dose (0.017 mg/kg/d) is below the reported therapeutic range and approximately 75-fold lower than doses required by the affected sister and mother. Pancreatic insulin disappears in an animal model of K(ATP)-induced NDM, unless glycemia is well controlled, thus, a dramatically lower glyburide requirement in the infant may reflect preserved insulin content because of early sulfonylurea intervention. Safe and effective initiation of glyburide in an insulin-naïve neonatal patient with K(ATP)-dependent PNDM argues for early detection and sulfonylurea intervention.

  7. Novel Insights into 46,XY Disorders of Sex Development due to NR5A1 Gene Mutation.

    PubMed

    Werner, Ralf; Mönig, Isabel; August, Julia; Freiberg, Clemens; Lünstedt, Ralf; Reiz, Benedikt; Wünsch, Lutz; Holterhus, Paul-Martin; Kulle, Alexandra; Döhnert, Ulla; Wudy, Stefan A; Richter-Unruh, Annette; Thorns, Christoph; Hiort, Olaf

    2015-01-01

    The differential diagnosis of 46,XY disorders of sex development (DSD) is based on the distinction between forms of gonadal dysgenesis and disorders of androgen biosynthesis and action. However, clinical and endocrine evaluations are often not conclusive. Here, we describe an adolescent female with hirsutism and hyperandrogenization at puberty. Her karyotype was 46,XY, and clinical investigation demonstrated clitoromegaly, but no uterine remnants were detected. Histology of the gonads revealed a testicular structure with a Sertoli-cell-only pattern. Endocrine evaluation showed hypergonadotropic hypogonadism, and the Sertoli cell markers inhibin B and anti-Müllerian hormone were also low. Several molecular genetic studies were initiated. While analyses of the androgen receptor gene, the SRD5A2 gene and HSD17B3 gene were uninformative, a novel p.L230R mutation was found in the NR5A1 gene. A mutant construct proved a severe dysfunction of this variant in functional analysis after recreation and transfection into HeLa cells. We conclude that the NR5A1 p.L230R mutation most likely leads to a spatial and time-dependent Leydig cell and Sertoli cell dysfunction during development not causing the classical gonadal dysgenesis phenotype. This case demonstrates that the current classification should be updated to encompass the overlapping phenotypes of some genetic conditions within 46,XY DSD.

  8. Whole exome sequencing in congenital pain insensitivity identifies a novel causative intronic NTRK1-mutation due to uniparental disomy.

    PubMed

    Kurth, Ingo; Baumgartner, Manuela; Schabhüttl, Maria; Tomni, Cecilia; Windhager, Reinhard; Strom, Tim M; Wieland, Thomas; Gremel, Kurt; Auer-Grumbach, Michaela

    2016-09-01

    Congenital insensitivity to pain and anhidrosis (CIPA), also known as hereditary sensory and autonomic neuropathy type IV (HSAN IV), is characterized by recurrent episodes of unexplained high fever, loss of pain perception and temperature sensation, absent sweating, repeated traumatic and thermal injuries, and mild mental retardation. After exclusion of obviously pathogenic mutations in NTRK1, the most common cause of CIPA, whole exome sequencing (WES) was carried out in a CIPA patient with unrelated parents. No mutations in known HSAN genes were identified. However, filtering for genes carrying two rare sequence variations detected 13 homozygous single nucleotide variants (SNV), all being located on chromosome 1. Further analysis strongly suggested that this finding might be best explained by uniparental disomy of chromosome 1. Because NTRK1 is also located on chromosome 1, we re-evaluated WES data and detected a novel intronic sequence variation at position c.2188-12 C>A, homozygously because of uniparental disomy. Subsequent analysis of NTRK1 transcripts in peripheral blood cells of the patient revealed an influence of the variant on mRNA splicing. The C>A transversion generated a novel splice-site, which led to the incorporation of 10 intronic bases into the NTRK1 mRNA and consequently to a non-functional gene product. © 2016 Wiley Periodicals, Inc. PMID:27184211

  9. Severe Undervirilisation in a 46,XY Case Due to a Novel Mutation in HSD17B3 Gene

    PubMed Central

    Alikaşifoğlu, Ayfer; Vurallı, Doğuş; Hiort, Olaf; Gönç, Nazlı; Özön, Alev; Kandemir, Nurgün

    2015-01-01

    17-β-hydroxysteroid dehydrogenase type 3 (17β-HSD3) is an important enzyme involved in the final steps of androgen synthesis and is required for the development of normal male external genitalia. 46,XY individuals with deficiency of this enzyme present a wide clinical spectrum from a female appearance of the external genitalia through ambiguous genitalia to a predominantly male genitalia with micropenis or hypospadias. This paper reports a one-year-old 46,XY patient with 17β-HSD3 deficiency who presented with female external genitalia and bilaterally palpable gonads in the inguinal region. The low T/Δ4 ratio after human chorionic gonadotropin (hCG) stimulation suggested 17β-HSD3 deficiency. A homozygous mutation, c.761_762delAG, was determined at the intron 9/exon 10 splice site of the HSD17B3 gene. To the best of our knowledge, this mutation has not been reported thus far, but its localization and type would imply a complete disruption of the 17β-HSD3 which may explain the phenotype of our patient. PMID:26831562

  10. Increased frequency of co-existing JAK2 exon-12 or MPL exon-10 mutations in patients with low JAK2(V617F) allelic burden.

    PubMed

    Nussenzveig, Roberto H; Pham, Ha T; Perkins, Sherrie L; Prchal, Josef T; Agarwal, Archana M; Salama, Mohamed E

    2016-01-01

    The frequency of co-existing JAK2(V617F)/MPL and JAK2(V617F)/JAK2 exon-12 mutations has not been previously investigated in MPNs. Poor survival was reported in primary myelofibrosis with low JAK2(V617F) allelic burden. However, mutational status of JAK2 exon-12 or MPL were not reported in these patients. This study developed a cost-effective multiplex high resolution melt assay that screens for mutations in JAK2 gene exons-12 and -14 ((V617F)) and MPL gene exon-10. Co-existing mutations with JAK2(V617F) were detected in 2.9% (6/208; two JAK2 exon-12 and four MPL exon-10) patient specimens with known JAK2(V617F) (allelic-burden range: 0.1-96.8%). Co-existing mutations were detected in specimens with < 12% JAK2(V617F) allelic burden. Current WHO guidelines do not recommend further testing once JAK2(V617F) mutation is detected in MPNs. The findings, however, indicate that quantification of JAK2(V617F) allele burden may be clinically relevant in MPNs and in those with low allelic burden additional testing for JAK2 exon-12 and MPL exon-10 mutation should be pursued.

  11. Mutation Frequency of the Major Frontotemporal Dementia Genes, MAPT, GRN and C9ORF72 in a Turkish Cohort of Dementia Patients.

    PubMed

    Guven, Gamze; Lohmann, Ebba; Bras, Jose; Gibbs, J Raphael; Gurvit, Hakan; Bilgic, Basar; Hanagasi, Hasmet; Rizzu, Patrizia; Heutink, Peter; Emre, Murat; Erginel-Unaltuna, Nihan; Just, Walter; Hardy, John; Singleton, Andrew; Guerreiro, Rita

    2016-01-01

    'Microtubule-associated protein tau' (MAPT), 'granulin' (GRN) and 'chromosome 9 open reading frame72' (C9ORF72) gene mutations are the major known genetic causes of frontotemporal dementia (FTD). Recent studies suggest that mutations in these genes may also be associated with other forms of dementia. Therefore we investigated whether MAPT, GRN and C9ORF72 gene mutations are major contributors to dementia in a random, unselected Turkish cohort of dementia patients. A combination of whole-exome sequencing, Sanger sequencing and fragment analysis/Southern blot was performed in order to identify pathogenic mutations and novel variants in these genes as well as other FTD-related genes such as the 'charged multivesicular body protein 2B' (CHMP2B), the 'FUS RNA binding protein' (FUS), the 'TAR DNA binding protein' (TARDBP), the 'sequestosome1' (SQSTM1), and the 'valosin containing protein' (VCP). We determined one pathogenic MAPT mutation (c.1906C>T, p.P636L) and one novel missense variant (c.38A>G, p.D13G). In GRN we identified a probably pathogenic TGAG deletion in the splice donor site of exon 6. Three patients were found to carry the GGGGCC expansions in the non-coding region of the C9ORF72 gene. In summary, a complete screening for mutations in MAPT, GRN and C9ORF72 genes revealed a frequency of 5.4% of pathogenic mutations in a random cohort of 93 Turkish index patients with dementia. PMID:27632209

  12. High frequency of mutations in exon 10 of the porphobilinogen deaminase gene in patients with a CRIM-positive subtype of acute intermittent porphyria

    SciTech Connect

    Gu, X.F.; Rooij, F. de; Voortman, G.; Velde, K.T.; Nordmann, Y.; Grandchamp, B.

    1992-09-01

    Acute intermittent porphyria (AIP) is an autosomal dominant disease characterized by a partial deficiency of porphobilinogen (PBG) deaminase. Different subtypes of the disease have been defined, and more than 10 different mutations have been described. The authors focused their study on exon 10, since they previously found that three different mutations were located in this exon and that two of them seemed to be relatively common. They used denaturing gradient gel electrophoresis (DGGE) after in vitro amplification to detect all possible mutations in exon 10 in 41 unrelated AIP patients. In about one-fourth of these patients they could distinguish three abnormal migration patterns, indicating the presence of various mutations. Additional sequencing demonstrated the presence of three different single-base substitutions. Two of these mutations had already been described. A third one consisted of a C-to-T transition located at position 499 of the PBG deaminase mRNA and resulted in an Arg-to-Trp substitution. All three mutations were found in patients with crossreacting immunological material (CRIM)-positive forms of AlP. The high frequency of these mutations make DGGE analysis of exon 10 a useful approach allowing the direct detection of the DNA abnormality in most of the families with the CRIM-positive subtype of AlP. 23 refs., 3 figs., 1 tab.

  13. Common MEFV mutations among Jewish ethnic groups in Israel: high frequency of carrier and phenotype III states and absence of a perceptible biological advantage for the carrier state.

    PubMed

    Kogan, A; Shinar, Y; Lidar, M; Revivo, A; Langevitz, P; Padeh, S; Pras, M; Livneh, A

    2001-08-15

    Familial Mediterranean fever (FMF) is an autosomal recessive disease, characterized by recurrent attacks of fever and inflammation of serosal membranes and gradual development of nephropathic amyloidosis. The recent cloning of the FMF gene (MEFV) and identification of disease-associated mutations in most patients made the direct determination of FMF carrier frequency feasible. The aim of the present study was to investigate the carrier rate of the most common MEFV mutations among different Jewish ethnic groups in Israel. Further, an attempt was made to elucidate the possible biological advantage that the heterozygote state may confer. Three hundred Ashkenazi, 101 Iraqi, and 120 Moroccan Jews were screened for the E148Q, V726A, and M694V mutations (at least two most common mutations per group), with a resulting overall carrier frequency in the respective ethnic group of 14%, 29%, and 21%. No difference in morbidity between Ashkenazi carriers and non-carriers of MEFV mutations was discerned, although an excess of febrile episodes in carriers of the V726A and in carriers of either V726A or E148Q was evident (P < 0.02 and P < 0.05, respectively). The frequency of subjects with two MEFV mutations but not expressing FMF (phenotype III) was 1:300 in Ashkenazi Jews and 1:25 in Iraqi Jews, exceeding the reported rate of overt FMF in these ethnic groups by 40-240 fold. These results affirm the high carrier rate among the studied Jewish ethnic groups in Israel and suggest that most subjects with FMF mutations are unaffected.

  14. Nonsyndromic retinitis pigmentosa is highly prevalent in the Jerusalem region with a high frequency of founder mutations

    PubMed Central

    Banin, Eyal

    2015-01-01

    Purpose Nonsyndromic retinitis pigmentosa (RP) is the most common inherited retinal degeneration, and prevalence of the disease has been reported in populations of American and European origin with a relatively low consanguinity rate. Our aim was to determine the prevalence of nonsyndromic RP in the Jerusalem region, which has a population of about 1 million individuals with a high rate of consanguinity. Methods The patients’ clinical data included eye exam findings (visual acuity, anterior segment, and funduscopy) as well as electroretinographic (ERG) testing results under scotopic and photopic conditions. Mutation analysis on a subgroup of patients was performed mainly with candidate gene analysis and homozygosity mapping. Results We evaluated the medical records of patients with degenerative retinal diseases residing in the Jerusalem region who were examined over the past 20 years in a large tertiary medical center. A total of 453 individuals affected with nonsyndromic RP were diagnosed at our center, according to funduscopic findings and ERG testing. Based on the estimated population size of 945,000 individuals who reside in the vicinity of Jerusalem, the prevalence of nonsyndromic RP in this region is 1:2,086. The prevalence of RP was higher among Arab Muslims (1:1,798) compared to Jews (1:2,230), mainly due to consanguineous marriages that are more common in the Arab Muslim population. To identify the genetic causes of RP in our cohort, we recruited 383 patients from 183 different families for genetic analysis: 70 with autosomal recessive (AR) inheritance, 15 with autosomal dominant, 86 isolate cases, and 12 with an X-linked inheritance pattern. In 64 (35%) of the families, we identified the genetic cause of the disease, and we revised the inheritance pattern of 20 isolate cases to the AR pattern; 49% of the families in our cohort had AR inheritance. Interestingly, in 42 (66%) of the genetically identified families, the cause of disease was a founder

  15. Gaucher disease with prenatal onset and perinatal death due to compound heterozygosity for the missense R131C and null Rec Nci I GBA mutations.

    PubMed

    Goebl, April; Ferrier, Raechel A; Ferreira, Patrick; Pinto-Rojas, Alfredo; Matshes, Evan; Choy, Francis Y M

    2011-01-01

    Gaucher disease is an autosomal recessive disorder resulting from deficient activity of the lysosomal enzyme glucocerebrosidase (GBA, E.C.3.2.1.45). Three clinical forms of Gaucher disease have been described: type 1, nonneuronopathic; type 2, acute neuronopathic; and type 3, subacute neuronopathic (OMIM 230800, 230900, 231000). Over the past decade, recognition of a distinct, perinatal lethal form of Gaucher disease (PLGD) has led researchers and clinicians to evaluate Gaucher disease in the differential diagnosis of congenital ichthyosis and nonimmune hydrops fetalis. To date, more than 30 cases of PLGD have been genotyped and reported. It has been observed that homozygosity for recombinant GBA alleles, which are fundamentally null alleles, leads to early lethality, usually in utero or during the 1st few days of life, whereas genotypes involving a recombinant allele and a missense mutation may be less detrimental. Here, we report a case of Gaucher disease with prenatal onset and death within hours of birth, likely due to compound heterozygosity for the GBA Rec Nci I null allele and a R131C missense mutation. In view of the patient's severe clinical course, and based on reviews of other PLGD cases, we postulate that a missense mutation that abruptly disrupts the structure/function of GBA, in combination with a null allele, may result in early lethality in patients with PLGD. We also speculate that R131C is an extremely severe mutation that has occurred more than once in different populations and, in either the homozygous form or heterozygous with another severe mutation, will result in a poor prognosis.

  16. Perry syndrome due to the DCTN1 G71R mutation: a distinctive levodopa responsive disorder with behavioral syndrome, vertical gaze palsy, and respiratory failure.

    PubMed

    Newsway, Victoria; Fish, Mark; Rohrer, Jonathan D; Majounie, Elisa; Williams, Nigel; Hack, Melissa; Warren, Jason D; Morris, Huw R

    2010-04-30

    Perry syndrome is a rare form of autosomal dominant Parkinsonism with respiratory failure recently defined as being due to mutations in the DCTN1 gene. We describe a new family carrying a G71R mutation in the DCTN1 gene. The proband displayed a series of distinctive features not previously described in Perry syndrome: a disorder of vertical downward saccades accompanied by progressive midbrain atrophy, predominant nonmotor symptoms responsive to levodopa, distinctive craniocervical levodopa induced dyskinesias, and a good response to high-dose levodopa therapy and respiratory support. The family was initially thought to have autosomal dominant behavioral variant frontotemporal dementia with Parkinsonism. This report expands the clinical definition of this distinctive syndrome.

  17. Stickler-like syndrome due to a dominant negative mutation in the COL2A1 gene.

    PubMed

    Ballo, R; Beighton, P H; Ramesar, R S

    1998-10-30

    The type II collagenopathies include a wide spectrum of phenotypes ranging from mild spondylo epiphyseal dysplasia (SED) to severe achondrogenesis/hypochondrogenesis. Several attempts have been made at providing phenotype-genotype correlations in this group of disorders. In this report we discuss a South African family in which four members have a phenotype resembling Stickler syndrome type 1. Ocular problems and conductive deafness predominate, while skeletal changes resemble those of a mild form of multiple epiphyseal dysplasia (MED). In distinction to the classical form of Stickler syndrome, the affected persons have stubby digits. DNA analysis of the exons of the COL2A1 gene documented a C-T transversion in exon 39, resulting in an Arg704Cys substitution in the triple helical domain of the type II collagen peptide; this nontermination mutation may be indicative of further heterogeneity in the Stickler group of disorders or of a new syndrome amongst the type II collagenopathies. PMID:9800905

  18. Molecular principles behind Boceprevir resistance due to mutations in hepatitis C NS3/4A protease.

    PubMed

    Nagpal, Neha; Goyal, Sukriti; Wahi, Divya; Jain, Ritu; Jamal, Salma; Singh, Aditi; Rana, Preeti; Grover, Abhinav

    2015-10-01

    The hepatitis C virus (HCV) infection is a primary cause of chronic hepatitis which eventually progresses to cirrhosis and in some instances might advance to hepatocellular carcinoma. According to the WHO report, HCV infects 130-150 million people globally and every year 350,000 to 500,000 people die from hepatitis C virus infection. Great achievement has been made in viral treatment evolution, after the development of HCV NS3/4A protease inhibitor (Boceprevir). However, efficacy of Boceprevir is compromised by the emergence of drug resistant variants. The molecular principle behind drug resistance of the protease mutants such as (V36M, T54S and R155K) is still poorly understood. Therefore in this study, we employed a series of computational strategies to analyze the binding of antiviral drug, Boceprevir to HCV NS3/4A protease mutants. Our results clearly demonstrate that the point mutations (V36M, T54S and R155K) in protease are associated with lowering of its binding affinity with Boceprevir. Exhaustive analysis of the simulated Boceprevir-bound wild and mutant complexes revealed variations in hydrophobic interactions, hydrogen bond occupancy and salt bridge interactions. Also, substrate envelope analysis scrutinized that the studied mutations reside outside the substrate envelope which may affect the Boceprevir affinity towards HCV protease but not the protease enzymatic activity. Furthermore, structural analyses of the binding site volume and flexibility show impairment in flexibility and stability of the binding site residues in mutant structures. In order to combat Boceprevir resistance, renovation of binding interactions between the drug and protease may be valuable. The structural insight from this study reveals the mechanism of the Boceprevir resistance and the results can be valuable for the design of new PIs with improved efficiency. PMID:26055089

  19. Severe infantile epileptic encephalopathy due to mutations in PLCB1: expansion of the genotypic and phenotypic disease spectrum

    PubMed Central

    Ngoh, Adeline; McTague, Amy; Wentzensen, Ingrid M; Meyer, Esther; Applegate, Carolyn; Kossoff, Eric H; Batista, Denise A; Wang, Tao; Kurian, Manju A

    2014-01-01

    Homozygous deletions of chromosome 20p12.3, disrupting the promoter region and first three coding exons of the phospholipase C β1 gene (PLCB1), have previously been described in two reports of early infantile epileptic encephalopathy (EIEE). Both children were born to consanguineous parents, one presented with infantile spasms, the other with migrating partial seizures of infancy. We describe an infant presenting with severe intractable epilepsy (without a specific EIEE electroclinical syndrome diagnosis) and neurodevelopmental delay associated with compound heterozygous mutations in PLCB1. A case note review and molecular genetic investigations were performed for a child, approximately 10 months of age, admitted to Johns Hopkins University Hospital for developmental delay and new-onset seizures. The patient presented at 6 months of age with developmental delay, followed by the onset of intractable, focal, and generalized seizures associated with developmental regression from 10 months of age. Presently, at 2 years of age, the child has severe motor and cognitive delays. Diagnostic microarray revealed a heterozygous 476kb deletion of 20p12.3 (encompassing PLCB1), which was also detected in the mother. The genomic breakpoints for the heterozygous deletion were determined. In order to investigate the presence of a second PLCB1 mutation, direct Sanger sequencing of the coding region and flanking intronic regions was undertaken, revealing a novel heterozygous intron 1 splice site variant (c.99+1G>A) in both the index individual and the father. Advances in molecular genetic testing have greatly improved diagnostic rates in EIEE, and this report further confirms the important role of microarray investigation in this group of disorders. PLCB1-EIEE is now reported in a number of different EIEE phenotypes and our report provides further evidence for phenotypic pleiotropy encountered in early infantile epilepsy syndromes. PMID:24684524

  20. Molecular principles behind Boceprevir resistance due to mutations in hepatitis C NS3/4A protease.

    PubMed

    Nagpal, Neha; Goyal, Sukriti; Wahi, Divya; Jain, Ritu; Jamal, Salma; Singh, Aditi; Rana, Preeti; Grover, Abhinav

    2015-10-01

    The hepatitis C virus (HCV) infection is a primary cause of chronic hepatitis which eventually progresses to cirrhosis and in some instances might advance to hepatocellular carcinoma. According to the WHO report, HCV infects 130-150 million people globally and every year 350,000 to 500,000 people die from hepatitis C virus infection. Great achievement has been made in viral treatment evolution, after the development of HCV NS3/4A protease inhibitor (Boceprevir). However, efficacy of Boceprevir is compromised by the emergence of drug resistant variants. The molecular principle behind drug resistance of the protease mutants such as (V36M, T54S and R155K) is still poorly understood. Therefore in this study, we employed a series of computational strategies to analyze the binding of antiviral drug, Boceprevir to HCV NS3/4A protease mutants. Our results clearly demonstrate that the point mutations (V36M, T54S and R155K) in protease are associated with lowering of its binding affinity with Boceprevir. Exhaustive analysis of the simulated Boceprevir-bound wild and mutant complexes revealed variations in hydrophobic interactions, hydrogen bond occupancy and salt bridge interactions. Also, substrate envelope analysis scrutinized that the studied mutations reside outside the substrate envelope which may affect the Boceprevir affinity towards HCV protease but not the protease enzymatic activity. Furthermore, structural analyses of the binding site volume and flexibility show impairment in flexibility and stability of the binding site residues in mutant structures. In order to combat Boceprevir resistance, renovation of binding interactions between the drug and protease may be valuable. The structural insight from this study reveals the mechanism of the Boceprevir resistance and the results can be valuable for the design of new PIs with improved efficiency.

  1. Analysis of 454 sequencing error rate, error sources, and artifact recombination for detection of Low-frequency drug resistance mutations in HIV-1 DNA

    PubMed Central

    2013-01-01

    Background 454 sequencing technology is a promising approach for characterizing HIV-1 populations and for identifying low frequency mutations. The utility of 454 technology for determining allele frequencies and linkage associations in HIV infected individuals has not been extensively investigated. We evaluated the performance of 454 sequencing for characterizing HIV populations with defined allele frequencies. Results We constructed two HIV-1 RT clones. Clone A was a wild type sequence. Clone B was identical to clone A except it contained 13 introduced drug resistant mutations. The clones were mixed at ratios ranging from 1% to 50% and were amplified by standard PCR conditions and by PCR conditions aimed at reducing PCR-based recombination. The products were sequenced using 454 pyrosequencing. Sequence analysis from standard PCR amplification revealed that 14% of all sequencing reads from a sample with a 50:50 mixture of wild type and mutant DNA were recombinants. The majority of the recombinants were the result of a single crossover event which can happen during PCR when the DNA polymerase terminates synthesis prematurely. The incompletely extended template then competes for primer sites in subsequent rounds of PCR. Although less often, a spectrum of other distinct crossover patterns was also detected. In addition, we observed point mutation errors ranging from 0.01% to 1.0% per base as well as indel (insertion and deletion) errors ranging from 0.02% to nearly 50%. The point errors (single nucleotide substitution errors) were mainly introduced during PCR while indels were the result of pyrosequencing. We then used new PCR conditions designed to reduce PCR-based recombination. Using these new conditions, the frequency of recombination was reduced 27-fold. The new conditions had no effect on point mutation errors. We found that 454 pyrosequencing was capable of identifying minority HIV-1 mutations at frequencies down to 0.1% at some nucleotide positions. Conclusion

  2. Ontogeny of the barley plant as related to mutation expression and detection of pollen mutations

    SciTech Connect

    Hodgdon, A.L.; Marcus, A.H.; Arenaz, P.; Rosichan, J.L.; Bogyo, T.P.; Nilan, R.A.

    1980-05-29

    Clustering of mutant pollen grains in a population of normal pollen due to premeiotic mutational events complicates translating mutation frequencies into rates. Embryo ontogeny in barley will be described and used to illustrate the formation of such mutant clusters. The nature of the statistics for mutation frequency will be described from a study of the reversion frequencies of various waxy mutants in barley. Computer analysis by a jackknife method of the reversion frequencies of a waxy mutant treated with the mutagen sodium azide showed a significantly higher reversion frequency than untreated material. Problems of the computer analysis suggest a better experimental design for pollen mutation experiments. Preliminary work on computer modeling for pollen development and mutation will be described.

  3. Definition of Shifts of Optical Transitions Frequencies due to Pulse Perturbation Action by the Photon Echo Signal Form

    NASA Astrophysics Data System (ADS)

    Lisin, V. N.; Shegeda, A. M.; Samartsev, V. V.

    2015-09-01

    A relative phase shift between the different groups of excited dipoles, which appears as result of its frequency splitting due to action of a pulse of electric or magnetic fields, depends on a time, if the pulse overlaps in time with echo-pulse. As а consequence, the echo waveform is changed. The echo time form is modulated. The inverse modulation period well enough approximates Zeeman and pseudo-Stark splitting in the cases of magnetic and, therefore, electrical fields. Thus the g-factors of ground 4I15/2 and excited 4F9/2 optical states of Er3+ ion in LuLiF4 and YLiF4 have been measured and pseudo-Stark shift of R1 line in ruby has been determined.

  4. Spectrum of genetic changes in patients with non-syndromic hearing impairment and extremely high carrier frequency of 35delG GJB2 mutation in Belarus.

    PubMed

    Danilenko, Nina; Merkulava, Elena; Siniauskaya, Marina; Olejnik, Olga; Levaya-Smaliak, Anastasia; Kushniarevich, Alena; Shymkevich, Andrey; Davydenko, Oleg

    2012-01-01

    The genetic nature of sensorineural hearing loss (SNHL) has so far been studied for many ethnic groups in various parts of the world. The single-nucleotide guanine deletion (35delG) of the GJB2 gene coding for connexin 26 was shown to be the main genetic cause of autosomal recessive deafness among Europeans. Here we present the results of the first study of GJB2 and three mitochondrial mutations among two groups of Belarusian inhabitants: native people with normal hearing (757 persons) and 391 young patients with non-syndromic SNHL. We have found an extremely high carrier frequency of 35delG GJB2 mutation in Belarus -5.7%. This point deletion has also been detected in 53% of the patients with SNHL. The 312del14 GJB2 was the second most common mutation in the Belarus patient cohort. Mitochondrial A1555G mt-RNR1 substitution was found in two SNHL patients (0.55%) but none were found in the population cohort. No individuals carried the A7445G mutation of mitochondrial mt-TS1. G7444A as well as T961G substitutions were detected in mitochondrial mt-RNR1 at a rate of about 1% both in the patient and population cohorts. A possible reason for Belarusians having the highest mutation carrier frequency in Europe 35delG is discussed.

  5. Autosomal dominant hypercalciuria in a mouse model due to a mutation of the epithelial calcium channel, TRPV5.

    PubMed

    Loh, Nellie Y; Bentley, Liz; Dimke, Henrik; Verkaart, Sjoerd; Tammaro, Paolo; Gorvin, Caroline M; Stechman, Michael J; Ahmad, Bushra N; Hannan, Fadil M; Piret, Sian E; Evans, Holly; Bellantuono, Ilaria; Hough, Tertius A; Fraser, William D; Hoenderop, Joost G J; Ashcroft, Frances M; Brown, Steve D M; Bindels, René J M; Cox, Roger D; Thakker, Rajesh V

    2013-01-01

    Hypercalciuria is a major cause of nephrolithiasis, and is a common and complex disorder involving genetic and environmental factors. Identification of genetic factors for monogenic forms of hypercalciuria is hampered by the limited availability of large families, and to facilitate such studies, we screened for hypercalciuria in mice from an N-ethyl-N-nitrosourea mutagenesis programme. We identified a mouse with autosomal dominant hypercalciuria (HCALC1). Linkage studies mapped the Hcalc1 locus to a 11.94 Mb region on chromosome 6 containing the transient receptor potential cation channel, subfamily V, members 5 (Trpv5) and 6 (Trpv6) genes. DNA sequence analysis of coding regions, intron-exon boundaries and promoters of Trpv5 and Trpv6 identified a novel T to C transition in codon 682 of TRPV5, mutating a conserved serine to a proline (S682P). Compared to wild-type littermates, heterozygous (Trpv5(682P/+)) and homozygous (Trpv5(682P/682P)) mutant mice had hypercalciuria, polyuria, hyperphosphaturia and a more acidic urine, and ∼10% of males developed tubulointerstitial nephritis. Trpv5(682P/682P) mice also had normal plasma parathyroid hormone but increased 1,25-dihydroxyvitamin D(3) concentrations without increased bone resorption, consistent with a renal defect for the hypercalciuria. Expression of the S682P mutation in human embryonic kidney cells revealed that TRPV5-S682P-expressing cells had a lower baseline intracellular calcium concentration than wild-type TRPV5-expressing cells, suggesting an altered calcium permeability. Immunohistological studies revealed a selective decrease in TRPV5-expression from the renal distal convoluted tubules of Trpv5(682P/+) and Trpv5(682P/682P) mice consistent with a trafficking defect. In addition, Trpv5(682P/682P) mice had a reduction in renal expression of the intracellular calcium-binding protein, calbindin-D(28K), consistent with a specific defect in TRPV5-mediated renal calcium reabsorption. Thus, our findings indicate

  6. Common mutations in the phosphofructokinase-M gene in Ashkenazi Jewish patients with glycogenesis VII - and their population frequency

    SciTech Connect

    Sherman, J.B.; Raben, N.; Nicastri, C.; Adams, E.M.; Plotz, P.H. ); Argov, Z. ); Nakajima, Hiromu ); Eng, C.M.; Cowan, T.M. )

    1994-08-01

    Phosphofructokinase (PFK) catalyzes the rate-limiting step of glycolysis. Deficiency of the muscle enzyme is manifested by exercise intolerance and a compensated hemolytic anemia. Case reports of this autosomal recessive disease suggest a predominance in Ashkenazi Jews in the United States. The authors have explored the genetic basis for this illness in nine affected families and surveyed the normal Ashkenazi population for the mutations found. Genomic DNA was amplified using PCR, and denaturing gradient-gel electrophoresis. The polymorphic exons were sequenced or digested with restriction enzymes. A previously described splicing mutation, [Delta]5, accounted for 11 (61%) of 18 abnormal alleles in the nine families. A single base deletion leading to a frameshift mutation in exon 22 ([Delta]C-22) was found in six of seven alleles. A third mutation, resulting in a nonconservative amino acid substitution in exon 4, accounted for the remaining allele. Thus, three mutations could account for an illness in this group, and two mutations could account for 17 of 18 alleles. In screening 250 normal Ashkenazi individuals for all three mutations, they found only one [Delta]5 allele. Clinical data revealed no correlation between the particular mutations and symptoms, but male patients were more symptomatic than females, and only males had frank hemolysis and hyperuricemia. Because PFK deficiency in Ashkenazi Jews is caused by a limited number of mutations, screening genomic DNA from peripheral blood for the described mutations in this population should enable rapid diagnosis without muscle biopsy. 41 refs., 4 figs., 2 tabs.

  7. An assessment of the frequency of mutations in the GBA and VPS35 genes in Hungarian patients with sporadic Parkinson's disease.

    PubMed

    Török, Rita; Zádori, Dénes; Török, Nóra; Csility, Éva; Vécsei, László; Klivényi, Péter

    2016-01-01

    Parkinson's disease (PD) is the second most common neurodegenerative disorder, with cases of either familial or sporadic origin. Several polymorphisms in a number of genes have been proved to have an important role in the development of PD. Particular attention has recently been paid to genes of the glucocerebrosidase (GBA) and the vacuolar protein sorting-associated protein 35 (VPS35). In this study, the three most common mutations (L444P, N370S and R120W) of the GBA gene and the D620N mutation of the VPS35 gene were examined in 124 Hungarian patients diagnosed with sporadic PD (SPD) and 122 control subjects. The frequency of the L444P mutation of the GBA gene proved to be higher in the PD patients (2.4%) than in the controls (0%), although the difference was not statistically significant. All the patients who carried the mutant allele were in the early-onset PD (EOPD) group. However, neither the R120W nor the N370S variant of the GBA gene nor D620N mutation of the VPS35 gene were detected among the PD cases or the controls. Even though these results suggest that the studied mutations are quite rare in SPD patients, the most frequent L444P mutation of the GBA gene may be associated with the development of EOPD in the Hungarian population.

  8. High frequency and allele-specific differences of BRCA1 founder mutations in breast cancer and ovarian cancer patients from Belarus.

    PubMed

    Bogdanova, N V; Antonenkova, N N; Rogov, Y I; Karstens, J H; Hillemanns, P; Dörk, T

    2010-10-01

    Breast cancer and ovarian cancer are common malignancies in Belarus accounting for about 3500 and 800 new cases per year, respectively. For breast cancer, the rates and age of onset appear to vary significantly in regions differentially affected by the Chernobyl accident. We assessed the frequency and distribution of three BRCA1 founder mutations 5382insC, 4153delA and Cys61Gly in two hospital-based series of 1945 unselected breast cancer patients and of 201 unselected ovarian cancer patients from Belarus as well as in 1019 healthy control females from the same population. Any of these mutations were identified in 4.4% of the breast cancer patients, 26.4% of the ovarian cancer patients and 0.5% of the controls. In the breast cancer patients, BRCA1 mutations were strongly associated with earlier age at diagnosis, with oestrogen receptor (ER) negative tumours and with a first-degree family history of breast cancer, although only 35% of the identified BRCA1 mutation carriers had such a family history. There were no marked differences in the regional distribution of BRCA1 mutations, so that the significant differences in age at diagnosis and family history of breast cancer patients from areas afflicted by the Chernobyl accident could not be explained by BRCA1. We next observed a higher impact and a shifted mutational spectrum of BRCA1 in the series of Byelorussian ovarian cancer patients where the three founder mutations accounted for 26.4% (53/201). While the Cys61Gly mutation appeared underrepresented in ovarian cancer as compared with breast cancer cases from the same population (p = 0.01), the 4153delA mutation made a higher contribution to ovarian cancer than to breast cancer (p < 0.01). BRCA1 mutations were significantly enriched among ovarian cancer cases with a first-degree family history of breast or ovarian cancer, whereas the median age at ovarian cancer diagnosis was not different between mutation carriers and non-carriers. Taken together, these results

  9. NAA10 mutation causing a novel intellectual disability syndrome with Long QT due to N-terminal acetyltransferase impairment

    PubMed Central

    Casey, Jillian P.; Støve, Svein I.; McGorrian, Catherine; Galvin, Joseph; Blenski, Marina; Dunne, Aimee; Ennis, Sean; Brett, Francesca; King, Mary D.; Arnesen, Thomas; Lynch, Sally Ann

    2015-01-01

    We report two brothers from a non-consanguineous Irish family presenting with a novel syndrome characterised by intellectual disability, facial dysmorphism, scoliosis and long QT. Their mother has a milder phenotype including long QT. X-linked inheritance was suspected. Whole exome sequencing identified a novel missense variant (c.128 A > C; p.Tyr43Ser) in NAA10 (X chromosome) as the cause of the family’s disorder. Sanger sequencing confirmed that the mutation arose de novo in the carrier mother. NAA10 encodes the catalytic subunit of the major human N-terminal acetylation complex NatA. In vitro assays for the p.Tyr43Ser mutant enzyme showed a significant decrease in catalytic activity and reduced stability compared to wild-type Naa10 protein. NAA10 has previously been associated with Ogden syndrome, Lenz microphthalmia syndrome and non-syndromic developmental delay. Our findings expand the clinical spectrum of NAA10 and suggest that the proposed correlation between mutant Naa10 enzyme activity and phenotype severity is more complex than anticipated; the p.Tyr43Ser mutant enzyme has less catalytic activity than the p.Ser37Pro mutant associated with lethal Ogden syndrome but results in a milder phenotype. Importantly, we highlight the need for cardiac assessment in males and females with NAA10 variants as both patients and carriers can have long QT. PMID:26522270

  10. Misfolding of chloramphenicol acetyltransferase due to carboxy-terminal truncation can be corrected by second-site mutations.

    PubMed

    Van der Schueren, J; Robben, J; Volckaert, G

    1998-12-01

    Folding of chloramphenicol acetyltransferase (CAT) in Escherichia coli is hampered by deletion of the carboxy-terminal tail including the last residue of the carboxy-terminal alpha-helix. Such truncated CAT polypeptides quantitatively aggregate into cytoplasmic inclusion bodies, which results in absence of a chloramphenicol-resistant phenotype for the producing host. In this paper, a genetic approach is presented to examine this aggregation process in more detail. Random mutagenesis of inactive CAT followed by direct phenotypic selection for revertants with restored chloramphenicol resistance was used to isolate second-site suppressors of inactive truncation mutants of CAT. Two random mutagenesis procedures, independently of each other, yielded a unique substitution of Phe for Leu at amino acid position 145. This second-site mutation does not drastically affect the proteins' stability under normal growth conditions of E. coli. Hence, the introduction of Phe at amino acid position 145 improves the ability of the protein to fold into a soluble, enzymatically active conformation. The conservative character of the Leu145Phe replacement indicates that limited changes at crucial positions can have important effects on protein folding in vivo.

  11. Elevation of 20-carbon long chain bases due to a mutation in serine palmitoyltransferase small subunit b results in neurodegeneration.

    PubMed

    Zhao, Lihong; Spassieva, Stefka; Gable, Kenneth; Gupta, Sita D; Shi, Lan-Ying; Wang, Jieping; Bielawski, Jacek; Hicks, Wanda L; Krebs, Mark P; Naggert, Juergen; Hannun, Yusuf A; Dunn, Teresa M; Nishina, Patsy M

    2015-10-20

    Sphingolipids typically have an 18-carbon (C18) sphingoid long chain base (LCB) backbone. Although sphingolipids with LCBs of other chain lengths have been identified, the functional significance of these low-abundance sphingolipids is unknown. The LCB chain length is determined by serine palmitoyltransferase (SPT) isoenzymes, which are trimeric proteins composed of two large subunits (SPTLC1 and SPTLC2 or SPTLC3) and a small subunit (SPTssa or SPTssb). Here we report the identification of an Sptssb mutation, Stellar (Stl), which increased the SPT affinity toward the C18 fatty acyl-CoA substrate by twofold and significantly elevated 20-carbon (C20) LCB production in the mutant mouse brain and eye, resulting in surprising neurodegenerative effects including aberrant membrane structures, accumulation of ubiquitinated proteins on membranes, and axon degeneration. Our work demonstrates that SPT small subunits play a major role in controlling SPT activity and substrate affinity, and in specifying sphingolipid LCB chain length in vivo. Moreover, our studies also suggest that excessive C20 LCBs or C20 LCB-containing sphingolipids impair protein homeostasis and neural functions.

  12. NAA10 mutation causing a novel intellectual disability syndrome with Long QT due to N-terminal acetyltransferase impairment.

    PubMed

    Casey, Jillian P; Støve, Svein I; McGorrian, Catherine; Galvin, Joseph; Blenski, Marina; Dunne, Aimee; Ennis, Sean; Brett, Francesca; King, Mary D; Arnesen, Thomas; Lynch, Sally Ann

    2015-01-01

    We report two brothers from a non-consanguineous Irish family presenting with a novel syndrome characterised by intellectual disability, facial dysmorphism, scoliosis and long QT. Their mother has a milder phenotype including long QT. X-linked inheritance was suspected. Whole exome sequencing identified a novel missense variant (c.128 A > C; p.Tyr43Ser) in NAA10 (X chromosome) as the cause of the family's disorder. Sanger sequencing confirmed that the mutation arose de novo in the carrier mother. NAA10 encodes the catalytic subunit of the major human N-terminal acetylation complex NatA. In vitro assays for the p.Tyr43Ser mutant enzyme showed a significant decrease in catalytic activity and reduced stability compared to wild-type Naa10 protein. NAA10 has previously been associated with Ogden syndrome, Lenz microphthalmia syndrome and non-syndromic developmental delay. Our findings expand the clinical spectrum of NAA10 and suggest that the proposed correlation between mutant Naa10 enzyme activity and phenotype severity is more complex than anticipated; the p.Tyr43Ser mutant enzyme has less catalytic activity than the p.Ser37Pro mutant associated with lethal Ogden syndrome but results in a milder phenotype. Importantly, we highlight the need for cardiac assessment in males and females with NAA10 variants as both patients and carriers can have long QT. PMID:26522270

  13. Congenital central hypothyroidism due to a homozygous mutation in the thyrotropin beta-subunit gene follows an autosomal recessive inheritance.

    PubMed

    Doeker, B M; Pfäffle, R W; Pohlenz, J; Andler, W

    1998-05-01

    A 5-month-old infant of nonconsanguineous parents had severe hypothyroidism. Undetectable serum levels of T3 and T4 in combination with an undetectable baseline TSH level led to the diagnosis of central hypothyroidism. Administration of TRH failed to increase serum TSH, but not PRL, confirming isolated TSH deficiency. Measurement of the TSH in serum with three different immunoassays that recognize different epitopes of the TSH molecule failed to detect TSH, suggesting an aberrant or absent TSH. Direct sequencing of the entire coding region of the human TSH beta-subunit gene revealed a homozygous single base pair deletion in codon 105, resulting in a frame shift with a premature stop at codon 114. The truncated TSH beta peptide lacks the terminal five amino acids. Furthermore, the cysteine in codon 105 that is believed to be important for the interaction of the TSH beta-subunit with the alpha-subunit, is replaced with a valine (C105V), supporting the theory of a conformational change in the TSH molecule. Genotyping confirmed that the proposita was homozygous for this mutation, whereas her unaffected parents, the paternal grand-mother, and the maternal grandfather were heterozygous. Thus, isolated TSH deficiency follows an autosomal recessive mode of inheritance in this kindred.

  14. Elevation of 20-carbon long chain bases due to a mutation in serine palmitoyltransferase small subunit b results in neurodegeneration.

    PubMed

    Zhao, Lihong; Spassieva, Stefka; Gable, Kenneth; Gupta, Sita D; Shi, Lan-Ying; Wang, Jieping; Bielawski, Jacek; Hicks, Wanda L; Krebs, Mark P; Naggert, Juergen; Hannun, Yusuf A; Dunn, Teresa M; Nishina, Patsy M

    2015-10-20

    Sphingolipids typically have an 18-carbon (C18) sphingoid long chain base (LCB) backbone. Although sphingolipids with LCBs of other chain lengths have been identified, the functional significance of these low-abundance sphingolipids is unknown. The LCB chain length is determined by serine palmitoyltransferase (SPT) isoenzymes, which are trimeric proteins composed of two large subunits (SPTLC1 and SPTLC2 or SPTLC3) and a small subunit (SPTssa or SPTssb). Here we report the identification of an Sptssb mutation, Stellar (Stl), which increased the SPT affinity toward the C18 fatty acyl-CoA substrate by twofold and significantly elevated 20-carbon (C20) LCB production in the mutant mouse brain and eye, resulting in surprising neurodegenerative effects including aberrant membrane structures, accumulation of ubiquitinated proteins on membranes, and axon degeneration. Our work demonstrates that SPT small subunits play a major role in controlling SPT activity and substrate affinity, and in specifying sphingolipid LCB chain length in vivo. Moreover, our studies also suggest that excessive C20 LCBs or C20 LCB-containing sphingolipids impair protein homeostasis and neural functions. PMID:26438849

  15. Elevation of 20-carbon long chain bases due to a mutation in serine palmitoyltransferase small subunit b results in neurodegeneration

    PubMed Central

    Zhao, Lihong; Spassieva, Stefka; Gable, Kenneth; Gupta, Sita D.; Shi, Lan-Ying; Wang, Jieping; Bielawski, Jacek; Hicks, Wanda L.; Krebs, Mark P.; Naggert, Juergen; Hannun, Yusuf A.; Dunn, Teresa M.; Nishina, Patsy M.

    2015-01-01

    Sphingolipids typically have an 18-carbon (C18) sphingoid long chain base (LCB) backbone. Although sphingolipids with LCBs of other chain lengths have been identified, the functional significance of these low-abundance sphingolipids is unknown. The LCB chain length is determined by serine palmitoyltransferase (SPT) isoenzymes, which are trimeric proteins composed of two large subunits (SPTLC1 and SPTLC2 or SPTLC3) and a small subunit (SPTssa or SPTssb). Here we report the identification of an Sptssb mutation, Stellar (Stl), which increased the SPT affinity toward the C18 fatty acyl-CoA substrate by twofold and significantly elevated 20-carbon (C20) LCB production in the mutant mouse brain and eye, resulting in surprising neurodegenerative effects including aberrant membrane structures, accumulation of ubiquitinated proteins on membranes, and axon degeneration. Our work demonstrates that SPT small subunits play a major role in controlling SPT activity and substrate affinity, and in specifying sphingolipid LCB chain length in vivo. Moreover, our studies also suggest that excessive C20 LCBs or C20 LCB-containing sphingolipids impair protein homeostasis and neural functions. PMID:26438849

  16. NAA10 mutation causing a novel intellectual disability syndrome with Long QT due to N-terminal acetyltransferase impairment.

    PubMed

    Casey, Jillian P; Støve, Svein I; McGorrian, Catherine; Galvin, Joseph; Blenski, Marina; Dunne, Aimee; Ennis, Sean; Brett, Francesca; King, Mary D; Arnesen, Thomas; Lynch, Sally Ann

    2015-11-02

    We report two brothers from a non-consanguineous Irish family presenting with a novel syndrome characterised by intellectual disability, facial dysmorphism, scoliosis and long QT. Their mother has a milder phenotype including long QT. X-linked inheritance was suspected. Whole exome sequencing identified a novel missense variant (c.128 A > C; p.Tyr43Ser) in NAA10 (X chromosome) as the cause of the family's disorder. Sanger sequencing confirmed that the mutation arose de novo in the carrier mother. NAA10 encodes the catalytic subunit of the major human N-terminal acetylation complex NatA. In vitro assays for the p.Tyr43Ser mutant enzyme showed a significant decrease in catalytic activity and reduced stability compared to wild-type Naa10 protein. NAA10 has previously been associated with Ogden syndrome, Lenz microphthalmia syndrome and non-syndromic developmental delay. Our findings expand the clinical spectrum of NAA10 and suggest that the proposed correlation between mutant Naa10 enzyme activity and phenotype severity is more complex than anticipated; the p.Tyr43Ser mutant enzyme has less catalytic activity than the p.Ser37Pro mutant associated with lethal Ogden syndrome but results in a milder phenotype. Importantly, we highlight the need for cardiac assessment in males and females with NAA10 variants as both patients and carriers can have long QT.

  17. Taste dysfunction in BTBR mice due to a mutation of Itpr3, the inositol triphosphate receptor 3 gene.

    PubMed

    Tordoff, Michael G; Ellis, Hillary T

    2013-09-16

    The BTBR T+ tf/J (BTBR) mouse strain is indifferent to exemplars of sweet, Polycose, umami, bitter, and calcium tastes, which share in common transduction by G protein-coupled receptors (GPCRs). To investigate the genetic basis for this taste dysfunction, we screened 610 BTBR×NZW/LacJ F2 hybrids, identified a potent QTL on chromosome 17, and isolated this in a congenic strain. Mice carrying the BTBR/BTBR haplotype in the 0.8-Mb (21-gene) congenic region were indifferent to sweet, Polycose, umami, bitter, and calcium tastes. To assess the contribution of a likely causative culprit, Itpr3, the inositol triphosphate receptor 3 gene, we produced and tested Itpr3 knockout mice. These were also indifferent to GPCR-mediated taste compounds. Sequencing the BTBR form of Itpr3 revealed a unique 12 bp deletion in Exon 23 (Chr 17: 27238069; Build 37). We conclude that a spontaneous mutation of Itpr3 in a progenitor of the BTBR strain produced a heretofore unrecognized dysfunction of GPCR-mediated taste transduction.

  18. Non-syndromic hereditary gingival fibromatosis in three Chinese families is not due to SOS1 gene mutations.

    PubMed

    Ma, Yanyan; Sun, Zheng; Hu, Ying; Liu, Yi; Jin, Lingling; Zhang, Fenqiu

    2014-12-01

    Non-syndromic hereditary gingival fibromatosis (HGF) is a rare condition, characterized by a progressive gingival hyperplasia that occurs as an isolated disease. Hitherto, only one insertion (g.126,142-126,143insC) in son-of-sevenless-1 (SOS1) gene has been associated with non-syndromic HGF in a Brazilian family. The aim of the present study was to determine if SOS1 is the causative gene of non-syndromic HGF in the Chinese population. Peripheral blood samples were collected from six affected and seven unaffected individuals from three Chinese families with history of non-syndromic HGF. Genomic DNA was extracted and SOS1 gene exons were sequenced. Neither g.126,142-126,143insC nor any other novel mutation was detected in SOS1 gene. Our results suggest that the SOS1 may not be the gene responsible for HGF in these three Chinese families and, therefore, it is possible that other genes are involved in the manifestation of HGF in these Chinese HGF families.

  19. Severe renal tubulopathy in a newborn due to BCS1L gene mutation: effects of different treatment modalities on the clinical course.

    PubMed

    Ezgu, Fatih; Senaca, Sara; Gunduz, Mehmet; Tumer, Leyla; Hasanoglu, Alev; Tiras, Ulku; Unsal, Rukiye; Bakkaloglu, Sevcan A

    2013-10-10

    Very early onset Toni-Debré-Fanconi Syndrome, a disorder of proximal renal tubules of the kidney which results in the increased urinary excretion of glucose, amino acids, uric acid, phosphate and bicarbonate, could be the manifestation of various inborn errors. Defects of oxidative phosphorylation are a heterogeneous group of disorders with various clinical presentations. Recently, patients with early liver failure, renal tubulopathy and encephalopathy due to the mutations in the BCS1L gene coding for a structural protein in mitochondrial complex III have been described. Ten-day-old female newborn was referred to our clinic because of intractable acidosis. Physical examination revealed severe hypotonia, and hepatomegaly. The laboratory examinations revealed lactic acidosis, increased blood alanine, alanine aminotransferase and aspartate aminotransferase levels, generalized aminoaciduria and glucosuria. The tubular reabsorption of phosphate was reduced. Because of multisystem involvement, mitochondrial disease was suspected and the mutational analysis of the BCS1L gene revealed homozygous P99L mutation. As the patient was unresponsive to bicarbonate replacement, oral dichloroacetate and peritoneal dialysis, continuous high dose intravenous sodium bicarbonate therapy with a dose up to 1.25 mEq/kg/h was started. The patient got on well until the age of 9 months when she died of sepsis. It was stressed that high dose intravenous continuous sodium bicarbonate therapy could be an alternative treatment option in patients with severe acidosis and renal tubulopathy resistant to dichloroacetate and peritoneal dialysis. Patients with BCS1L mutations should be considered in the differential diagnosis of severe tubulopathy in the newborn period.

  20. The Effect of Dose Rate on the Frequency of Specific-Locus Mutations Induced in Mouse Spermatogonia is Restricted to Larger Lesions; a Retrospective Analysis of Historical Data

    SciTech Connect

    Russell, Liane B; Hunsicker, Patricia R

    2012-01-01

    A series of 19 large-scale germ-cell mutagenesis experiments conducted several decades ago led to the conclusion that low-LET radiation delivered to mouse spermatogonia at dose rates of 0.8 R/min and below induced only about one-third as many specific-locus mutations as did single, acute exposures at 24 R/min and above. A two-hit origin of the mutations was deemed unlikely in view of the then prevailing evidence for the small size of genetic lesions in spermatogonia. Instead, the dose-rate effect was hypothesized to be the result of a repair system that exists in spermatogonia, but not in more mature male reproductive cells. More recent genetic and molecular studies on the marker genes have identified the phenotypes associated with specific states of the mutant chromosomes, and it is now possible retrospectively to classify individual past mutations as "large lesions" or "other lesions". The mutation-frequency difference between high and low dose rates is restricted to the large lesion mutations, for which the dose-curve slopes differ by a factor exceeding 3.4. For other lesion mutations, there is essentially no difference between the slopes for protracted and acute irradiations; induced other lesions frequencies per unit dose remain similar for dose rates ranging over more than 7 orders of magnitude. For large lesions, these values rise sharply at dose rates >0.8 R/min, though they remain similar within the whole range of protracted doses, failing to provide evidence for a threshold dose rate. The downward bend at high doses that had been noted for X-ray-induced specific-locus mutations as a whole and ascribed to a positive correlation between spermatogonial death and mutation load is now found to be restricted to large lesion mutations. There is a marked difference between the mutation spectra (distributions among the seven loci) for large lesions and other lesions. Within each class, however, the spectra are similar for acute and protracted irradiation.

  1. Defects in tRNA Anticodon Loop 2'-O-Methylation Are Implicated in Nonsyndromic X-Linked Intellectual Disability due to Mutations in FTSJ1.

    PubMed

    Guy, Michael P; Shaw, Marie; Weiner, Catherine L; Hobson, Lynne; Stark, Zornitza; Rose, Katherine; Kalscheuer, Vera M; Gecz, Jozef; Phizicky, Eric M

    2015-12-01

    tRNA modifications are crucial for efficient and accurate protein synthesis, and modification defects are frequently associated with disease. Yeast trm7Δ mutants grow poorly due to lack of 2'-O-methylated C32 (Cm32 ) and Gm34 on tRNA(Phe) , catalyzed by Trm7-Trm732 and Trm7-Trm734, respectively, which in turn results in loss of wybutosine at G37 . Mutations in human FTSJ1, the likely TRM7 homolog, cause nonsyndromic X-linked intellectual disability (NSXLID), but the role of FTSJ1 in tRNA modification is unknown. Here, we report that tRNA(Phe) from two genetically independent cell lines of NSXLID patients with loss-of-function FTSJ1 mutations nearly completely lacks Cm32 and Gm34 , and has reduced peroxywybutosine (o2yW37 ). Additionally, tRNA(Phe) from an NSXLID patient with a novel FTSJ1-p.A26P missense allele specifically lacks Gm34 , but has normal levels of Cm32 and o2yW37 . tRNA(Phe) from the corresponding Saccharomyces cerevisiae trm7-A26P mutant also specifically lacks Gm34 , and the reduced Gm34 is not due to weaker Trm734 binding. These results directly link defective 2'-O-methylation of the tRNA anticodon loop to FTSJ1 mutations, suggest that the modification defects cause NSXLID, and may implicate Gm34 of tRNA(Phe) as the critical modification. These results also underscore the widespread conservation of the circuitry for Trm7-dependent anticodon loop modification of eukaryotic tRNA(Phe) . PMID:26310293

  2. Sizes of abdominal organs in adults with severe short stature due to severe, untreated, congenital GH deficiency caused by a homozygous mutation in the GHRH receptor gene

    PubMed Central

    Oliveira, Carla R. P.; Salvatori, Roberto; Nóbrega, Luciana M. A.; Carvalho, Erick O. M.; Menezes, Menilson; Farias, Catarine T.; Britto, Allan V. O.; Pereira, Rossana M. C.; Aguiar-Oliveira, Manuel H.

    2008-01-01

    Summary Objective To assess the sizes of intra-abdominal organs of adult subjects with untreated severe congenital isolated GH deficiency (IGHD) due to lack of functional GHRH receptor (GHRH-R), and to verify whether there is proportionality between size of organ and adult stature and body surface area (BSA). Subjects and methods By using ultrasound, we studied the sizes (absolute and corrected by height, weight and BSA) of the intra-abdominal organs of 18 adult subjects with IGHD (eight females, IGHD group) who have never received GH replacement therapy. They were all homozygous for the same null mutation (IVS1 + 1G → A) in the GHRH receptor gene (GHRH-R). They were compared with normal controls from the same region. Results After correction for BSA, subjects lacking a functional GHRH-R have normal prostate and ovaries size, small spleen and uterus, and large liver, pancreas and kidney. Conclusions Size of individual abdominal organs is influenced in different ways by severe and congenital lack of GH due to a GHRH-R mutation. PMID:18034778

  3. MUTANT FREQUENCY AND MUTATIONAL SPECTRA IN THETK AND HPRT GENES OF N-ETHYL-N-NITROSOUREA TREATED MOUSE LYMPHOMA CELLS

    EPA Science Inventory

    Abstract

    The mouse lymphoma assay (MLA) utilizing the Tk locus is widely used to identify chemical mutagens. The autosomal location of the Tk locus allows for the detection of a wide range of mutational events, from point mutations to chromosome alterations. However, the ...

  4. [Mutation spectrum of Gaucher disease in Tunisia: high frequency of N370S/Rec NciI compound heterozygous].

    PubMed

    Cherif, W; Ben Turkia, H; Tebib, N; Amaral, O; Ben Rhouma, F; Abdelmoula, M S; Azzouz, H; Caillaud, C; Sà Miranda, M-C; Abdelhak, S; Ben Dridi, M-F

    2007-01-01

    Gaucher disease is the most common lysosomal storage disorder, it results from the inherited deficiency of the enzyme glucocerebrosidase, the accumulation of its substrate causes many clinical manifestations. Since the discovery of GBA gene, more than 200 different mutations have been identified, but only handful mutations are recurrent (N370S, L444P and c.84insG). In order to determine the mutation spectrum in Tunisia, we performed recurrent mutation screening in ten unrelated Tunisian children with Gaucher disease. Screening of recurrent mutation by PCR/RFLP and direct sequencing, has shown that N370S is the most frequent mutation (6/20 mutant alleles, 30%), followed by recombinant allele (RecNciI) which is found in five patients (5/20 mutant alleles, 25%), the L444P mutation represent 20% (4/20 mutant alleles). Our findings revealed that five among ten studied patients, were compound heterozygous N370S/RecNciI (50%). The screening of these mutations provides a simple tool for molecular diagnosis of Gaucher disease in Tunisian patients and allows also genetic counselling for their family members.

  5. The arrhythmogenic human HRC point mutation S96A leads to spontaneous Ca(2+) release due to an impaired ability to buffer store Ca(2+).

    PubMed

    Zhang, Joe Z; McLay, Janet C; Jones, Peter P

    2014-09-01

    The Ser96Ala (S96A) mutation within the histidine rich Ca(2+) binding protein (HRC) has recently been linked to cardiac arrhythmias in idiopathic dilated cardiomyopathy patients, potentially attributable to an increase in spontaneous Ca(2+) release events. However, the molecular mechanism connecting the S96A mutation of HRC to increased Ca(2+) release events remains unclear. Previous findings by our group indicate that these spontaneous Ca(2+) release events may be linked to store overload induced Ca(2+) release (SOICR) via the cardiac ryanodine receptor (RyR2). Therefore, in the present study we sought to determine whether HRC wild type (HRC WT) and S96A mutant (HRC S96A) expression has a direct effect on SOICR. Using both cytosolic and intra-Ca(2+) store measurements in human embryonic kidney cells expressing RyR2, we found that HRC WT significantly inhibited the propensity for SOICR by buffering store free Ca(2+) and inhibiting store Ca(2+) uptake. In contrast, HRC S96A exhibited a markedly suppressed inhibitory effect on SOICR, which was attributed to an impaired ability to buffer store Ca(2+) and reduce store Ca(2+) uptake. In addition to impairing the ability of HRC to regulate bulk store Ca(2+), a proximity ligation assay demonstrated that the S96A mutation also disrupts the Ca(2+) microdomain around the RyR2, as it alters the Ca(2+) dependent association of RyR2 and HRC. Importantly, in contrast to previous reports, the absence of triadin in our experimental model illustrates that the S96A mutation in HRC can alter the propensity for SOICR without any interaction with triadin. Collectively, our results demonstrate that the human HRC mutation S96A leads to an increase in spontaneous Ca(2+) release and ultimately arrhythmias by disrupting the regulation of intra-store free Ca(2+). This is primarily due to an impaired ability to act as an effective bulk and local microdomain store Ca(2+) buffer.

  6. Tay-Sachs disease in an Arab family due to c.78G>A HEXA nonsense mutation encoding a p.W26X early truncation enzyme peptide.

    PubMed

    Haghighi, Alireza; Masri, Amira; Kornreich, Ruth; Desnick, Robert J

    2011-12-01

    Tay-Sachs disease (TSD), a pan-ethnic, autosomal recessive, neurodegenerative, lysosomal disease, results from deficient β-hexosaminidase A activity due to β-hexosaminidase α-subunit (HEXA) mutations. Prenatal/premarital carrier screening programs in the Ashkenazi Jewish community have markedly reduced disease occurrence. We report the first Jordanian Arab TSD patient diagnosed by deficient β-hexosaminidase A activity. HEXA mutation analysis revealed homozygosity for a nonsense mutation, c.78G>A (p.W26X). Previously reported in Arab patients, this mutation is a candidate for TSD screening in Arab populations.

  7. Tay-Sachs disease in an Arab family due to c.78G>A HEXA nonsense mutation encoding a p.W26X early truncation enzyme peptide.

    PubMed

    Haghighi, Alireza; Masri, Amira; Kornreich, Ruth; Desnick, Robert J

    2011-12-01

    Tay-Sachs disease (TSD), a pan-ethnic, autosomal recessive, neurodegenerative, lysosomal disease, results from deficient β-hexosaminidase A activity due to β-hexosaminidase α-subunit (HEXA) mutations. Prenatal/premarital carrier screening programs in the Ashkenazi Jewish community have markedly reduced disease occurrence. We report the first Jordanian Arab TSD patient diagnosed by deficient β-hexosaminidase A activity. HEXA mutation analysis revealed homozygosity for a nonsense mutation, c.78G>A (p.W26X). Previously reported in Arab patients, this mutation is a candidate for TSD screening in Arab populations. PMID:21967858

  8. Ontogeny of the barley plant as related to mutation expression and detection of pollen mutations

    SciTech Connect

    Hodgdon, A.L.; Marcus, A.H.; Arenaz, P.; Rosichan, J.L.; Bogyo, T.P.; Nilan, R.A.

    1981-01-01

    Clustering of mutant pollen grains in a population of normal pollen due to premeiotic mutational events complicates translating mutation frequencies into rates. Embryo ontogeny in barley will be described and used to illustrate the formation of such mutant clusters. The nature of the statistics for mutation frequency will be described from a study of the reversion frequencies of various waxy mutants in barley. Computer analysis by a ''jackknife'' method of the reversion of a waxy mutant treated with the mutagen sodium azide showed a significantly higher reversion frequency than untreated material. Problems of the computer analysis suggest a better experimental design for pollen mutation experiments. Preliminary work on computer modeling for pollen development and mutation will be described.

  9. High frequency of vitamin B12 deficiency in asymptomatic individuals homozygous to MTHFR C677T mutation is associated with endothelial dysfunction and homocysteinemia.

    PubMed

    Zittan, E; Preis, M; Asmir, I; Cassel, A; Lindenfeld, N; Alroy, S; Halon, D A; Lewis, B S; Shiran, A; Schliamser, J E; Flugelman, M Y

    2007-07-01

    The aim of this study was to examine the association of homozygosity for the methylenetetrahydrofolate reductase (MTHFR) C677T mutation and vitamin B12 deficiency in 360 asymptomatic individuals and to investigate forearm endothelial function in C677T homozygotes. MTHFR C677T mutation and levels of vitamin B12, folic acid, and homocysteine were measured in study participants. Frequency of homozygosity for the C677T mutation was 67/360 (18.6%). Homocysteine levels were elevated in homozygous compared with heterozygous subjects or those without the mutation (20.6 +/- 18.8 vs. 9.4 +/- 3.2 mumol/l; P < 0.0001). The number of subjects with vitamin B12 deficiency (<150 pmol/l) was significantly higher among the homozygote than the heterozygote subjects or subjects without mutation [20/67 (29.8%) vs. 27/293 (9.2%); P < 0.0001]. Homozygote subjects had 4.2 times higher probability of having B12 deficiency (95% confidence interval = 2.1-8.3). Forearm endothelial function was assessed in 33 homozygote and 12 control subjects. Abnormal endothelial function was observed in homozygous subjects and was worse in homozygote subjects with vitamin B12 deficiency. Endothelial function was normalized after B12 and folic acid treatment. We found that homozygosity for the C677T mutation is strongly associated with B12 deficiency. Coexistence of homozygosity for the C677T mutation and B12 deficiency is associated with endothelial dysfunction and can be corrected with vitamin B12 and folic acid treatment. PMID:17449548

  10. Mutation Frequency of the Major Frontotemporal Dementia Genes, MAPT, GRN and C9ORF72 in a Turkish Cohort of Dementia Patients

    PubMed Central

    Guven, Gamze; Lohmann, Ebba; Bras, Jose; Gibbs, J. Raphael; Gurvit, Hakan; Bilgic, Basar; Hanagasi, Hasmet; Rizzu, Patrizia; Heutink, Peter; Emre, Murat; Erginel-Unaltuna, Nihan; Just, Walter; Hardy, John; Singleton, Andrew; Guerreiro, Rita

    2016-01-01

    ‘Microtubule-associated protein tau’ (MAPT), ‘granulin’ (GRN) and ‘chromosome 9 open reading frame72’ (C9ORF72) gene mutations are the major known genetic causes of frontotemporal dementia (FTD). Recent studies suggest that mutations in these genes may also be associated with other forms of dementia. Therefore we investigated whether MAPT, GRN and C9ORF72 gene mutations are major contributors to dementia in a random, unselected Turkish cohort of dementia patients. A combination of whole-exome sequencing, Sanger sequencing and fragment analysis/Southern blot was performed in order to identify pathogenic mutations and novel variants in these genes as well as other FTD-related genes such as the ‘charged multivesicular body protein 2B’ (CHMP2B), the ‘FUS RNA binding protein’ (FUS), the ‘TAR DNA binding protein’ (TARDBP), the ‘sequestosome1’ (SQSTM1), and the ‘valosin containing protein’ (VCP). We determined one pathogenic MAPT mutation (c.1906C>T, p.P636L) and one novel missense variant (c.38A>G, p.D13G). In GRN we identified a probably pathogenic TGAG deletion in the splice donor site of exon 6. Three patients were found to carry the GGGGCC expansions in the non-coding region of the C9ORF72 gene. In summary, a complete screening for mutations in MAPT, GRN and C9ORF72 genes revealed a frequency of 5.4% of pathogenic mutations in a random cohort of 93 Turkish index patients with dementia. PMID:27632209

  11. Next-generation sequencing identifies high frequency of mutations in potentially clinically actionable genes in sebaceous carcinoma.

    PubMed

    Tetzlaff, Michael T; Singh, Rajesh R; Seviour, Elena G; Curry, Jonathan L; Hudgens, Courtney W; Bell, Diana; Wimmer, Daniel A; Ning, Jing; Czerniak, Bogdan A; Zhang, Li; Davies, Michael A; Prieto, Victor G; Broaddus, Russell R; Ram, Prahlad; Luthra, Rajyalakshmi; Esmaeli, Bita

    2016-09-01

    Sebaceous carcinoma (SC) is a rare but aggressive malignancy with frequent recurrence and metastases. Surgery is the mainstay of therapy, but effective systemic therapies are lacking because the molecular alterations driving SC remain poorly understood. To identify these, we performed whole-exome next-generation sequencing of 409 cancer-associated genes on 27 SCs (18 primary/locally recurrent ocular, 5 paired metastatic ocular, and 4 primary extraocular) from 20 patients. In ocular SC, we identified 139 non-synonymous somatic mutations (median/lesion 3; range 0-23). Twenty-five of 139 mutations (18%) occurred in potentially clinically actionable genes in 6 of 16 patients. The most common mutations were mutations in TP53 (n = 9), RB1 (n = 6), PIK3CA (n = 2), PTEN (n = 2), ERBB2 (n = 2), and NF1 (n = 2). TP53 and RB1 mutations were restricted to ocular SC and correlated with aberrant TP53 and RB protein expression. Systematic pathway analyses demonstrated convergence of these mutations to activation of the PI3K signalling cascade, and PI3K pathway activation was confirmed in tumours with PTEN and/or PIK3CA mutations. Considerable inter-tumoural heterogeneity was observed between paired primary and metastatic ocular SCs. In primary extraocular SC, we identified 77 non-synonymous somatic mutations (median/lesion 22.5; range 3-29). This overall higher mutational load was attributed to a microsatellite instability phenotype in three of four patients and somatically acquired mutations in mismatch repair genes in two of four patients. Eighteen of 77 mutations (23%) were in potentially clinically actionable genes in three of four patients, including BTK, FGFR2, PDGFRB, HRAS, and NF1 mutations. Identification of potentially clinically actionable mutations in 9 of 20 SC patients (45%) underscores the importance of next-generation sequencing to expand the spectrum of genotype-matched targeted therapies. Frequent activation of PI3K signalling pathways provides a strong

  12. Temporal frequency of knockdown resistance mutations, F1534C and V1016G, in Aedes aegypti in Chiang Mai city, Thailand and the impact of the mutations on the efficiency of thermal fogging spray with pyrethroids.

    PubMed

    Plernsub, Suriya; Saingamsook, Jassada; Yanola, Jintana; Lumjuan, Nongkran; Tippawangkosol, Pongsri; Walton, Catherine; Somboon, Pradya

    2016-10-01

    In Thailand, control of dengue outbreaks is currently attained by the use of space sprays, particularly thermal fogging using pyrethroids, with the aim of killing infected Aedes mosquito vectors in epidemic areas. However, the principal dengue vector, Aedes aegypti, is resistant to pyrethroids conferred mainly by mutations in the voltage-gated sodium channel gene, F1534C and V1016G, termed knockdown resistance (kdr). The objectives of this study were to determine the temporal frequencies of F1534C and V1016G in Ae. aegypti populations in relation to pyrethroid resistance in Chiang Mai city, and to evaluate the impact of the mutations on the efficacy of thermal fogging with the pyrethroid deltamethrin. Larvae and pupae were collected from several areas around Chiang Mai city during 2011-2015 and reared to adulthood for bioassays for deltamethrin susceptibility. These revealed no trend of increasing deltamethrin resistance during the study period (mortality 58.0-69.5%, average 62.8%). This corresponded to no overall change in the frequencies of the C1534 allele (0.55-0.66, average 0.62) and G1016 allele (0.34-0.45, average 0.38), determined using allele specific amplification. Only three genotypes of kdr mutations were detected: C1534 homozygous (VV/CC); G1016/C1534 double heterozygous (VG/FC); and G1016 homozygous (GG/FF) indicating that the F1534C and V1016G mutations occurred on separate haplotypic backgrounds and a lack of recombination between them to date. The F1 progeny females were used to evaluate the efficacy of thermal fogging spray with Damthrin-SP(®) (deltamethrin+S-bioallethrin+piperonyl butoxide) using a caged mosquito bioassay. The thermal fogging spray killed 100% and 61.3% of caged mosquito bioassay placed indoors and outdoors, respectively. The outdoor spray had greater killing effect on C1534 homozygous and had partially effect on double heterozygous mosquitoes, but did not kill any G1016 homozygous mutants living outdoors. As this selection

  13. Atrial proarrhythmia due to increased inward rectifier current (I(K1)) arising from KCNJ2 mutation--a simulation study.

    PubMed

    Kharche, Sanjay; Garratt, Clifford J; Boyett, Mark R; Inada, Shin; Holden, Arun V; Hancox, Jules C; Zhang, Henggui

    2008-01-01

    Atrial fibrillation (AF) has been linked to increased inward rectifier potassium current, I(K1), either due to AF-induced electrical remodelling, or from functional changes due to the Kir2.1 V93I mutation. The aim of this simulation study was to identify at cell and tissue levels' mechanisms by which increased I(K1) facilitates and perpetuates AF. The Courtemanche et al. human atrial cell action potential (AP) model was modified to incorporate reported changes in I(K1) induced by the Kir2.1 V93I mutation in both heterozygous (Het) and homozygous (Hom) mutant forms. The modified models for wild type (WT), Het and Hom conditions were incorporated into homogeneous 1D, 2D and 3D tissue models. Restitution curves of AP duration (APD), effective refractory period (ERP) and conduction velocity (CV) were computed and both the temporal and the spatial vulnerability of atrial tissue to re-entry were measured. The lifespan and tip meandering pattern of re-entry were also characterised. For comparison, parallel simulations were performed by incorporating into the Courtmanche et al. model a linear increase in maximal I(K1) conductance. It was found that the gain-in-function of V93I 'mutant'I(K1) led to abbreviated atrial APs and flattened APD, ERP and CV restitution curves. It also hyperpolarised atrial resting membrane potential and slowed down intra-atrial conduction. V93I 'mutant'I(K1) reduced the tissue's temporal vulnerability but increased spatial vulnerability to initiate and sustain re-entry, resulting in an increased overall susceptibility of atrial tissue to arrhythmogenesis. In the 2D model, spiral waves self-terminated for WT (lifespan < 3.3 s) tissue, but persisted in Het and Hom tissues for the whole simulation period (lifespan > 10 s). The tip of the spiral wave meandered more in WT tissue than in Het and Hom tissues. Increased I(K1) due to augmented maximal conductance produced similar results to those of Het and Hom Kir2.1 V93I mutant conditions. In the 3D

  14. Mitochondrial NADP(H) deficiency due to a mutation in NADK2 causes dienoyl-CoA reductase deficiency with hyperlysinemia.

    PubMed

    Houten, Sander M; Denis, Simone; Te Brinke, Heleen; Jongejan, Aldo; van Kampen, Antoine H C; Bradley, Edward J; Baas, Frank; Hennekam, Raoul C M; Millington, David S; Young, Sarah P; Frazier, Dianne M; Gucsavas-Calikoglu, Muge; Wanders, Ronald J A

    2014-09-15

    Dienoyl-CoA reductase (DECR) deficiency with hyperlysinemia is a rare disorder affecting the metabolism of polyunsaturated fatty acids and lysine. The molecular basis of this condition is currently unknown. We describe a new case with failure to thrive, developmental delay, lactic acidosis and severe encephalopathy suggestive of a mitochondrial disorder. Exome sequencing revealed a causal mutation in NADK2. NADK2 encodes the mitochondrial NAD kinase, which is crucial for NADP biosynthesis evidenced by decreased mitochondrial NADP(H) levels in patient fibroblasts. DECR and also the first step in lysine degradation are performed by NADP-dependent oxidoreductases explaining their in vivo deficiency. DECR activity was also deficient in lysates of patient fibroblasts and could only be rescued by transfecting patient cells with functional NADK2. Thus NADPH is not only crucial as a cosubstrate, but can also act as a molecular chaperone that activates and stabilizes enzymes. In addition to polyunsaturated fatty acid oxidation and lysine degradation, NADPH also plays a role in various other mitochondrial processes. We found decreased oxygen consumption and increased extracellular acidification in patient fibroblasts, which may explain why the disease course is consistent with clinical criteria for a mitochondrial disorder. We conclude that DECR deficiency with hyperlysinemia is caused by mitochondrial NADP(H) deficiency due to a mutation in NADK2.

  15. Respiratory complex I dysfunction due to mitochondrial DNA mutations shifts the voltage threshold for opening of the permeability transition pore toward resting levels.

    PubMed

    Porcelli, Anna Maria; Angelin, Alessia; Ghelli, Anna; Mariani, Elisa; Martinuzzi, Andrea; Carelli, Valerio; Petronilli, Valeria; Bernardi, Paolo; Rugolo, Michela

    2009-01-23

    We have studied mitochondrial bioenergetics in HL180 cells (a cybrid line harboring the T14484C/ND6 and G14279A/ND6 mtDNA mutations of Leber hereditary optic neuropathy, leading to an approximately 50% decrease of ATP synthesis) and XTC.UC1 cells (derived from a thyroid oncocytoma bearing a disruptive frameshift mutation in MT-ND1, which impairs complex I assembly). The addition of rotenone to HL180 cells and of antimycin A to XTC.UC1 cells caused fast mitochondrial membrane depolarization that was prevented by treatment with cyclosporin A, intracellular Ca2+ chelators, and antioxidant. Both cell lines also displayed an anomalous response to oligomycin, with rapid onset of depolarization that was prevented by cyclosporin A and by overexpression of Bcl-2. These findings indicate that depolarization by respiratory chain inhibitors and oligomycin was due to opening of the mitochondrial permeability transition pore (PTP). A shift of the threshold voltage for PTP opening close to the resting potential may therefore be the underlying cause facilitating cell death in diseases affecting complex I activity. This study provides a unifying reading frame for previous observations on mitochondrial dysfunction, bioenergetic defects, and Ca2+ deregulation in mitochondrial diseases. Therapeutic strategies aimed at normalizing the PTP voltage threshold may be instrumental in ameliorating the course of complex I-dependent mitochondrial diseases.

  16. A Missense Mutation in the Human Cytochrome b5 Gene causes 46,XY Disorder of Sex Development due to True Isolated 17,20 Lyase Deficiency

    PubMed Central

    Idkowiak, Jan; Randell, Tabitha; Dhir, Vivek; Patel, Pushpa; Shackleton, Cedric H. L.; Taylor, Norman F.; Krone, Nils

    2012-01-01

    Context: Isolated 17,20 lyase deficiency is commonly defined by apparently normal 17α-hydroxylase activity but severely reduced 17,20 lyase activity of the bifunctional enzyme cytochrome P450 (CYP) enzyme 17A1 (CYP17A1), resulting in sex steroid deficiency but normal glucocorticoid and mineralocorticoid reserve. Cytochrome b5 (CYB5A) is thought to selectively enhance 17,20 lyase activity by facilitating the allosteric interaction of CYP17A1 with its electron donor P450 oxidoreductase (POR). Objective: We investigated a large consanguineous family including three siblings with 46,XY disorder of sex development (DSD) presenting with isolated 17,20 lyase deficiency. Design: We investigated the clinical and biochemical phenotype, conducted genetic analyses, and functionally characterized the identified CYB5A mutation in cell-based CYP17A1 coexpression assays. Results: All three siblings presented with 46,XY DSD, sex steroid deficiency, normal mineralocorticoids and glucocorticoids, and a urine steroid metabolome suggestive of isolated 17,20 lyase deficiency. CYP17A1 and POR sequences were normal, but we detected a homozygous CYB5A missense mutation (g.28,400A→T; p.H44L). Functional in vitro analysis revealed normal CYP17A1 17α-hydroxylase activity but severely impaired 17,20 lyase activity. In silico analysis suggested the disruption of CYB5A heme binding by p.H44L. Conclusion: We have identified the first human CYB5A missense mutation as the cause of isolated 17,20 lyase deficiency in three individuals with 46,XY DSD. Detailed review of previously reported cases with apparently isolated 17,20 lyase deficiency due to mutant CYP17A1 and POR reveals impaired 17α-hydroxylase activity as assessed by steroid metabolome analysis and short cosyntropin testing. This suggests that truly isolated 17,20 lyase deficiency is observed only in individuals with inactivating CYB5A mutations. PMID:22170710

  17. High frequency of TERT promoter mutation in small cell carcinoma of bladder, but not in small cell carcinoma of other origins.

    PubMed

    Zheng, Xiaoyong; Zhuge, Jian; Bezerra, Stephania M; Faraj, Sheila F; Munari, Enrico; Fallon, John T; Yang, Ximing J; Argani, Pedram; Netto, George J; Zhong, Minghao

    2014-01-01

    TERT promoter mutations were recently discovered in melanoma by next generation sequencing. Subsequently, several malignancies including urothelial carcinoma were also found to be associated with the same TERT promoter mutations. Small cell carcinoma (SCC) of the urinary bladder is a rare subtype with an aggressive clinical course. Despite the frequent occurrence of TERT promoter mutations in urothelial carcinoma, the incidence of the mutations in SCC of the urinary bladder is unknown. In addition, as a potential molecular marker to distinguish SCC of the urinary bladder from SCC of the prostate, lung (SCLC) and other origins, this information may be clinically useful. We collected a total of 11 cases of SCC of the urinary bladder (10 cases are primary SCC of the urinary bladder; 1 case has primary SCC of the urinary bladder and liver metastasis). We also included 20 cases of SCLC, 2 cases of SCC of the prostate, 5 cases of Merkel cell carcinoma, and 6 cases of SCC from other sites (cervical, GE junction, breast, and soft tissue). In addition, 3 cases of non-neoplastic tissue from the matched SCC of bladder patient and 14 cases of benign urinary bladder were also included. All tumor sections have been examined to confirm the diagnosis and to make sure more than 20% are of tumor content. Genomic DNA was isolated from FFPE tissue and a fragment of the TERT promoter (145 bp) was amplified by PCR. The TERT promoter mutations are determined by bi-directional Sanger sequencing. All (11/11) SCC of the urinary bladder bear TERT promoter mutation C228T. Neither of SCC from all other origins nor matched non-neoplastic tissue contains the TERT promoter mutations. We demonstrated a high frequency TERT promoter mutation in SCC of the urinary bladder, but not in SCC of other origin, such as the prostate. The findings further illustrate molecular differences between SCC of the urinary bladder and SCC of other origins, despite their shared morphologic and immunophenotypic

  18. In-vitro suppression of metabolic activity in malignant human glioblastomas due to pulsed - low frequency electric potential exposures

    NASA Astrophysics Data System (ADS)

    Schlichting, Abby; Waynant, Ronald W.; Tata, Darrell B.

    2010-02-01

    The role of pulsed - low repetition frequency electric potential was investigated in suppressing the metabolic activities of aggressive human brain cancer cells. Twenty four hours post exposure the glioblastomas were found to be significantly inhibited in their metabolic activity. The findings herein reveal a near complete inhibition of glioblastoma's metabolic activity through selective applications of low frequency pulsed electric potentials.

  19. Increased Variation in Adh Enzyme Activity in Drosophila Mutation-Accumulation Experiment Is Not Due to Transposable Elements at the Adh Structural Gene

    PubMed Central

    Aquadro, C. F.; Tachida, H.; Langley, C. H.; Harada, K.; Mukai, T.

    1990-01-01

    We present here a molecular analysis of the region surrounding the structural gene encoding alcohol dehydrogenase (Adh) in 47 lines of Drosophila melanogaster that have each accumulated mutations for 300 generations. While these lines show a significant increase in variation of alcohol dehydrogenase enzyme activity compared to control lines, we found no restriction map variation in a 13-kb region including the complete Adh structural gene and roughly 5 kb of both 5' and 3' sequences. Thus, the rapid accumulation of ADH activity variation after 28,200 allele generations does not appear to have been due to the mobilization of transposable elements into or out of the Adh structural gene region. PMID:1963870

  20. A misleading false-negative result using Neisseria gonorrhoeae opa MGB multiplex PCR assay in patient's rectal sample due to partial mutations of the opa gene.

    PubMed

    Vahidnia, Ali; van Empel, Pieter Jan; Costa, Sandra; Oud, Rob T N; van der Straaten, Tahar; Bliekendaal, Harry; Spaargaren, Joke

    2015-07-01

    A 53-year-old homosexual man presented at his general practitioner (GP) practice with a suspicion of sexually transmitted infection. Initial NAAT screening was performed for Chlamydia trachomatis and Neisseria gonorrhoeae. The patient was positive for Neisseria gonorrhoeae both for his urine and rectal sample. The subsequent confirmation test for Neisseria gonorrhoeae by a second laboratory was only confirmed for the urine sample and the rectal sample was negative. We report a case of a potential false-negative diagnosis of Neisseria gonorrhoeae due to mutations of DNA sequence in the probe region of opa-MGB assay of the rectal sample. The patient did not suffer any discomfort as diagnosis of Neisseria gonorrhoeae in his urine sample had already led to treatment by prescribing the patient with Ceftriaxone 500 mg IV dissolved in 1 ml lidocaine 2% and 4 mL saline. The patient also received a prescription for Azithromycin (2x500 mg).

  1. New features of different frequency generating systems due to the use of electrodeless rigidly mounted VBA quartz crystal resonator

    NASA Technical Reports Server (NTRS)

    Jendly, A.; Graf, E.; Busca, G.; Brownsea, D. A.

    1984-01-01

    The BVA 5 MHz crystal equipped frequency sources exhibit a new blend of performances such as 10 to 11 daily stability, 5x10-13 short term stability (1 to 30 s time intervals) and close to the carrier low phase noise (1 Hz : -120 dBc, 10 Hz : -140 dBc), whereby retaining the customary crystal oscillator benefits of small volume, high reliability and low price, as opposed to more sophisticated frequency generators which would be required to achieve comparable performances. Examples illustrating the impact of the Oscilloquartz BVA oven-controlled crystal oscillator in different frequency generating systems are presented: cesium frequency standards; hydrogen frequency standard; a precision distribution sub-system for satellite ground stations; and high hierarchy exchanges of digital networks, synchronized by the master-slave method are discussed.

  2. Frequency lock-in and phase synchronization of vortex shedding behind circular cylinder due to surface waves

    NASA Astrophysics Data System (ADS)

    Gunnoo, Hans; Abcha, Nizar; Ezersky, Alexander

    2016-02-01

    The influence of harmonic surface wave on non-regular Karman Vortex Street is investigated. In our experiments, Karman Street arises behind a vertical circular cylinder in a water flow and harmonic surface waves propagating upstream. It is found that surface waves can modify regimes of shedding in Karman Street: frequency lock-in and synchronization of vortex shedding can arise. Intensive surface waves can excite symmetric vortex street instead of chess-like street, and completely suppress shedding behind the cylinder. It is shown experimentally that such effects occur if frequency of harmonic surface wave is approximately twice higher than the frequency of vortex shedding. Region of frequency lock-in is found on the plane amplitude-frequency of surface wave.

  3. [Analysis of transcript mutations due to transcriptional slippage in rat p53 tumor suppressor gene with the use of yeast functional assay].

    PubMed

    Ba, Y

    1999-05-01

    Transcriptional slippage was previously found in Escherichia coli during RNA elongation at runs of 10 or more As or Ts, resulting in the addition of untemplated A or U residues. To evaluate the incidence of transcriptional slippage in vivo, we employed a yeast functional assay, and analyzed the frequency and spectrum of mutations in mRNA of the tumor suppressor p53 in rat tissues. In this assay, yeast are transfected with p53 PCR products and a gapped p53 expression vector, which allow homologous recombination in vivo and yield a percentage of red colonies which reflects the proportion of mutant PCR products. Insertion mutations of single base of adenine (A) at stretches of 6 As were frequently detected in the liver samples of LEC rats which develop spontaneous hepatitis and hepatocellular carcinoma. For excluding the possibility of artifacts involvement, p53 cDNA was amplified by PCR from plasmids containing wild-type p53 and tested with the yeast functional assay, which resulted in no A insertion after sequencing 23 mutant clones. Furthermore, in vitro transcript of wild-type p53 was synthesized by SP6 RNA polymerase, and then, reverse-transcribed, PCR-amplified, and tested with the yeast functional assay. The overall rate of A insertion was much lower than that in the LEC rat liver. Since A insertions were found predominantly at nucleotides 293-298 in exon 4, an exon 4-specific yeast functional assay was developed. A insertion was detected in 4.8% of the PCR product of mRNA but 0-0.1% from genomic DNA, which suggested that such A insertion was caused by transcriptional slippage in vivo. The A insertion rate abruptly increased in acute hepatitis stage in the LEC rat liver, while the rate slowly increased by aging in control WKAH rat liver. It was suggested that cell damage and aging were primarily responsible for the increased rate of transcriptional slippage.

  4. Frequency of the codon 807 mutation in the cGMP phosphodiesterase beta-subunit gene in Irish setters and other dog breeds with hereditary retinal degeneration.

    PubMed

    Aguirre, G D; Baldwin, V; Weeks, K M; Acland, G M; Ray, K

    1999-01-01

    Rod-cone dysplasia 1 (rcd1) in Irish setters is caused by a nonsense mutation in the cGMP phosphodiesterase beta-subunit gene (PDE6B). We examined the frequency of the mutant allele in the Irish setter population and determined if the defect is present in dogs of other breeds which are affected with other inherited photoreceptor diseases. Between 1994 and 1997, samples were obtained from 436 clinically normal Irish setters, a red wolf, and dogs from 23 different breeds. The mutation in codon 807 of PDE6B was detected in genomic DNA by heteroduplex analysis, allele-specific PCR, or restriction enzyme digestion. Of the 436 samples from clinically normal setters, 34 contained the mutation in one of the two PDE6B alleles (carrier rate = 7.8%). In contrast, the same mutation was not found in the red wolf or dogs of other breeds affected with PRA or inherited photoreceptor diseases. The high percentage of tested carriers, however, is not representative of the number of carriers in the population since some dogs tested were closely related and did not represent a random sample of the Irish setter breed.

  5. Frequency of Hereditary Hemochromatosis (HFE) Gene Mutations in Egyptian Beta Thalassemia Patients and its Relation to Iron Overload

    PubMed Central

    Enein, Azza Aboul; El Dessouky, Nermine A.; Mohamed, Khalda S.; Botros, Shahira K.A.; Abd El Gawad, Mona F.; Hamdy, Mona; Dyaa, Nehal

    2016-01-01

    AIM: This study aimed to detect the most common HFE gene mutations (C282Y, H63D, and S56C) in Egyptian beta thalassemia major patients and its relation to their iron status. SUBJECTS AND METHODS: The study included 50 beta thalassemia major patients and 30 age and sex matched healthy persons as a control group. Serum ferritin, serum iron and TIBC level were measured. Detection of the three HFE gene mutations (C282Y, H63D and S65C) was done by PCR-RFLP analysis. Confirmation of positive cases for the mutations was done by sequencing. RESULTS: Neither homozygote nor carrier status for the C282Y or S65C alleles was found. The H63D heterozygous state was detected in 5/50 (10%) thalassemic patients and in 1/30 (3.3%) controls with no statistically significant difference between patients and control groups (p = 0.22). Significantly higher levels of the serum ferritin and serum iron in patients with this mutation (p = 001). CONCLUSION: Our results suggest that there is an association between H63D mutation and the severity of iron overload in thalassemic patients. PMID:27335591

  6. Analysis of mutant frequencies and mutation spectra in hMTH1 knockdown TK6 cells exposed to UV radiation.

    PubMed

    Fotouhi, Asal; Hagos, Winta Woldai; Ilic, Marina; Wojcik, Andrzej; Harms-Ringdahl, Mats; de Gruijl, Frank; Mullenders, Leon; Jansen, Jacob G; Haghdoost, Siamak

    2013-01-01

    Ultraviolet radiation is a highly mutagenic agent that damages the DNA by the formation of mutagenic photoproducts at dipyrimidine sites and by oxidative DNA damages via reactive oxygen species (ROS). ROS can also give rise to mutations via oxidation of dNTPs in the nucleotide pool, e.g. 8-oxo-dGTP and 2-OH-dATP and subsequent incorporation during DNA replication. Here we show that expression of human MutT homolog 1 (hMTH1) which sanitizes the nucleotide pool by dephosphorylating oxidized dNTPs, protects against mutagenesis induced by long wave UVA light and by UVB light but not by short wave UVC light. Mutational spectra analyses of UVA-induced mutations at the endogenous Thymidine kinase gene in human lymphoblastoid cells revealed that hMTH1 mainly protects cells from transitions at GC and AT base pairs.

  7. Infertility in a line of mice with the high growth mutation is due to luteal insufficiency resulting from disruption at the hypothalamic-pituitary axis.

    PubMed

    Cargill, S L; Medrano, J F; Anderson, G B

    1999-07-01

    Animals with extreme body growth frequently experience poor reproductive performance, but the cause for this association has not been clearly established. A line of mice homozygous for the high growth (hg) mutation, a mutation that has a major effect on post-weaning growth, exhibits several reproductive deficits including an abnormally high incidence of luteal failure. The objective of the present study was to investigate luteal failure in high-growth (HG) mice during pregnancy and to determine whether the cause of the apparent luteal failure resides in the ovary or the hypothalamic-pituitary unit. In HG females with a demonstrated history of infertility, progesterone injections (1 mg s.c. daily) beginning on Day 1 postcoitum (p.c.) increased the proportion of animals pregnant at Day 17 of gestation. Twice-daily injections of 100 microgram of ovine prolactin (PRL) in alkaline saline given to another group of females beginning on Day 1 p.c. increased the proportion of HG females that were pregnant on Day 6 of gestation compared with saline-injected HG females, although PRL did not increase the pregnancy rate in HG females when compared with a group of noninjected control females. When ovaries from HG females were transplanted into ovariectomized congenic C57 hosts, the C57 graft hosts displayed normal estrous cycles, and upon mating the majority of graft hosts became pregnant. In contrast, when ovaries from C57 females were transplanted into ovariectomized HG hosts, the HG graft hosts displayed normal estrous cycles, but upon mating most were unable to maintain pregnancy. These results suggest that the hypothalamic-pituitary unit of the HG female provides an inadequate signal to the ovaries to maintain pregnancy. Luteal failure in HG females may be due to insufficient PRL as required for establishment and early maintenance of the CL during pregnancy in mice.

  8. The Forces Applied by Cilia Depend Linearly on Their Frequency Due to Constant Geometry of the Effective Stroke

    PubMed Central

    Teff, Zvi; Priel, Zvi; Gheber, Levi A.

    2008-01-01

    Mucus propelling cilia are excitable by many stimulants, and have been shown to increase their beating frequency up to threefold, by physiological extracellular stimulants, such as adenosine-triphosphate, acetylcholine, and others. This is thought to represent the evolutionary adaptation of mucociliary systems to the need of rapid and efficient cleansing the airways of foreign particles. However, the mucus transport velocity depends not only on the beat frequency of the cilia, but on their beat pattern as well, especially in the case of mucus bearing cilia that beat in a complex, three-dimensional fashion. In this study, we directly measured the force applied by live ciliary tissues with an atomic force microscope, and found that it increases linearly with the beating frequency. This implies that the arc swept by the cilia during their effective stroke remains unchanged during frequency increase, thus leading to a linear dependence of transport velocity on the beat frequency. Combining the atomic force microscope measurements with optical measurements, we have indications that the recovery stroke is performed on a less inclined plane, leading to an effective shortening of the overall path traveled by the cilia tip during this nontransporting phase of their beat pattern. This effect is observed to be independent of the type of stimulant (temperature or chemical), chemical (adenosine-triphosphate or acetylcholine), or concentration (1 μM–100 μM), indicating that this behavior may result from internal details of the cilium mechanical structure. PMID:17872955

  9. Localized frameshift mutation generates selective, high-frequency phase variation of a surface lipoprotein encoded by a mycoplasma ABC transporter operon.

    PubMed Central

    Theiss, P; Wise, K S

    1997-01-01

    The wall-less mycoplasmas have revealed unusual microbial strategies for adaptive variation of antigenic membrane proteins exposed during their surface colonization of host cells. In particular, high-frequency mutations affecting the expression of selected surface lipoproteins have been increasingly documented for this group of organisms. A novel manifestation of mutational phase variation is shown here to occur in Mycoplasma fermentans, a chronic human infectious agent and possible AIDS-associated pathogen. A putative ABC type transport operon encoding four gene products is identified. The 3' distal gene encoding P78, a known surface-exposed antigen and the proposed substrate-binding lipoprotein of the transporter, is subject to localized hypermutation in a short homopolymeric tract of adenine residues located in the N-terminal coding region of the mature product. High-frequency, reversible insertion/deletion frameshift mutations lead to selective phase variation in P78 expression, whereas the putative nucleotide-binding protein, P63, encoded by the most 5' gene of the operon, is continually expressed. Mutation-based phase variation in specific surface-exposed microbial transporter components may provide an adaptive advantage for immune evasion, while continued expression of other elements of the same transporter may preserve essential metabolic functions and confer alternative substrate specificity. These features could be critical in mycoplasmas, where limitations in both transcriptional regulators and transport systems may prevail. This study also documents that P63 contains an uncharacteristic hydrophobic sequence between predicted nucleotide binding motifs and displays an amphiphilic character in detergent fractionation. Both features are consistent with an evolutionary adaptation favoring integral association of this putative energy-transducing component with the single mycoplasma membrane. PMID:9190819

  10. Diminishing high-frequency directivity due to a source effect: Empirical evidence from small earthquakes in the Abruzzo region, Italy

    NASA Astrophysics Data System (ADS)

    Pacor, F.; Gallovič, F.; Puglia, R.; Luzi, L.; D'Amico, M.

    2016-05-01

    The aim of this study is to investigate the directivity effects of ~250 aftershocks (magnitudes 3-5.5) of the Mw 6.1 2009 L'Aquila earthquake (central Italy). To this end, we estimate the apparent source spectra at each station removing path and site effects inferred by standard Generalized Inversion Technique. Then, we evaluate the residuals between the apparent source spectra and the event mean source spectrum at selected frequencies. We investigate azimuthal and frequency dependence of the residuals for 40 events with the best station coverage. For most of events with the strongest directivity effect (Mw 3.4-4.0), we observe a remarkable decrease of the directivity amplification at high frequencies, which has not yet been documented for such relatively small-magnitude events. Since there is negligible distance dependence, we ascribe this observation to a source phenomenon such as significant small-scale rupture propagation complexity.

  11. Analysis of core damage frequency due to external events at the DOE (Department of Energy) N-Reactor

    SciTech Connect

    Lambright, J.A.; Bohn, M.P.; Daniel, S.L. ); Baxter, J.T. ); Johnson, J.J.; Ravindra, M.K.; Hashimoto, P.O.; Mraz, M.J.; Tong, W.H.; Conoscente, J.P. ); Brosseau, D.A. )

    1990-11-01

    A complete external events probabilistic risk assessment has been performed for the N-Reactor power plant, making full use of all insights gained during the past ten years' developments in risk assessment methodologies. A detailed screening analysis was performed which showed that all external events had negligible contribution to core damage frequency except fires, seismic events, and external flooding. A limited scope analysis of the external flooding risk indicated that it is not a major risk contributor. Detailed analyses of the fire and seismic risks resulted in total (mean) core damage frequencies of 1.96E-5 and 4.60E-05 per reactor year, respectively. Detailed uncertainty analyses were performed for both fire and seismic risks. These results show that the core damage frequency profile for these events is comparable to that found for existing commercial power plants if proposed fixes are completed as part of the restart program. 108 refs., 85 figs., 80 tabs.

  12. A Low Frequency of Losses in 11q Chromosome Is Associated with Better Outcome and Lower Rate of Genomic Mutations in Patients with Chronic Lymphocytic Leukemia.

    PubMed

    Hernández, José Ángel; Hernández-Sánchez, María; Rodríguez-Vicente, Ana Eugenia; Grossmann, Vera; Collado, Rosa; Heras, Cecilia; Puiggros, Anna; Martín, Ana África; Puig, Noemí; Benito, Rocío; Robledo, Cristina; Delgado, Julio; González, Teresa; Queizán, José Antonio; Galende, Josefina; de la Fuente, Ignacio; Martín-Núñez, Guillermo; Alonso, José María; Abrisqueta, Pau; Luño, Elisa; Marugán, Isabel; González-Gascón, Isabel; Bosch, Francesc; Kohlmann, Alexander; González, Marcos; Espinet, Blanca; Hernández-Rivas, Jesús María

    2015-01-01

    To analyze the impact of the 11q deleted (11q-) cells in CLL patients on the time to first therapy (TFT) and overall survival (OS), 2,493 patients with CLL were studied. 242 patients (9.7%) had 11q-. Fluorescence in situ hybridization (FISH) studies showed a threshold of 40% of deleted cells to be optimal for showing that clinical differences in terms of TFT and OS within 11q- CLLs. In patients with ≥40% of losses in 11q (11q-H) (74%), the median TFT was 19 months compared with 44 months in CLL patients with <40% del(11q) (11q-L) (P<0.0001). In the multivariate analysis, only the presence of 11q-L, mutated IGHV status, early Binet stage and absence of extended lymphadenopathy were associated with longer TFT. Patients with 11q-H had an OS of 90 months, while in the 11q-L group the OS was not reached (P = 0.008). The absence of splenomegaly (P = 0.02), low LDH (P = 0.018) or β2M (P = 0.006), and the presence of 11q-L (P = 0.003) were associated with a longer OS. In addition, to detect the presence of mutations in the ATM, TP53, NOTCH1, SF3B1, MYD88, FBXW7, XPO1 and BIRC3 genes, a select cohort of CLL patients with losses in 11q was sequenced by next-generation sequencing of amplicons. Eighty % of CLLs with 11q- showed mutations and fewer patients with low frequencies of 11q- had mutations among genes examined (50% vs 94.1%, P = 0.023). In summary, CLL patients with <40% of 11q- had a long TFT and OS that could be associated with the presence of fewer mutated genes.

  13. A Low Frequency of Losses in 11q Chromosome Is Associated with Better Outcome and Lower Rate of Genomic Mutations in Patients with Chronic Lymphocytic Leukemia

    PubMed Central

    Rodríguez-Vicente, Ana Eugenia; Grossmann, Vera; Collado, Rosa; Heras, Cecilia; Puiggros, Anna; Martín, Ana África; Puig, Noemí; Benito, Rocío; Robledo, Cristina; Delgado, Julio; González, Teresa; Queizán, José Antonio; Galende, Josefina; de la Fuente, Ignacio; Martín-Núñez, Guillermo; Alonso, José María; Abrisqueta, Pau; Luño, Elisa; Marugán, Isabel; González-Gascón, Isabel; Bosch, Francesc; Kohlmann, Alexander; González, Marcos; Espinet, Blanca; Hernández-Rivas, Jesús María

    2015-01-01

    To analyze the impact of the 11q deleted (11q-) cells in CLL patients on the time to first therapy (TFT) and overall survival (OS), 2,493 patients with CLL were studied. 242 patients (9.7%) had 11q-. Fluorescence in situ hybridization (FISH) studies showed a threshold of 40% of deleted cells to be optimal for showing that clinical differences in terms of TFT and OS within 11q- CLLs. In patients with ≥40% of losses in 11q (11q-H) (74%), the median TFT was 19 months compared with 44 months in CLL patients with <40% del(11q) (11q-L) (P<0.0001). In the multivariate analysis, only the presence of 11q-L, mutated IGHV status, early Binet stage and absence of extended lymphadenopathy were associated with longer TFT. Patients with 11q-H had an OS of 90 months, while in the 11q-L group the OS was not reached (P = 0.008). The absence of splenomegaly (P = 0.02), low LDH (P = 0.018) or β2M (P = 0.006), and the presence of 11q-L (P = 0.003) were associated with a longer OS. In addition, to detect the presence of mutations in the ATM, TP53, NOTCH1, SF3B1, MYD88, FBXW7, XPO1 and BIRC3 genes, a select cohort of CLL patients with losses in 11q was sequenced by next-generation sequencing of amplicons. Eighty % of CLLs with 11q- showed mutations and fewer patients with low frequencies of 11q- had mutations among genes examined (50% vs 94.1%, P = 0.023). In summary, CLL patients with <40% of 11q- had a long TFT and OS that could be associated with the presence of fewer mutated genes. PMID:26630574

  14. A Low Frequency of Losses in 11q Chromosome Is Associated with Better Outcome and Lower Rate of Genomic Mutations in Patients with Chronic Lymphocytic Leukemia.

    PubMed

    Hernández, José Ángel; Hernández-Sánchez, María; Rodríguez-Vicente, Ana Eugenia; Grossmann, Vera; Collado, Rosa; Heras, Cecilia; Puiggros, Anna; Martín, Ana África; Puig, Noemí; Benito, Rocío; Robledo, Cristina; Delgado, Julio; González, Teresa; Queizán, José Antonio; Galende, Josefina; de la Fuente, Ignacio; Martín-Núñez, Guillermo; Alonso, José María; Abrisqueta, Pau; Luño, Elisa; Marugán, Isabel; González-Gascón, Isabel; Bosch, Francesc; Kohlmann, Alexander; González, Marcos; Espinet, Blanca; Hernández-Rivas, Jesús María

    2015-01-01

    To analyze the impact of the 11q deleted (11q-) cells in CLL patients on the time to first therapy (TFT) and overall survival (OS), 2,493 patients with CLL were studied. 242 patients (9.7%) had 11q-. Fluorescence in situ hybridization (FISH) studies showed a threshold of 40% of deleted cells to be optimal for showing that clinical differences in terms of TFT and OS within 11q- CLLs. In patients with ≥40% of losses in 11q (11q-H) (74%), the median TFT was 19 months compared with 44 months in CLL patients with <40% del(11q) (11q-L) (P<0.0001). In the multivariate analysis, only the presence of 11q-L, mutated IGHV status, early Binet stage and absence of extended lymphadenopathy were associated with longer TFT. Patients with 11q-H had an OS of 90 months, while in the 11q-L group the OS was not reached (P = 0.008). The absence of splenomegaly (P = 0.02), low LDH (P = 0.018) or β2M (P = 0.006), and the presence of 11q-L (P = 0.003) were associated with a longer OS. In addition, to detect the presence of mutations in the ATM, TP53, NOTCH1, SF3B1, MYD88, FBXW7, XPO1 and BIRC3 genes, a select cohort of CLL patients with losses in 11q was sequenced by next-generation sequencing of amplicons. Eighty % of CLLs with 11q- showed mutations and fewer patients with low frequencies of 11q- had mutations among genes examined (50% vs 94.1%, P = 0.023). In summary, CLL patients with <40% of 11q- had a long TFT and OS that could be associated with the presence of fewer mutated genes. PMID:26630574

  15. High frequency of mutations in codon 98 of the peripheral myelin protein Po gene in 20 French CMT1 patients

    SciTech Connect

    Rougher, H.; LeGuern, E. Gouider, R.

    1996-03-01

    Charcot-Marie-Tooth disease, characterized by distal muscle weakness and amyotrophy, decreased or absent tendon reflexes, and high arched feet, is the most common inherited peripheral neuropathy, with a prevalence of 1 in 2,500. Two types of CMT have been distinguished on the basis of nerve conduction velocities. CMT type 1 is the most frequent, with markedly slowed velocities ({<=}40 m/s) associated with hypertrophic onion bulb changes on nerve biopsy. Autosomal dominant CMT1 is genetically heterogeneous: CMT1A is caused by a 1.5-Mb duplication in 17p11.2 and, more rarely, by a point mutation in tha PMP22 (peripheral myelin protein, 22 kD) gene located in the duplicated region; CMT1B results from mutations in the Po (peripheral myelin protein zero) gene in 1q22-23. Forty-five percent (7/16) of the published mutations associated with CMT1 occur in exon 3 of Po. In order to determine the cause of CMT1 in 20 unrelated patients without 17p11.2 duplications, mutations were sought in exon 3 of Po with three techniques: nonradioactive SSCP, automated sequencing, and PCR enzymatic restriction. 18 refs., 2 figs.

  16. Temporal and spatial evolution characteristics of disturbance wave in a hypersonic boundary layer due to single-frequency entropy disturbance.

    PubMed

    Wang, Zhenqing; Tang, Xiaojun; Lv, Hongqing; Shi, Jianqiang

    2014-01-01

    By using a high-order accurate finite difference scheme, direct numerical simulation of hypersonic flow over an 8° half-wedge-angle blunt wedge under freestream single-frequency entropy disturbance is conducted; the generation and the temporal and spatial nonlinear evolution of boundary layer disturbance waves are investigated. Results show that, under the freestream single-frequency entropy disturbance, the entropy state of boundary layer is changed sharply and the disturbance waves within a certain frequency range are induced in the boundary layer. Furthermore, the amplitudes of disturbance waves in the period phase are larger than that in the response phase and ablation phase and the frequency range in the boundary layer in the period phase is narrower than that in these two phases. In addition, the mode competition, dominant mode transformation, and disturbance energy transfer exist among different modes both in temporal and in spatial evolution. The mode competition changes the characteristics of nonlinear evolution of the unstable waves in the boundary layer. The development of the most unstable mode along streamwise relies more on the motivation of disturbance waves in the upstream than that of other modes on this motivation.

  17. Temporal and Spatial Evolution Characteristics of Disturbance Wave in a Hypersonic Boundary Layer due to Single-Frequency Entropy Disturbance

    PubMed Central

    Lv, Hongqing; Shi, Jianqiang

    2014-01-01

    By using a high-order accurate finite difference scheme, direct numerical simulation of hypersonic flow over an 8° half-wedge-angle blunt wedge under freestream single-frequency entropy disturbance is conducted; the generation and the temporal and spatial nonlinear evolution of boundary layer disturbance waves are investigated. Results show that, under the freestream single-frequency entropy disturbance, the entropy state of boundary layer is changed sharply and the disturbance waves within a certain frequency range are induced in the boundary layer. Furthermore, the amplitudes of disturbance waves in the period phase are larger than that in the response phase and ablation phase and the frequency range in the boundary layer in the period phase is narrower than that in these two phases. In addition, the mode competition, dominant mode transformation, and disturbance energy transfer exist among different modes both in temporal and in spatial evolution. The mode competition changes the characteristics of nonlinear evolution of the unstable waves in the boundary layer. The development of the most unstable mode along streamwise relies more on the motivation of disturbance waves in the upstream than that of other modes on this motivation. PMID:25143983

  18. Accumulation capacitance frequency dispersion of III-V metal-insulator-semiconductor devices due to disorder induced gap states

    SciTech Connect

    Galatage, R. V.; Zhernokletov, D. M.; Dong, H.; Brennan, B.; Hinkle, C. L.; Wallace, R. M.; Vogel, E. M.

    2014-07-07

    The origin of the anomalous frequency dispersion in accumulation capacitance of metal-insulator-semiconductor devices on InGaAs and InP substrates is investigated using modeling, electrical characterization, and chemical characterization. A comparison of the border trap model and the disorder induced gap state model for frequency dispersion is performed. The fitting of both models to experimental data indicate that the defects responsible for the measured dispersion are within approximately 0.8 nm of the surface of the crystalline semiconductor. The correlation between the spectroscopically detected bonding states at the dielectric/III-V interface, the interfacial defect density determined using capacitance-voltage, and modeled capacitance-voltage response strongly suggests that these defects are associated with the disruption of the III-V atomic bonding and not border traps associated with bonding defects within the high-k dielectric.

  19. Accumulation capacitance frequency dispersion of III-V metal-insulator-semiconductor devices due to disorder induced gap states

    NASA Astrophysics Data System (ADS)

    Galatage, R. V.; Zhernokletov, D. M.; Dong, H.; Brennan, B.; Hinkle, C. L.; Wallace, R. M.; Vogel, E. M.

    2014-07-01

    The origin of the anomalous frequency dispersion in accumulation capacitance of metal-insulator-semiconductor devices on InGaAs and InP substrates is investigated using modeling, electrical characterization, and chemical characterization. A comparison of the border trap model and the disorder induced gap state model for frequency dispersion is performed. The fitting of both models to experimental data indicate that the defects responsible for the measured dispersion are within approximately 0.8 nm of the surface of the crystalline semiconductor. The correlation between the spectroscopically detected bonding states at the dielectric/III-V interface, the interfacial defect density determined using capacitance-voltage, and modeled capacitance-voltage response strongly suggests that these defects are associated with the disruption of the III-V atomic bonding and not border traps associated with bonding defects within the high-k dielectric.

  20. Myocardial contractile depression from high-frequency vibration is not due to increased cross-bridge breakage.

    PubMed

    Campbell, K B; Wu, Y; Kirkpatrick, R D; Slinker, B K

    1998-04-01

    Experiments were conducted in 10 isolated rabbit hearts at 25 degrees C to test the hypothesis that vibration-induced depression of myocardial contractile function was the result of increased cross-bridge breakage. Small-amplitude sinusoidal changes in left ventricular volume were administered at frequencies of 25, 50, and 76.9 Hz. The resulting pressure response consisted of a depressive response [delta Pd(t), a sustained decrease in pressure that was not at the perturbation frequency] and an infrequency response [delta Pf(t), that part at the perturbation frequency]. delta Pd(t) represented the effects of contractile depression. A cross-bridge model was applied to delta Pf(t) to estimate cross-bridge cycling parameters. Responses were obtained during Ca2+ activation and during Sr2+ activation when the time course of pressure development was slowed by a factor of 3. delta Pd(t) was strongly affected by whether the responses were activated by Ca2+ or by Sr2+. In the Sr(2+)-activated state, delta Pd(t) declined while pressure was rising and relaxation rate decreased. During Ca2+ and Sr2+ activation, velocity of myofilament sliding was insignificant as a predictor of delta Pd(t) or, when it was significant, participated by reducing delta Pd(t) rather than contributing to its magnitude. Furthermore, there was no difference in cross-bridge cycling rate constants when the Ca(2+)-activated state was compared with the Sr(2+)-activated state. An increase in cross-bridge detachment rate constant with volume-induced change in cross-bridge distortion could not be detected. Finally, processes responsible for delta Pd(t) occurred at slower frequencies than those of cross-bridge detachment. Collectively, these results argue against a cross-bridge detachment basis for vibration-induced myocardial depression.

  1. Linkage disequilibrium, SNP frequency change due to selection, and association mapping in popcorn chromosome regions containing QTLs for quality traits

    PubMed Central

    Paes, Geísa Pinheiro; Viana, José Marcelo Soriano; Silva, Fabyano Fonseca e; Mundim, Gabriel Borges

    2016-01-01

    Abstract The objectives of this study were to assess linkage disequilibrium (LD) and selection-induced changes in single nucleotide polymorphism (SNP) frequency, and to perform association mapping in popcorn chromosome regions containing quantitative trait loci (QTLs) for quality traits. Seven tropical and two temperate popcorn populations were genotyped for 96 SNPs chosen in chromosome regions containing QTLs for quality traits. The populations were phenotyped for expansion volume, 100-kernel weight, kernel sphericity, and kernel density. The LD statistics were the difference between the observed and expected haplotype frequencies (D), the proportion of D relative to the expected maximum value in the population, and the square of the correlation between the values of alleles at two loci. Association mapping was based on least squares and Bayesian approaches. In the tropical populations, D-values greater than 0.10 were observed for SNPs separated by 100-150 Mb, while most of the D-values in the temperate populations were less than 0.05. Selection for expansion volume indirectly led to increase in LD values, population differentiation, and significant changes in SNP frequency. Some associations were observed for expansion volume and the other quality traits. The candidate genes are involved with starch, storage protein, lipid, and cell wall polysaccharides synthesis. PMID:27007903

  2. Linkage disequilibrium, SNP frequency change due to selection, and association mapping in popcorn chromosome regions containing QTLs for quality traits.

    PubMed

    Paes, Geísa Pinheiro; Viana, José Marcelo Soriano; Silva, Fabyano Fonseca E; Mundim, Gabriel Borges

    2016-03-01

    The objectives of this study were to assess linkage disequilibrium (LD) and selection-induced changes in single nucleotide polymorphism (SNP) frequency, and to perform association mapping in popcorn chromosome regions containing quantitative trait loci (QTLs) for quality traits. Seven tropical and two temperate popcorn populations were genotyped for 96 SNPs chosen in chromosome regions containing QTLs for quality traits. The populations were phenotyped for expansion volume, 100-kernel weight, kernel sphericity, and kernel density. The LD statistics were the difference between the observed and expected haplotype frequencies (D), the proportion of D relative to the expected maximum value in the population, and the square of the correlation between the values of alleles at two loci. Association mapping was based on least squares and Bayesian approaches. In the tropical populations, D-values greater than 0.10 were observed for SNPs separated by 100-150 Mb, while most of the D-values in the temperate populations were less than 0.05. Selection for expansion volume indirectly led to increase in LD values, population differentiation, and significant changes in SNP frequency. Some associations were observed for expansion volume and the other quality traits. The candidate genes are involved with starch, storage protein, lipid, and cell wall polysaccharides synthesis. PMID:27007903

  3. The molecular basis of homocystinuria due to cystathionine {beta}-synthase deficiency in Italian families, and report of four novel mutations

    SciTech Connect

    Sebastio, G.; Sperandeo, M.P.; Panico, M.

    1995-06-01

    Four new mutations in the cystathionine {beta}-synthase (CBS) gene have been identified in Italian patients with homocystinuria. The first mutation is a G-to-A transition at base 374 in exon 3, causing an arginine-to-glutamic acid substitution at position 125 of the protein (R125Q). This mutation has been found in homozygosity in a patient partially responsive to pyridoxine treatment. The second mutation is a C-to-T transition at base 770 in exon 7, causing a threonine-to-methionine substitution at amino acid 257 of the protein (T257M). This mutation has been observed in homozygosity in a patient non-responsive to the cofactor treatment. The third mutation, found in heterozygosity in a patient responsive to pyridoxine treatment, is an insertion of 68 bp in exon 8 at base 844, which introduces a premature termination codon. The fourth mutation is C-to-T transition in exon 2 at base 262, causing a proline-to-serine substitution at position 88 of the protein (P88S). This mutation is carried on a single allele in three affected sisters responsive to the cofactor treatment. In addition, six previously reported mutations (A114V, E131D, P145L, I278T, G307S, and A{sub 1224-2}C) have been tested in 14 independent Italian families. Mutations A114V and I278T are carried by three and by seven independent alleles, respectively. The other four mutations - including G307S and A{sub 1224-2}C, common among northern European patients - have not been detected. 21 refs., 6 figs., 5 tabs.

  4. Aminoacyl-tRNA synthetases are multivalent suppressors of defects due to human equivalent mutations in yeast mt tRNA genes.

    PubMed

    Montanari, Arianna; De Luca, Cristina; Frontali, Laura; Francisci, Silvia

    2010-09-01

    The use of the yeast model for the study of the molecular and cellular effects of the pathogenic base substitutions in human mitochondrial tRNA genes has recently been validated by the finding that the suppressing factors identified in yeast (the mitochondrial protein elongation factor EF-Tu and the cognate aminoacyl-tRNA synthetase) have suppressing activities also in human cells. In this paper we report a detailed analysis of the cross-suppressing activities of valyl- and leucyl-tRNA synthetases on different tRNA mutants. Glycerol growth, respiration, Northern analysis consistently show that similar suppressing effects can be obtained by these two yeast synthetases and by the orthologous human enzymes. As a whole the present data indicate that the suppression by mt aa-RS is probably not related to the enzyme activities per se, and may be due to a stabilizing chaperon-like effect of the synthetase molecules on the tRNA structure altered by the mutations.

  5. A girl with permanent neonatal diabetes due to KCNJ11 mutation presented with Mauriac syndrome after improper adjustment in sulfonylurea dosage over 6 years.

    PubMed

    Chai-Udom, Rapeepun; Sahakitrungruang, Taninee; Wacharasindhu, Suttipong; Supornsilchai, Vichit

    2016-09-01

    Mauriac syndrome is characterized by growth impairment, Cushingoid features, and hepatomegaly in patients with poorly controlled type 1 diabetes mellitus (T1DM). We report a novel presentation of Mauriac syndrome in a 9-year-old girl who was diagnosed with neonatal diabetes at 3 months of age due to the p.R201C mutation in KCNJ11. She was initially treated successfully with glipizide at a dose of 0.85 mg/kg/day but after being lost to follow-up and having improper adjustment in dose over many years, the recent dose of 0.6 mg/kg/day appears to have been insufficient for glycemic control but enough to maintain a low level of C-peptide and prevent diabetic ketoacidosis. With proper insulin administration, all presenting clinical characteristics were resolved within 1 month. A review of the literature relating to clinical manifestations of Mauriac syndrome in children with diabetes was performed and included in this report for comparison with our patient. While Mauriac syndrome has been traditionally associated with T1DM, the presence of Mauriac syndrome should not be excluded in other types of diabetes mellitus.

  6. Congenital myasthenic syndrome due to mutation in CHRNE gene with clinical worsening and thymic hyperplasia attributed to association with autoimmune-myasthenia gravis.

    PubMed

    Santos, Ernestina; Moreira, Isabel; Coutinho, Ester; Gonçalves, Guilherme; Lopes, Carlos; Lopes Lima, José; Leite, M Isabel

    2015-12-01

    We report a patient with congenital myasthenic syndrome (CMS) due to mutation in CHRNE with symptoms since the age of 4; mild to moderate fatigable weakness involved mainly ocular, bulbar and limb muscles; functional impact of the disease in their development and physical activity was modest. By the age of 34, the patient experienced gradual worsening of fatigue with dyspnoea and pronounced limb weakness, requiring significant increase of pyridostigmine. Further, a remarkable and sustained clinical improvement followed thymectomy with hyperplastic thymus. Despite of the absence of detectable antibodies to acetyl-choline receptor (AChR) (including clustered-AChR), muscle-specific kinase and low-density lipoprotein receptor-related protein-4 antibodies in the serum obtained nine years after thymectomy, the clinical, genetic and histological features are in keeping with the extremely rare association of two rare neuromuscular junction disorders - CMS and myasthenia gravis (MG). The inexistence of other conditions that could potentially associate with thymic hyperplasia also supports the diagnosis of MG. PMID:26363966

  7. Resistance to DDT and Pyrethroids and Increased kdr Mutation Frequency in An. gambiae after the Implementation of Permethrin-Treated Nets in Senegal

    PubMed Central

    Ndiath, Mamadou O.; Sougoufara, Seynabou; Gaye, Abdoulaye; Mazenot, Catherine; Konate, Lassana; Faye, Oumar; Sokhna, Cheikh; Trape, Jean-Francois

    2012-01-01

    Introduction The aim of this study was to evaluate the susceptibility to insecticides of An. gambiae mosquitoes sampled in Dielmo (Senegal), in 2010, 2 years after the implementation of Long Lasting Insecticide-treated Nets (LLINs) and to report the evolution of kdr mutation frequency from 2006 to 2010. Methods WHO bioassay susceptibility tests to 6 insecticides were performed on adults F0, issuing from immature stages of An. gambiae s.l., sampled in August 2010. Species and molecular forms as well as the presence of L1014F and L1014S kdr mutations were assessed by PCR. Longitudinal study of kdr mutations was performed on adult mosquitoes sampled monthly by night landing catches from 2006 to 2010. Findings No specimen studied presented the L1014S mutation. During the longitudinal study, L1014F allelic frequency rose from 2.4% in year before the implementation of LLINs to 4.6% 0–12 months after and 18.7% 13–30 months after. In 2010, An. gambiae were resistant to DDT, Lambda-cyhalothrin, Deltamethrin and Permethrin (mortality rates ranging from 46 to 63%) but highly susceptible to Fenitrothion and Bendiocarb (100% mortality). There was significantly more RR genotype among An. gambiae surviving exposure to DDT or Pyrethroids. An. arabiensis represented 3.7% of the sampled mosquitoes (11/300) with no kdr resistance allele detected. An. gambiae molecular form M represented 29.7% of the mosquitoes with, among them, kdr genotypes SR (18%) and SS (82%). An. gambiae molecular form S represented 66% of the population with, among them, kdr genotype SS (33.3%), SR (55.6%) and RR (11.1%). Only 2 MS hybrid mosquitoes were sampled and presented SS kdr genotype. Conclusion Biological evidence of resistance to DDT and pyrethroids was detected among An. gambiae mosquitoes in Dielmo (Senegal) within 24 months of community use of LLINs. Molecular identification of L1014F mutation indicated that target site resistance increased after the implementation of LLINs. PMID:22384107

  8. Gene structure and mutations of glutaryl-coenzyme A dehydrogenase: Impaired association of enzyme subunits that is due to an A421V substitution causes glutaric acidemia type I in the Amish

    SciTech Connect

    Biery, B.J.; Stein, D.E.; Goodman, S.I.

    1996-11-01

    The structure of the human glutaryl coenzyme A dehydrogenase (GCD) gene was determined to contain 11 exons and to span {approximately}7 kb. Fibroblast DNA from 64 unrelated glutaric academia type I (GA1) patients was screened for mutations by PCR amplification and analysis of SSCP. Fragments with altered electrophoretic mobility were subcloned and sequenced to detect mutations that caused GA1. This report describes the structure of the GCD gene, as well as point mutations and polymorphisms found in 7 of its 11 exons. Several mutations were found in more than one patient, but no one prevalent mutation was detected in the general population. As expected from pedigree analysis, a single mutant allele causes GA1 in the Old Order Amish of Lancaster County, Pennsylvania. Several mutations have been expressed in Escherichia coli, and all produce diminished enzyme activity. Reduced activity in GCD encoded by the A421V mutation in the Amish may be due to impaired association of enzyme subunits. 13 refs., 5 figs., 3 tabs.

  9. Divergent Metabolic Phenotype between Two Sisters with Congenital Generalized Lipodystrophy Due to Double AGPAT2 Homozygous Mutations. A Clinical, Genetic and In Silico Study

    PubMed Central

    Cortés, Víctor A.; Smalley, Susan V.; Goldenberg, Denisse; Lagos, Carlos F.; Hodgson, María I.; Santos, José L.

    2014-01-01

    Congenital generalized lipodystrophy (CGL) is a rare autosomal recessive disorder characterized by extreme reduction of white adipose tissue (WAT) mass. CGL type 1 is the most frequent form and is caused by mutations in AGPAT2. Genetic and clinical studies were performed in two affected sisters of a Chilean family. These patients have notoriously dissimilar metabolic abnormalities that correlate with differential levels of circulating leptin and soluble leptin receptor fraction. Sequencing of AGPAT2 exons and exon-intron boundaries revealed two homozygous mutations in both sisters. Missense mutation c.299G>A changes a conserved serine in the acyltransferase NHX4D motif of AGPAT2 (p.Ser100Asn). Intronic c.493-1G>C mutation destroy a conserved splicing site that likely leads to exon 4 skipping and deletion of whole AGPAT2 substrate binding domain. In silico protein modeling provided insights of the mechanisms of lack of catalytic activity owing to both mutations. PMID:24498038

  10. Theory of modulation transfer function artifacts due to mid-spatial-frequency errors and its application to optical tolerancing.

    PubMed

    Tamkin, John M; Milster, Tom D; Dallas, William

    2010-09-01

    Aspheric and free-form surfaces are powerful surface forms that allow designers to achieve better performance with fewer lenses and smaller packages. Unlike spheres, these surfaces are fabricated with processes that leave a signature, or "structure," that is primarily in the mid-spatial-frequency region. These structured surface errors create ripples in the modulation transfer function (MTF) profile. Using Fourier techniques with generalized functions, the drop in MTF is derived and shown to exhibit a nonlinear relationship with the peak-to-valley height of the structured surface error.

  11. Blood flow and oxygenation changes due to low-frequency repetitive transcranial magnetic stimulation of the cerebral cortex

    NASA Astrophysics Data System (ADS)

    Mesquita, Rickson C.; Faseyitan, Olufunsho K.; Turkeltaub, Peter E.; Buckley, Erin M.; Thomas, Amy; Kim, Meeri N.; Durduran, Turgut; Greenberg, Joel H.; Detre, John A.; Yodh, Arjun G.; Hamilton, Roy H.

    2013-06-01

    Transcranial magnetic stimulation (TMS) modulates processing in the human brain and is therefore of interest as a treatment modality for neurologic conditions. During TMS administration, an electric current passing through a coil on the scalp creates a rapidly varying magnetic field that induces currents in the cerebral cortex. The effects of low-frequency (1 Hz), repetitive TMS (rTMS) on motor cortex cerebral blood flow (CBF) and tissue oxygenation in seven healthy adults, during/after 20 min stimulation, is reported. Noninvasive optical methods are employed: diffuse correlation spectroscopy (DCS) for blood flow and diffuse optical spectroscopy (DOS) for hemoglobin concentrations. A significant increase in median CBF (33%) on the side ipsilateral to stimulation was observed during rTMS and persisted after discontinuation. The measured hemodynamic parameter variations enabled computation of relative changes in cerebral metabolic rate of oxygen consumption during rTMS, which increased significantly (28%) in the stimulated hemisphere. By contrast, hemodynamic changes from baseline were not observed contralateral to rTMS administration (all parameters, p>0.29). In total, these findings provide new information about hemodynamic/metabolic responses to low-frequency rTMS and, importantly, demonstrate the feasibility of DCS/DOS for noninvasive monitoring of TMS-induced physiologic effects.

  12. Blood flow and oxygenation changes due to low-frequency repetitive transcranial magnetic stimulation of the cerebral cortex

    PubMed Central

    Faseyitan, Olufunsho K.; Turkeltaub, Peter E.; Buckley, Erin M.; Thomas, Amy; Kim, Meeri N.; Durduran, Turgut; Greenberg, Joel H.; Detre, John A.; Yodh, Arjun G.; Hamilton, Roy H.

    2013-01-01

    Abstract. Transcranial magnetic stimulation (TMS) modulates processing in the human brain and is therefore of interest as a treatment modality for neurologic conditions. During TMS administration, an electric current passing through a coil on the scalp creates a rapidly varying magnetic field that induces currents in the cerebral cortex. The effects of low-frequency (1 Hz), repetitive TMS (rTMS) on motor cortex cerebral blood flow (CBF) and tissue oxygenation in seven healthy adults, during/after 20 min stimulation, is reported. Noninvasive optical methods are employed: diffuse correlation spectroscopy (DCS) for blood flow and diffuse optical spectroscopy (DOS) for hemoglobin concentrations. A significant increase in median CBF (33%) on the side ipsilateral to stimulation was observed during rTMS and persisted after discontinuation. The measured hemodynamic parameter variations enabled computation of relative changes in cerebral metabolic rate of oxygen consumption during rTMS, which increased significantly (28%) in the stimulated hemisphere. By contrast, hemodynamic changes from baseline were not observed contralateral to rTMS administration (all parameters, p>0.29). In total, these findings provide new information about hemodynamic/metabolic responses to low-frequency rTMS and, importantly, demonstrate the feasibility of DCS/DOS for noninvasive monitoring of TMS-induced physiologic effects. PMID:23757042

  13. LETTER TO THE EDITOR: Temperature increase in the fetus due to radio frequency exposure during magnetic resonance scanning

    NASA Astrophysics Data System (ADS)

    Gowland, P. A.; DeWilde, J.

    2008-11-01

    This letter uses data from the literature to estimate the temperature rise in the fetus due to RF deposition within normal SAR limits for the pregnant woman. The results suggest that caution should be exercised when performing fetal MRI at high SAR levels until further data are available. It makes several recommendations related to fetal MRI and fetal SAR modelling.

  14. Epidermolytic palmoplantar keratoderma due to a novel type of keratin mutation, a 3-bp insertion in the keratin 9 helix termination motif.

    PubMed

    Coleman, C M; Munro, C S; Smith, F J; Uitto, J; McLean, W H

    1999-03-01

    Epidermolytic palmoplantar keratoderma (EPPK) is an autosomal dominant genodermatosis characterized by diffuse keratoderma, typically with an erythematous border. Histologically, palmoplantar epidermis shows suprabasal cytolysis and ultrastructurally, tonofilament aggregation with overlying epidermolytic hyperkeratosis. Mutations in the KRT9 gene, encoding keratin 9 (K9), a cytoskeletal protein expressed exclusively in suprabasal keratinocytes of palmoplantar epidermis, have been reported to cause EPPK. To date, all KRT9 defects reported in EPPK have been missense mutations in exon 1, which encodes the start of the alpha-helical rod domain. However, based on studies of other keratin disorders, it was postulated that mutations at the other end of the rod domain might also produce the EPPK phenotype. Here, we report the first mutation in the 2B domain of KRT9, 1362ins3, leading to an insertion of histidine in the helix termination motif of the K9 polypeptide. Insertional mutations have not been previously described in keratins. The phenotype of this case is similar to EPPK caused by 1A domain mutations, demonstrating that mutations in either of the helix boundary motif sequences of K9 are detrimental to keratin function and keratinocyte structure.

  15. Complex hydrologic changes in frequency-magnitude response due to shifting agricultural practices in the Midwestern U.S.

    NASA Astrophysics Data System (ADS)

    Takbiri, Z.; Czuba, J. A.; Foufoula-Georgiou, E.

    2014-12-01

    Hydrologic change is occurring in many basins throughout the Midwestern U.S. not only in the mean annual streamflow but across a spectrum of magnitudes and frequencies. Disentangling the causative mechanisms responsible for these changes such as anthropogenic factors, e.g., artificial drainage to increase agricultural productivity, and climatic shifts in precipitation patterns is important for planning effective mitigation strategies. We have begun unraveling these changes in a human impacted agricultural landscape in the Midwestern U.S., specifically two subbasins of the Minnesota River Basin in Minnesota: the Redwood and Whetstone River Basins, where there has been a shift in agriculture from small grains to soybeans. This shift occurred at different times for each basin (1976 and 1991, respectively) and when soy covered about 20% of the basin area an apparent shift in the hydrologic regime also occurred as evidence by visual inspection of the hydrographs. Precisely quantifying the nature of this hydrologic regime shift however is a challenge and this work adds in this direction. Using Copulas and the joint probability distribution of daily precipitation and streamflow, we quantified a significantly higher dependence between precipitation and streamflow increments in the mid-quantiles (0.1-0.6; attributed to the artificial drainage to the stream rather than the slower infiltration and subsurface runoff) and no significant change for high quantiles (because for extreme storms the artificially fast drainage does not differ much hydrologically from the naturally fast overland flow). We further performed a multi-scale analysis of streamflow increments via wavelets to quantify the changes in the magnitude and frequency of the rising and falling limbs of hydrographs, confirming the above findings. Since precipitation changes were confirmed not to be significant, it is suggested that streamflow changes are largely driven by a change in land use and not climate in these

  16. TED, an autonomous and rare maize transposon of the mutator superfamily with a high gametophytic excision frequency.

    PubMed

    Li, Yubin; Harris, Linda; Dooner, Hugo K

    2013-09-01

    Mutator (Mu) elements, one of the most diverse superfamilies of DNA transposons, are found in all eukaryotic kingdoms, but are particularly numerous in plants. Most of the present knowledge on the transposition behavior of this superfamily comes from studies of the maize (Zea mays) Mu elements, whose transposition is mediated by the autonomous Mutator-Don Robertson (MuDR) element. Here, we describe the maize element TED (for Transposon Ellen Dempsey), an autonomous cousin that differs significantly from MuDR. Element excision and reinsertion appear to require both proteins encoded by MuDR, but only the single protein encoded by TED. Germinal excisions, rare with MuDR, are common with TED, but arise in one of the mitotic divisions of the gametophyte, rather than at meiosis. Instead, transposition-deficient elements arise at meiosis, suggesting that the double-strand breaks produced by element excision are repaired differently in mitosis and meiosis. Unlike MuDR, TED is a very low-copy transposon whose number and activity do not undergo dramatic changes upon inbreeding or outcrossing. Like MuDR, TED transposes mostly to unlinked sites and can form circular transposition products. Sequences closer to TED than to MuDR were detected only in the grasses, suggesting a rather recent evolutionary split from a common ancestor.

  17. α(+)-Thalassemia Due to a Frameshift Mutation of the α2-Globin Gene [codons 55/56 (+T) or HBA2: c.168dup].

    PubMed

    Waye, John S; Eng, Barry; Hanna, Meredith; Hohenadel, Betty-Ann; Nakamura, Lisa M; Walker, Lynda

    2015-01-01

    We report a case of α(+)-thalassemia (α(+)-thal) trait in a Chinese-Canadian family caused by a novel frameshift mutation of the α2-globin gene, specifically the duplication of a single nucleotide at amino acid codon 56 [HBA2: c.168dup]. The mutation results in substitution of a termination codon (TAA) for lysine (AAG) at amino acid position 56.

  18. Standing striations due to ionization instability in atmospheric pressure He/H2O radio frequency capacitive discharges

    NASA Astrophysics Data System (ADS)

    Kawamura, E.; Lieberman, M. A.; Lichtenberg, A. J.

    2016-10-01

    One-dimensional particle-in-cell (PIC) simulations of a narrow gap atmospheric pressure He/2%{{\\text{H}}2}\\text{O} radio frequency capacitive discharge showed standing striations in the bulk plasma region while previously conducted PIC simulations of a narrow gap atmospheric pressure He/0.1%{{\\text{N}}2} discharges [1] showed no such instabilities. We successively modified the base He/{{\\text{H}}2}\\text{O} chemistry to make it more similar to the He/{{\\text{N}}2} chemistry in order to determine the cause of the striations. Setting the e–{{\\text{H}}2}\\text{O} scattering, attachment, vibrational and rotational excitation rates to zero did not suppress the striations. However, a systematic reduction of the e–ion recombination cross section resulted in a transition to a stable state with no striations. The results are interpreted in terms of a model in which the balance between bulk direct ionization and bulk recombination loss determines the bulk plasma equilibrium. Perturbing the equilibrium, we find that the striations are consistent with an ionization instability induced by non-local electron kinetics that form a spatially-varying high energy tail of the electron energy distribution, causing the ionization rate coefficient to decrease with increasing electron temperature T e and root-mean-square electric field E in the instability regime.

  19. Altered mRNA Splicing, Chondrocyte Gene Expression and Abnormal Skeletal Development due to SF3B4 Mutations in Rodriguez Acrofacial Dysostosis

    PubMed Central

    Nevarez, Lisette; Pogue, Robert; Krakow, Deborah; Cohn, Daniel H.

    2016-01-01

    The acrofacial dysostoses (AFD) are a genetically heterogeneous group of inherited disorders with craniofacial and limb abnormalities. Rodriguez syndrome is a severe, usually perinatal lethal AFD, characterized by severe retrognathia, oligodactyly and lower limb abnormalities. Rodriguez syndrome has been proposed to be a severe form of Nager syndrome, a non-lethal AFD that results from mutations in SF3B4, a component of the U2 small nuclear ribonucleoprotein particle (U2 snRNP). Furthermore, a case with a phenotype intermediate between Rodriguez and Nager syndromes has been shown to have an SF3B4 mutation. We identified heterozygosity for SF3B4 mutations in Rodriguez syndrome, confirming that the phenotype is a dominant disorder that is allelic with Nager syndrome. The mutations led to reduced SF3B4 synthesis and defects in mRNA splicing, primarily exon skipping. The mutations also led to reduced expression in growth plate chondrocytes of target genes, including the DLX5, DLX6, SOX9, and SOX6 transcription factor genes, which are known to be important for skeletal development. These data provide mechanistic insight toward understanding how SF3B4 mutations lead to the skeletal abnormalities observed in the acrofacial dysostoses. PMID:27622494

  20. Postmortem diagnosis of Marfan syndrome in a case of sudden death due to aortic rupture: Detection of a novel FBN1 frameshift mutation.

    PubMed

    Wang, Yunyun; Chen, Shu; Wang, Rongshuai; Huang, Sizhe; Yang, Mingzhen; Liu, Liang; Liu, Qian

    2016-04-01

    To investigate the sudden death of a 36-year-old Chinese man, a medicolegal autopsy was performed, combining forensic pathological examinations and genetic sequencing analysis to diagnose the cause of death. Genomic DNA samples were extracted from blood and subjected to high-throughput sequencing. Major findings included a dilated aortic root with a ruptured and dissected aorta and consequent tamponade of the pericardial sac. Moreover, arachnodactyly and other skeletal deformities were noted. By sequencing the fibrillin-1 gene (FBN1), five genetic variations were found, including four previously known single nucleotide polymorphisms (SNPs) and a novel frameshift mutation, leading to the diagnosis of Marfan syndrome. The frameshift mutation (c.4921delG, p.glu1641llysFsX9) detected in exon 40 led to a stop codon after the next 8 amino acids. The four SNPs included a splice site mutation (c.3464-5 G>A, rs11853943), a synonymous mutation (p.Asn625Asn, rs25458), and two missense mutations (p.Pro1148Ala, rs140598; p.Cys472Tyr, rs4775765). Genetic screening was recommended for the relatives as it was reported that the father and brother of the deceased had died at the ages of 40 and 25, respectively, from sudden cardiac failure. The son of the deceased lacked the relevant mutations. This report emphasizes the important contribution of medicolegal postmortem analysis on the molecular pathogenesis study of Marfan syndrome and early diagnosis of at-risk relatives.

  1. The Tsk2/+ mouse fibrotic phenotype is due to a gain-of-function mutation in the PIIINP segment of the Col3a1 gene.

    PubMed

    Long, Kristen B; Li, Zhenghui; Burgwin, Chelsea M; Choe, Susanna G; Martyanov, Viktor; Sassi-Gaha, Sihem; Earl, Josh P; Eutsey, Rory A; Ahmed, Azad; Ehrlich, Garth D; Artlett, Carol M; Whitfield, Michael L; Blankenhorn, Elizabeth P

    2015-03-01

    Systemic sclerosis (SSc) is a polygenic, autoimmune disorder of unknown etiology, characterized by the excessive accumulation of extracellular matrix (ECM) proteins, vascular alterations, and autoantibodies. The tight skin (Tsk)2/+ mouse model of SSc demonstrates signs similar to SSc including tight skin and excessive deposition of dermal ECM proteins. By linkage analysis, we mapped the Tsk2 gene mutation to <3 megabases on chromosome 1. We performed both RNA sequencing of skin transcripts and genome capture DNA sequencing of the region spanning this interval in Tsk2/+ and wild-type littermates. A missense point mutation in the procollagen III amino terminal propeptide segment (PIIINP) of collagen, type III, alpha 1 (Col3a1) was found to be the best candidate for Tsk2; hence, both in vivo and in vitro genetic complementation tests were used to prove that this Col3a1 mutation is the Tsk2 gene. All previously documented mutations in the human Col3a1 gene are associated with the Ehlers-Danlos syndrome, a connective tissue disorder that leads to a defect in type III collagen synthesis. To our knowledge, the Tsk2 point mutation is the first documented gain-of-function mutation associated with Col3a1, which leads instead to fibrosis. This discovery provides insight into the mechanism of skin fibrosis manifested by Tsk2/+ mice. PMID:25330296

  2. Frequencies of pyrethroid resistance-associated mutations of Vssc1 and CYP6D1 in field populations of Musca domestica L. in Turkey.

    PubMed

    Taşkın, Vatan; Başkurt, Sibel; Doğaç, Ersin; Taşkin, Belgin Göçmen

    2011-12-01

    House flies were collected from 16 different provinces in the Aegean and Mediterranean regions of Turkey, and the frequencies of pyrethroid resistance-associated mutations in Vssc1 and CYP6D1 in these field-collected populations were studied. Although there is no organized resistance management program for house fly control in Turkey, it is known that different groups of insecticides, including pyrethroids, are used. The frequencies of both Vssc1 and CYP6D1 alleles were weighted toward the susceptibles, with Vssc1-susceptible alleles having higher frequencies in both regions (0.75 in Aegean and 0.69 in Mediterranean populations) than CYP6D1-susceptible alleles (0.65 in Aegean and 0.56 in Mediterranean populations). The frequencies of kdr-his alleles were higher than the frequencies of kdr alleles in these populations. While the frequencies of kdr-his alleles were close to each other in the Aegean (0.23) and Mediterranean (0.17) populations, the frequencies of kdr alleles remarkably differed in these two regions, with values of 0.02 and 0.14, respectively. In contrast to Europe, Asia, and the U.S.A., no super-kdr allele was detected in the samples from both regions. We identified six and eight different Vssc1+CYP6D1 genotype classes in the Aegean and Mediterranean regions, respectively. The three most common genotype classes in the regions were susceptible Vssc1 with heterozygous CYP6D1v1 (29%), sus/kdr-his1 with heterozygous CYP6D1v1 (23%), and susceptible Vssc1 with CYP6D1 (22%). The total frequencies of these three most common genotype classes (approximately 75%) obtained in our study were very close to the value obtained in Florida in a previous study, which was related by the similarity of temperature patterns between Florida and the corresponding regions of Turkey. This may reflect the lack of overwintering fitness cost associated with resistance alleles in both climates. PMID:22129395

  3. Phenotypic variability in a seven-generation Swedish family segregating autosomal dominant hearing impairment due to a novel EYA4 frameshift mutation.

    PubMed

    Frykholm, Carina; Klar, Joakim; Arnesson, Hanna; Rehnman, Anna-Carin; Lodahl, Marianne; Wedén, Ulla; Dahl, Niklas; Tranebjærg, Lisbeth; Rendtorff, Nanna D

    2015-05-25

    Linkage to an interval overlapping the DFNA10 locus on chromosome 6q22-23 was found through genome wide linkage analysis in a seven-generation Swedish family segregating postlingual, autosomal dominant nonsyndromic sensorineural hearing impairment. A novel heterozygous frame-shift mutation (c.579_580insTACC, p.(Asp194Tyrfs*52)) in EYA4 was identified that truncates the so-called variable region of the protein. The mutation is predicted to result in haploinsufficiency of the EYA4 product. No evidence for dilated cardiomyopathy was found in the family, contrasting to a previous family with a deletion resulting in a similar truncation in the variable region. A highly variable age of onset was seen in the mutation carriers. For assessment of the aetiology of this variability, clinical and audiometric data analyses were performed. The affected family members all had similar cross-sectional and longitudinal deterioration of pure tone average (PTA) once the process of hearing deterioration had started, and no gender, parent-of-origin or family branch differences on PTA could be found. Age at onset varied between the family branches. In summary, this is the ninth published genetically verified DFNA10 family. The results imply that unidentified factors, genetic or environmental, other than the EYA4 mutation, are of importance for the age at onset of DFNA10, and that mutation early in the variable region of the EYA4 protein can occur in the absence of dilated cardiomyopathy.

  4. Comparable frequencies of coding mutations and loss of imprinting in human pluripotent cells derived by nuclear transfer and defined factors.

    PubMed

    Johannesson, Bjarki; Sagi, Ido; Gore, Athurva; Paull, Daniel; Yamada, Mitsutoshi; Golan-Lev, Tamar; Li, Zhe; LeDuc, Charles; Shen, Yufeng; Stern, Samantha; Xu, Nanfang; Ma, Hong; Kang, Eunju; Mitalipov, Shoukhrat; Sauer, Mark V; Zhang, Kun; Benvenisty, Nissim; Egli, Dieter

    2014-11-01

    The recent finding that reprogrammed human pluripotent stem cells can be derived by nuclear transfer into human oocytes as well as by induced expression of defined factors has revitalized the debate on whether one approach might be advantageous over the other. Here we compare the genetic and epigenetic integrity of human nuclear-transfer embryonic stem cell (NT-ESC) lines and isogenic induced pluripotent stem cell (iPSC) lines, derived from the same somatic cell cultures of fetal, neonatal, and adult origin. The two cell types showed similar genome-wide gene expression and DNA methylation profiles. Importantly, NT-ESCs and iPSCs had comparable numbers of de novo coding mutations, but significantly more than parthenogenetic ESCs. As iPSCs, NT-ESCs displayed clone- and gene-specific aberrations in DNA methylation and allele-specific expression of imprinted genes. The occurrence of these genetic and epigenetic defects in both NT-ESCs and iPSCs suggests that they are inherent to reprogramming, regardless of derivation approach.

  5. Pulmonary hypoplasia-diaphragmatic hernia-anophthalmia-cardiac defect (PDAC) syndrome due to STRA6 mutations--what are the minimal criteria?

    PubMed

    Segel, Reeval; Levy-Lahad, Ephrat; Pasutto, Francesca; Picard, Elie; Rauch, Anita; Alterescu, Gheona; Schimmel, Michael S

    2009-11-01

    Microphthalmic syndrome 9 (OMIM601186) is a genetically and phenotypically variable condition, comprising anophthalmia, pulmonary hypoplasia, diaphragmatic hernia, and cardiac malformations (PDAC syndrome). Reported cases have all been associated with fetal/neonatal death or developmental delay. Recessive stimulated by retinoic acid gene 6 homolog (STRA6) mutations have recently been identified as the cause of cases of PDAC in which distinct, "bushy" eyebrows have been observed. We describe a patient with clinical anophthalmia, bushy eyebrows, patent ductus arteriosus, and normal development at age 30 months, who is a compound heterozygote for two novel STRA6 missense mutations. This patient's phenotype is consistent with the multisystemic malformations of PDAC syndrome, but is somewhat milder. This is the first living patient with compound heterozygous STRA6 mutations, which may explain her milder phenotype. We conclude that STRA6 analysis should be considered in all patients with clinical anophthalmia. Genetic counseling should be cautious with respect to long-term developmental outcomes.

  6. Postnatal microcephaly and pain insensitivity due to a de novo heterozygous DNM1L mutation causing impaired mitochondrial fission and function.

    PubMed

    Sheffer, Ruth; Douiev, Liza; Edvardson, Simon; Shaag, Avraham; Tamimi, Khaled; Soiferman, Devorah; Meiner, Vardiella; Saada, Ann

    2016-06-01

    An emerging class of mitochondrial disorders is caused by mutations in nuclear genes affecting mitochondrial dynamics and function. One of these is the DNM1L gene encoding the dynamin-related protein 1 (DRP1), which is pivotal in the mitochondrial fission process. Here, we describe a patient with a novel dominant-negative, de novo DNM1L mutation, which expands the clinical spectrum. The patient reported here exhibits a chronic neurological disorder, characterized by postnatal microcephaly, developmental delay, and pain insensitivity. Muscle biopsy disclosed decreased respiratory chain complex IV activity. Exome sequencing showed a de novo heterozygous c.1084G>A (p.G362S) mutation. Subsequent studies of patient skin fibroblasts showed markedly impaired mitochondrial fission and a partial respiratory chain defect while peroxisomal morphology remained intact. Human foreskin fibroblasts over-expressing the mutant DNM1L gene displayed aberrant mitochondrial morphology. © 2016 Wiley Periodicals, Inc. PMID:26992161

  7. Postnatal microcephaly and pain insensitivity due to a de novo heterozygous DNM1L mutation causing impaired mitochondrial fission and function.

    PubMed

    Sheffer, Ruth; Douiev, Liza; Edvardson, Simon; Shaag, Avraham; Tamimi, Khaled; Soiferman, Devorah; Meiner, Vardiella; Saada, Ann

    2016-06-01

    An emerging class of mitochondrial disorders is caused by mutations in nuclear genes affecting mitochondrial dynamics and function. One of these is the DNM1L gene encoding the dynamin-related protein 1 (DRP1), which is pivotal in the mitochondrial fission process. Here, we describe a patient with a novel dominant-negative, de novo DNM1L mutation, which expands the clinical spectrum. The patient reported here exhibits a chronic neurological disorder, characterized by postnatal microcephaly, developmental delay, and pain insensitivity. Muscle biopsy disclosed decreased respiratory chain complex IV activity. Exome sequencing showed a de novo heterozygous c.1084G>A (p.G362S) mutation. Subsequent studies of patient skin fibroblasts showed markedly impaired mitochondrial fission and a partial respiratory chain defect while peroxisomal morphology remained intact. Human foreskin fibroblasts over-expressing the mutant DNM1L gene displayed aberrant mitochondrial morphology. © 2016 Wiley Periodicals, Inc.

  8. Destabilization of the IFT-B cilia core complex due to mutations in IFT81 causes a Spectrum of Short-Rib Polydactyly Syndrome

    PubMed Central

    Duran, Ivan; Taylor, S. Paige; Zhang, Wenjuan; Martin, Jorge; Forlenza, Kimberly N.; Spiro, Rhonda P.; Nickerson, Deborah A.; Bamshad, Michael; Cohn, Daniel H.; Krakow, Deborah

    2016-01-01

    Short-rib polydactyly syndromes (SRPS) and Asphyxiating thoracic dystrophy (ATD) or Jeune Syndrome are recessively inherited skeletal ciliopathies characterized by profound skeletal abnormalities and are frequently associated with polydactyly and multiorgan system involvement. SRPS are produced by mutations in genes that participate in the formation and function of primary cilia and usually result from disruption of retrograde intraflagellar (IFT) transport of the cilium. Herein we describe a new spectrum of SRPS caused by mutations in the gene IFT81, a key component of the IFT-B complex essential for anterograde transport. In mutant chondrocytes, the mutations led to low levels of IFT81 and mutant cells produced elongated cilia, had altered hedgehog signaling, had increased post-translation modification of tubulin, and showed evidence of destabilization of additional anterograde transport complex components. These findings demonstrate the importance of IFT81 in the skeleton, its role in the anterograde transport complex, and expand the number of loci associated with SRPS. PMID:27666822

  9. USA300 and USA500 Clonal Lineages of Staphylococcus aureus Do Not Produce a Capsular Polysaccharide Due to Conserved Mutations in the cap5 Locus

    PubMed Central

    Li, Xue; Alam, Md Tauqeer; Read, Timothy D.; Sieth, Julia; Cywes-Bentley, Colette; Dobbins, Ginette; David, Michael Z.; Kumar, Neha; Eells, Samantha J.; Miller, Loren G.; Boxrud, David J.; Chambers, Henry F.; Lynfield, Ruth; Lee, Jean C.; Daum, Robert S.

    2015-01-01

    ABSTRACT The surface capsular polysaccharide (CP) is a virulence factor that has been used as an antigen in several successful vaccines against bacterial pathogens. A vaccine has not yet been licensed against Staphylococcus aureus, although two multicomponent vaccines that contain CP antigens are in clinical trials. In this study, we evaluated CP production in USA300 methicillin-resistant S. aureus (MRSA) isolates that have become the predominant community-associated MRSA clones in the United States. We found that all 167 USA300 MRSA and 50 USA300 methicillin-susceptible S. aureus (MSSA) isolates were CP negative (CP−). Moreover, all 16 USA500 isolates, which have been postulated to be the progenitor lineage of USA300, were also CP−. Whole-genome sequence analysis of 146 CP− USA300 MRSA isolates revealed they all carry a cap5 locus with 4 conserved mutations compared with strain Newman. Genetic complementation experiments revealed that three of these mutations (in the cap5 promoter, cap5D nucleotide 994, and cap5E nucleotide 223) ablated CP production in USA300 and that Cap5E75 Asp, located in the coenzyme-binding domain, is essential for capsule production. All but three USA300 MSSA isolates had the same four cap5 mutations found in USA300 MRSA isolates. Most isolates with a USA500 pulsotype carried three of these four USA300-specific mutations, suggesting the fourth mutation occurred in the USA300 lineage. Phylogenetic analysis of the cap loci of our USA300 isolates as well as publicly available genomes from 41 other sequence types revealed that the USA300-specific cap5 mutations arose sequentially in S. aureus in a common ancestor of USA300 and USA500 isolates. PMID:25852165

  10. Permanent neonatal diabetes due to mutations in KCNJ11 encoding Kir6.2: patient characteristics and initial response to sulfonylurea therapy.

    PubMed

    Sagen, Jørn V; Raeder, Helge; Hathout, Eba; Shehadeh, Naim; Gudmundsson, Kolbeinn; Baevre, Halvor; Abuelo, Dianne; Phornphutkul, Chanika; Molnes, Janne; Bell, Graeme I; Gloyn, Anna L; Hattersley, Andrew T; Molven, Anders; Søvik, Oddmund; Njølstad, Pål R

    2004-10-01

    Permanent neonatal diabetes (PND) can be caused by mutations in the transcription factors insulin promoter factor (IPF)-1, eukaryotic translation initiation factor-2alpha kinase 3 (EIF2AK3), and forkhead box-P3 and in key components of insulin secretion: glucokinase (GCK) and the ATP-sensitive K(+) channel subunit Kir6.2. We sequenced the gene encoding Kir6.2 (KCNJ11) in 11 probands with GCK-negative PND. Heterozygous mutations were identified in seven probands, causing three novel (F35V, Y330C, and F333I) and two known (V59M and R201H) Kir6.2 amino acid substitutions. Only two probands had a family history of diabetes. Subjects with the V59M mutation had neurological features including motor delay. Three mutation carriers tested had an insulin secretory response to tolbutamide, but not to glucose or glucagon. Glibenclamide was introduced in increasing doses to investigate whether sulfonylurea could replace insulin. At a glibenclamide dose of 0.3-0.4 mg. kg(-1). day(-1), insulin was discontinued. Blood glucose did not deteriorate, and HbA(1c) was stable or fell during 2-6 months of follow-up. An oral glucose tolerance test performed in one subject revealed that glucose-stimulated insulin release was restored. Mutations in Kir6.2 were the most frequent cause of PND in our cohort. Apparently insulin-dependent patients with mutations in Kir6.2 may be managed on an oral sulfonylurea with sustained metabolic control rather than insulin injections, illustrating the principle of pharmacogenetics applied in diabetes treatment.

  11. Calmodulin 2 Mutation N98S Is Associated with Unexplained Cardiac Arrest in Infants Due to Low Clinical Penetrance Electrical Disorders

    PubMed Central

    Jiménez-Jáimez, Juan; Palomino Doza, Julián; Ortega, Ángeles; Macías-Ruiz, Rosa; Perin, Francesca; Rodríguez-Vázquez del Rey, M. Mar; Ortiz-Genga, Martín; Monserrat, Lorenzo; Barriales-Villa, Roberto; Blanca, Enrique; Álvarez, Miguel; Tercedor, Luis

    2016-01-01

    Background Calmodulin 1, 2 and 3 (CALM) mutations have been found to cause cardiac arrest in children at a very early age. The underlying aetiology described is long QT syndrome (LQTS), catecholaminergic polymorphic ventricular tachycardia (CPVT) and idiopathic ventricular fibrillation (IVF). Little phenotypical data about CALM2 mutations is available. Objectives The aim of this paper is to describe the clinical manifestations of the Asn98Ser mutation in CALM2 in two unrelated children in southern Spain with apparently unexplained cardiac arrest/death. Methods Two unrelated children aged 4 and 7, who were born to healthy parents, were studied. Both presented with sudden cardiac arrest. The first was resuscitated after a VF episode, and the second died suddenly. In both cases the baseline QTc interval was within normal limits. Peripheral blood DNA was available to perform targeted gene sequencing. Results The surviving 4-year-old girl had a positive epinephrine test for LQTS, and polymorphic ventricular ectopic beats were seen on a previous 24-hour Holter recording from the deceased 7-year-old boy, suggestive of a possible underlying CPVT phenotype. A p.Asn98Ser mutation in CALM2 was detected in both cases. This affected a highly conserved across species residue, and the location in the protein was adjacent to critical calcium binding loops in the calmodulin carboxyl-terminal domain, predicting a high pathogenic effect. Conclusions Human calmodulin 2 mutation p.Asn98Ser is associated with sudden cardiac death in childhood with a variable clinical penetrance. Our results provide new phenotypical information about clinical behaviour of this mutation. PMID:27100291

  12. T-cell acute lymphoblastic leukemia in association with Börjeson-Forssman-Lehmann syndrome due to a mutation in PHF6.

    PubMed

    Chao, Mwe Mwe; Todd, Matthew A; Kontny, Udo; Neas, Katherine; Sullivan, Michael J; Hunter, Alasdair G; Picketts, David J; Kratz, Christian P

    2010-10-01

    Börjeson-Forssman-Lehmann syndrome (BFLS) is a rare X-linked mental retardation syndrome that is caused by germline mutations in PHF6. We describe a 9-year-old male with BFLS, who developed T-cell acute lymphoblastic leukemia (T-ALL). The PHF6 gene is located on the X chromosome and encodes a protein with two PHD-type zinc finger domains and four nuclear localization sequences. Previously, overexpression of Phf6 was observed in murine T-cell lymphomas. Our observation indicates that BFLS may represent a cancer predisposition syndrome and that mutations of PHF6 contribute to T-ALL.

  13. First description of azole-resistant Aspergillus fumigatus due to TR46/Y121F/T289A mutation in France.

    PubMed

    Lavergne, Rose-Anne; Morio, Florent; Favennec, Loïc; Dominique, Stéphane; Meis, Jacques F; Gargala, Gilles; Verweij, Paul E; Le Pape, Patrice

    2015-07-01

    Azole resistance in Aspergillus fumigatus is an emerging public health concern. Recently, a novel fungicide-driven mutation in the cyp51A gene and its promoter, TR46/Y121F/T289A, leading to high-level resistance to voriconazole has been identified in The Netherlands, Belgium, Germany, Denmark, Tanzania, and India in both clinical and environmental samples. Here we report the first description of A. fumigatus carrying this mutation in France, in a cystic fibrosis patient, underlining the need for extensive monitoring of Aspergillus resistance.

  14. Resistance to macrolides, lincosamides and streptogramin type B antibiotics due to a mutation in an rRNA operon of Streptomyces ambofaciens.

    PubMed Central

    Pernodet, J L; Boccard, F; Alegre, M T; Blondelet-Rouault, M H; Guérineau, M

    1988-01-01

    Streptomyces ambofaciens produces spiramycin, a macrolide antibiotic and expresses an inducible resistance to macrolides, lincosamides and streptogramin B antibiotics (MLS). From a mutant of S.ambofaciens exhibiting a constitutive MLS resistance phenotype a resistance determinant was cloned on a low copy number vector (pIJ61) through its expression in Streptomyces lividans. Further characterization has shown that this determinant corresponded to a mutant rRNA operon with a mutation in the 23S rRNA gene. In different organisms, mutations leading to MLS resistance have been located at a position corresponding to the adenine 2058 of Escherichia coli 23S rRNA. In the 23S rRNA from S.ambofaciens a similar position for the mutation has been postulated and DNA sequencing of this region has shown an adenine to guanine transition at a position corresponding to 2058. S.ambofaciens possesses four rRNA operons which we have cloned. In Streptomyces, contrary to other bacteria, a mutation in one among several rRNA operons confers a selectable MLS resistance phenotype. Possible reasons for this difference are discussed. Images PMID:2834204

  15. Neuropathologic Characterization of Pontocerebellar Hypoplasia Type 6 Associated With Cardiomyopathy and Hydrops Fetalis and Severe Multisystem Respiratory Chain Deficiency due to Novel RARS2 Mutations.

    PubMed

    Lax, Nichola Z; Alston, Charlotte L; Schon, Katherine; Park, Soo-Mi; Krishnakumar, Deepa; He, Langping; Falkous, Gavin; Ogilvy-Stuart, Amanda; Lees, Christoph; King, Rosalind H; Hargreaves, Iain P; Brown, Garry K; McFarland, Robert; Dean, Andrew F; Taylor, Robert W

    2015-07-01

    Autosomal recessive mutations in the RARS2 gene encoding the mitochondrial arginyl-transfer RNA synthetase cause infantile-onset myoencephalopathy pontocerebellar hypoplasia type 6 (PCH6). We describe 2 sisters with novel compound heterozygous RARS2 mutations who presented perinatally with neurologic features typical of PCH6 but with additional features including cardiomyopathy, hydrops, and pulmonary hypoplasia and who died at 1 day and 14 days of age. Magnetic resonance imaging findings included marked cerebellar hypoplasia, gyral immaturity, punctate lesions in cerebral white matter, and unfused deep cerebral grey matter. Enzyme histochemistry of postmortem tissues revealed a near-global cytochrome c oxidase-deficiency; assessment of respiratory chain enzyme activities confirmed severe deficiencies involving complexes I, III, and IV. Molecular genetic studies revealed 2 RARS2 gene mutations: a c.1A>G, p.? variant predicted to abolish the initiator methionine, and a deep intronic c.613-3927C>T variant causing skipping of exons 6-8 in the mature RARS2 transcript. Neuropathologic investigation included low brain weights, small brainstem and cerebellum, deep cerebral white matter pathology, pontine nucleus neuron loss (in 1 sibling), and peripheral nerve pathology. Mitochondrial respiratory chain immunohistochemistry in brain tissues confirmed an absence of complexes I and IV immunoreactivity with sparing of mitochondrial numbers. These cases expand the clinical spectrum of RARS2 mutations, including antenatal features and widespread mitochondrial respiratory chain deficiencies in postmortem brain tissues.

  16. Neuropathologic Characterization of Pontocerebellar Hypoplasia Type 6 Associated With Cardiomyopathy and Hydrops Fetalis and Severe Multisystem Respiratory Chain Deficiency due to Novel RARS2 Mutations.

    PubMed

    Lax, Nichola Z; Alston, Charlotte L; Schon, Katherine; Park, Soo-Mi; Krishnakumar, Deepa; He, Langping; Falkous, Gavin; Ogilvy-Stuart, Amanda; Lees, Christoph; King, Rosalind H; Hargreaves, Iain P; Brown, Garry K; McFarland, Robert; Dean, Andrew F; Taylor, Robert W

    2015-07-01

    Autosomal recessive mutations in the RARS2 gene encoding the mitochondrial arginyl-transfer RNA synthetase cause infantile-onset myoencephalopathy pontocerebellar hypoplasia type 6 (PCH6). We describe 2 sisters with novel compound heterozygous RARS2 mutations who presented perinatally with neurologic features typical of PCH6 but with additional features including cardiomyopathy, hydrops, and pulmonary hypoplasia and who died at 1 day and 14 days of age. Magnetic resonance imaging findings included marked cerebellar hypoplasia, gyral immaturity, punctate lesions in cerebral white matter, and unfused deep cerebral grey matter. Enzyme histochemistry of postmortem tissues revealed a near-global cytochrome c oxidase-deficiency; assessment of respiratory chain enzyme activities confirmed severe deficiencies involving complexes I, III, and IV. Molecular genetic studies revealed 2 RARS2 gene mutations: a c.1A>G, p.? variant predicted to abolish the initiator methionine, and a deep intronic c.613-3927C>T variant causing skipping of exons 6-8 in the mature RARS2 transcript. Neuropathologic investigation included low brain weights, small brainstem and cerebellum, deep cerebral white matter pathology, pontine nucleus neuron loss (in 1 sibling), and peripheral nerve pathology. Mitochondrial respiratory chain immunohistochemistry in brain tissues confirmed an absence of complexes I and IV immunoreactivity with sparing of mitochondrial numbers. These cases expand the clinical spectrum of RARS2 mutations, including antenatal features and widespread mitochondrial respiratory chain deficiencies in postmortem brain tissues. PMID:26083569

  17. The chlorophyll-deficient golden leaf mutation in cucumber is due to a single nucleotide substitution in CsChlI for magnesium chelatase I subunit

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The chlorophyll gives the green color in plants. Any mutations in chloroplhyll biosynthesis or regulation may result in colr changes. Leaf color mutants are common in higher plants, which can be used as markers in crop breeding or as a tool in understanding regulatory mechanisms in chlorophyll biosy...

  18. Evolution of Mutation Rate in Asexual Populations

    NASA Astrophysics Data System (ADS)

    Wylie, Scott; Levine, Herbert; Kessler, David

    2007-03-01

    Several evolution experiments with E. coli document the spontaneous emergence and eventual fixation of so called ``mutator'' alleles that increase the genomic mutation rate by the order of 100-fold. Variations in mutation rates are due to polymorphisms in the molecular machinery that copies and checks the genome for errors. These polymorphisms are coded in the genome and thus heritable. Like any heritable trait, elevated mutation rates are subject to natural selection and evolution. However, unlike other traits, mutation rate does not directly affect the rate at which an organism reproduces, i.e. its fitness. Rather, it affects the statistical distribution of the offspring's fitness. This fitness distribution, in turn, leads via ``hitchhiking'' to a change in the frequency of the mutator allele, i.e. evolution of the mutation rate itself. In our work we simulate a birth-death process that approximates simple asexual populations and we measure the fixation probability of rare mutators. We then develop an approximate analytic model of the population dynamics, the results of which agree reasonably well with simulation. In particular, we are able to analytically predict the ``effective fitness'' of mutators and the conditions under which they are expected to emerge.

  19. Familial Isolated Pituitary Adenomas (FIPA) and the Pituitary Adenoma Predisposition due to Mutations in the Aryl Hydrocarbon Receptor Interacting Protein (AIP) Gene

    PubMed Central

    Aaltonen, Lauri A.; Daly, Adrian F.

    2013-01-01

    Pituitary adenomas are one of the most frequent intracranial tumors and occur with a prevalence of approximately 1:1000 in the developed world. Pituitary adenomas have a serious disease burden, and their management involves neurosurgery, biological therapies, and radiotherapy. Early diagnosis of pituitary tumors while they are smaller may help increase cure rates. Few genetic predictors of pituitary adenoma development exist. Recent years have seen two separate, complimentary advances in inherited pituitary tumor research. The clinical condition of familial isolated pituitary adenomas (FIPA) has been described, which encompasses the familial occurrence of isolated pituitary adenomas outside of the setting of syndromic conditions like multiple endocrine neoplasia type 1 and Carney complex. FIPA families comprise approximately 2% of pituitary adenomas and represent a clinical entity with homogeneous or heterogeneous pituitary adenoma types occurring within the same kindred. The aryl hydrocarbon receptor interacting protein (AIP) gene has been identified as causing a pituitary adenoma predisposition of variable penetrance that accounts for 20% of FIPA families. Germline AIP mutations have been shown to associate with the occurrence of large pituitary adenomas that occur at a young age, predominantly in children/adolescents and young adults. AIP mutations are usually associated with somatotropinomas, but prolactinomas, nonfunctioning pituitary adenomas, Cushing disease, and other infrequent clinical adenoma types can also occur. Gigantism is a particular feature of AIP mutations and occurs in more than one third of affected somatotropinoma patients. Study of pituitary adenoma patients with AIP mutations has demonstrated that these cases raise clinical challenges to successful treatment. Extensive research on the biology of AIP and new advances in mouse Aip knockout models demonstrate multiple pathways by which AIP may contribute to tumorigenesis. This review assesses

  20. Hypertriglyceridaemia and low plasma HDL in a patient with apolipoprotein A-V deficiency due to a novel mutation in the APOA5 gene.

    PubMed

    Priore Oliva, C; Carubbi, F; Schaap, F G; Bertolini, S; Calandra, S

    2008-04-01

    APOA5 encodes a novel apolipoprotein (apo A-V) which appears to be a modulator of plasma triglyceride (TG). In apoA5 knock out mice plasma TG level increases almost fourfold, whereas in human APOA5 transgenic mice it decreases by 70%. Some SNPs in the APOA5 gene have been associated with variations in plasma TG in humans. In addition, hypertriglyceridaemic (HTG) patients have been identified who carried rare nonsense mutations in the APOA5 gene (Q139X and Q148X), predicted to result in apo A-V deficiency. In this study we report a 17-year-old male with high TG and low high density lipoprotein cholesterol (HDL-C), who at the age of two had been found to have severe HTG and eruptive xanthomas suggesting a chylomicronaemia syndrome. Plasma postheparin LPL activity, however, was normal and no mutations were found in LPL and APOC2 genes. The sequence of APOA5 gene revealed that the patient was homozygous for a point mutation (c.289 C>T) in exon 4, converting glutamine codon at position 97 into a termination codon (Q97X). Apo A-V was not detected in patient's plasma, indicating that he had complete apo A-V deficiency. The administration of a low-fat and low-oligosaccharide diet, either alone or supplemented with omega-3 fatty acids, started early in life, reduced plasma TG to a great extent but had a negligible effect on plasma HDL-C. Loss of function mutations of APOA5 gene may be the cause of severe HTG in patients without mutations in LPL and APOC2 genes. PMID:18324930

  1. Heat resistance and salt hypersensitivity in Lactococcus lactis due to spontaneous mutation of llmg_1816 (gdpP) induced by high-temperature growth.

    PubMed

    Smith, William M; Pham, Thi Huong; Lei, Lin; Dou, Junchao; Soomro, Aijaz H; Beatson, Scott A; Dykes, Gary A; Turner, Mark S

    2012-11-01

    During construction of several gene deletion mutants in Lactococcus lactis MG1363 which involved a high-temperature (37.5°C) incubation step, additional spontaneous mutations were observed which resulted in stable heat resistance and in some cases salt-hypersensitive phenotypes. Whole-genome sequencing of one strain which was both heat resistant and salt hypersensitive, followed by PCR and sequencing of four other mutants which shared these phenotypes, revealed independent mutations in llmg_1816 in all cases. This gene encodes a membrane-bound stress signaling protein of the GdpP family, members of which exhibit cyclic dimeric AMP (c-di-AMP)-specific phosphodiesterase activity. Mutations were predicted to lead to single amino acid substitutions or protein truncations. An independent llmg_1816 mutant (Δ1816), created using a suicide vector, also displayed heat resistance and salt hypersensitivity phenotypes which could be restored to wild-type levels following plasmid excision. L. lactis Δ1816 also displayed improved growth in response to sublethal concentrations of penicillin G. High-temperature incubation of a wild-type industrial L. lactis strain also resulted in spontaneous mutation of llmg_1816 and heat-resistant and salt-hypersensitive phenotypes, suggesting that this is not a strain-specific phenomenon and that it is independent of a plasmid integration event. Acidification of milk by the llmg_1816-altered strain was inhibited by lower salt concentrations than the parent strain. This study demonstrates that spontaneous mutations can occur during high-temperature growth of L. lactis and that inactivation of llmg_1816 leads to temperature resistance and salt hypersensitivity.

  2. MCT8 mutation analysis and identification of the first female with Allan-Herndon-Dudley syndrome due to loss of MCT8 expression.

    PubMed

    Frints, Suzanna Gerarda Maria; Lenzner, Steffen; Bauters, Mareike; Jensen, Lars Riff; Van Esch, Hilde; des Portes, Vincent; Moog, Ute; Macville, Merryn Victor Erik; van Roozendaal, Kees; Schrander-Stumpel, Constance Theresia Rimbertha Maria; Tzschach, Andreas; Marynen, Peter; Fryns, Jean-Pierre; Hamel, Ben; van Bokhoven, Hans; Chelly, Jamel; Beldjord, Chérif; Turner, Gillian; Gecz, Jozef; Moraine, Claude; Raynaud, Martine; Ropers, Hans Hilger; Froyen, Guy; Kuss, Andreas Walter

    2008-09-01

    Mutations in the thyroid monocarboxylate transporter 8 gene (MCT8/SLC16A2) have been reported to result in X-linked mental retardation (XLMR) in patients with clinical features of the Allan-Herndon-Dudley syndrome (AHDS). We performed MCT8 mutation analysis including 13 XLMR families with LOD scores >2.0, 401 male MR sibships and 47 sporadic male patients with AHDS-like clinical features. One nonsense mutation (c.629insA) and two missense changes (c.1A>T and c.1673G>A) were identified. Consistent with previous reports on MCT8 missense changes, the patient with c.1673G>A showed elevated serum T3 level. The c.1A>T change in another patient affects a putative translation start codon, but the same change was present in his healthy brother. In addition normal serum T3 levels were present, suggesting that the c.1A>T (NM_006517) variation is not responsible for the MR phenotype but indicates that MCT8 translation likely starts with a methionine at position p.75. Moreover, we characterized a de novo translocation t(X;9)(q13.2;p24) in a female patient with full blown AHDS clinical features including elevated serum T3 levels. The MCT8 gene was disrupted at the X-breakpoint. A complete loss of MCT8 expression was observed in a fibroblast cell-line derived from this patient because of unfavorable nonrandom X-inactivation. Taken together, these data indicate that MCT8 mutations are not common in non-AHDS MR patients yet they support that elevated serum T3 levels can be indicative for AHDS and that AHDS clinical features can be present in female MCT8 mutation carriers whenever there is unfavorable nonrandom X-inactivation.

  3. Familial isolated pituitary adenomas (FIPA) and the pituitary adenoma predisposition due to mutations in the aryl hydrocarbon receptor interacting protein (AIP) gene.

    PubMed

    Beckers, Albert; Aaltonen, Lauri A; Daly, Adrian F; Karhu, Auli

    2013-04-01

    Pituitary adenomas are one of the most frequent intracranial tumors and occur with a prevalence of approximately 1:1000 in the developed world. Pituitary adenomas have a serious disease burden, and their management involves neurosurgery, biological therapies, and radiotherapy. Early diagnosis of pituitary tumors while they are smaller may help increase cure rates. Few genetic predictors of pituitary adenoma development exist. Recent years have seen two separate, complimentary advances in inherited pituitary tumor research. The clinical condition of familial isolated pituitary adenomas (FIPA) has been described, which encompasses the familial occurrence of isolated pituitary adenomas outside of the setting of syndromic conditions like multiple endocrine neoplasia type 1 and Carney complex. FIPA families comprise approximately 2% of pituitary adenomas and represent a clinical entity with homogeneous or heterogeneous pituitary adenoma types occurring within the same kindred. The aryl hydrocarbon receptor interacting protein (AIP) gene has been identified as causing a pituitary adenoma predisposition of variable penetrance that accounts for 20% of FIPA families. Germline AIP mutations have been shown to associate with the occurrence of large pituitary adenomas that occur at a young age, predominantly in children/adolescents and young adults. AIP mutations are usually associated with somatotropinomas, but prolactinomas, nonfunctioning pituitary adenomas, Cushing disease, and other infrequent clinical adenoma types can also occur. Gigantism is a particular feature of AIP mutations and occurs in more than one third of affected somatotropinoma patients. Study of pituitary adenoma patients with AIP mutations has demonstrated that these cases raise clinical challenges to successful treatment. Extensive research on the biology of AIP and new advances in mouse Aip knockout models demonstrate multiple pathways by which AIP may contribute to tumorigenesis. This review assesses

  4. Retinal degeneration associated with RDH12 mutations results from decreased 11-cis retinal synthesis due to disruption of the visual cycle.

    PubMed

    Thompson, Debra A; Janecke, Andreas R; Lange, Jessica; Feathers, Kecia L; Hübner, Christian A; McHenry, Christina L; Stockton, David W; Rammesmayer, Gabriele; Lupski, James R; Antinolo, Guillermo; Ayuso, Carmen; Baiget, Montserrat; Gouras, Peter; Heckenlively, John R; den Hollander, Anneke; Jacobson, Samuel G; Lewis, Richard A; Sieving, Paul A; Wissinger, Bernd; Yzer, Suzanne; Zrenner, Eberhart; Utermann, Gerd; Gal, Andreas

    2005-12-15

    Retinoid dehydrogenases/reductases catalyze key oxidation-reduction reactions in the visual cycle that converts vitamin A to 11-cis retinal, the chromophore of the rod and cone photoreceptors. It has recently been shown that mutations in RDH12, encoding a retinol dehydrogenase, result in severe and early-onset autosomal recessive retinal dystrophy (arRD). In a cohort of 1011 individuals diagnosed with arRD, we have now identified 20 different disease-associated RDH12 mutations, of which 16 are novel, in a total of 22 individuals (2.2%). Haplotype analysis suggested a founder mutation for each of the three common mutations: p.L99I, p.T155I and c.806_810delCCCTG. Patients typically presented with early disease that affected the function of both rods and cones and progressed to legal blindness in early adulthood. Eleven of the missense variants identified in our study exhibited profound loss of catalytic activity when expressed in transiently transfected COS-7 cells and assayed for ability to convert all-trans retinal to all-trans retinol. Loss-of-function appeared to result from decreased protein stability, as expression levels were significantly reduced. For the p.T49M variant, differing activity profiles were associated with each of the alleles of the common p.R161Q RDH12 polymorphism, suggesting that genetic background may act as a modifier of mutation effect. A locus (LCA3) for Leber congenital amaurosis, a severe, early-onset form of arRD, maps close to RDH12 on chromosome 14q24. Haplotype analysis in the family in which LCA3 was mapped excluded RDH12 as the LCA3 gene and thus suggests the presence of a novel arRD gene in this region.

  5. Level alterations of the 2f (1)-f (2) distortion product due to hypoxia in the guinea pig depend on the stimulus frequency.

    PubMed

    Olzowy, Bernhard; von Gleichenstein, Gregor; Canis, Martin; Plesnila, Nikolaus; Strieth, Sebastian; Deppe, Christoph; Mees, Klaus

    2010-03-01

    Increased intracranial pressure (ICP) is known to affect the levels of distortion product otoacoustic emissions (DPOAEs) in a frequency-specific manner. DPOAEs might, therefore, be used for monitoring the ICP non-invasively. Hypoxia can also cause alterations of DPOAE levels, which can be distinguished from ICP-related changes only, when their characteristics, in particular frequency specificity, are known in detail. DPOAEs at f (2) = 2, 4, 8, 12 and 16 kHz and oxygen saturation (SaO(2)) were continuously monitored in nine spontaneously breathing guinea pigs, anaesthetized by i.m. administration of midazolam, medetomidin and fentanyl, during the respiration of a gas mixture of N(2)O and O(2) containing either 30% O(2) or 13% O(2). Fourteen hypoxic intervals in eight animals were included into final data analysis. Characteristic hypoxic level alterations with a level decrease and a remarkable level destabilization during hypoxia, and a pronounced reversible level decrease after reoxygenation were observed at the frequencies of 4, 8 and 16 kHz. At 2 and 12 kHz, the only reproducible effect of hypoxia was an increased fluctuation of the DPOAE level, which was significantly less pronounced compared with the other frequencies (P < 0.05 for 12 vs. 16 and 8 kHz and for 2 vs. 16 kHz). DPOAE level alterations due to hypoxia depend on the frequency in guinea pigs. Studies in human are warranted to improve non-invasive ICP monitoring with DPOAE by the detection of hypoxia-related changes. PMID:19629511

  6. Severe early onset retinitis pigmentosa in a Moroccan patient with Heimler syndrome due to novel homozygous mutation of PEX1 gene.

    PubMed

    Ratbi, Ilham; Jaouad, Imane Cherkaoui; Elorch, Hamza; Al-Sheqaih, Nada; Elalloussi, Mustapha; Lyahyai, Jaber; Berraho, Amina; Newman, William G; Sefiani, Abdelaziz

    2016-10-01

    Heimler syndrome (HS) is a rare recessive disorder characterized by sensorineural hearing loss (SNHL), amelogenesis imperfecta, nail abnormalities, and occasional or late-onset retinal pigmentation. It is the mildest form known to date of peroxisome biogenesis disorder caused by hypomorphic mutations of PEX1 and PEX6 genes. We report on a second Moroccan family with Heimler syndrome with early onset, severe visual impairment and important phenotypic overlap with Usher syndrome. The patient carried a novel homozygous missense variant c.3140T > C (p.Leu1047Pro) of PEX1 gene. As standard biochemical screening of blood for evidence of a peroxisomal disorder did not provide a diagnosis in the individuals with HS, patients with SNHL and retinal pigmentation should have mutation analysis of PEX1 and PEX6 genes. PMID:27633571

  7. Severe early onset retinitis pigmentosa in a Moroccan patient with Heimler syndrome due to novel homozygous mutation of PEX1 gene.

    PubMed

    Ratbi, Ilham; Jaouad, Imane Cherkaoui; Elorch, Hamza; Al-Sheqaih, Nada; Elalloussi, Mustapha; Lyahyai, Jaber; Berraho, Amina; Newman, William G; Sefiani, Abdelaziz

    2016-10-01

    Heimler syndrome (HS) is a rare recessive disorder characterized by sensorineural hearing loss (SNHL), amelogenesis imperfecta, nail abnormalities, and occasional or late-onset retinal pigmentation. It is the mildest form known to date of peroxisome biogenesis disorder caused by hypomorphic mutations of PEX1 and PEX6 genes. We report on a second Moroccan family with Heimler syndrome with early onset, severe visual impairment and important phenotypic overlap with Usher syndrome. The patient carried a novel homozygous missense variant c.3140T > C (p.Leu1047Pro) of PEX1 gene. As standard biochemical screening of blood for evidence of a peroxisomal disorder did not provide a diagnosis in the individuals with HS, patients with SNHL and retinal pigmentation should have mutation analysis of PEX1 and PEX6 genes.

  8. Charcot-Marie-Tooth neuropathy due to a novel EGR2 gene mutation with mild phenotype--usefulness of human mapping chip linkage analysis in a Czech family.

    PubMed

    Safka Brožková, Dana; Nevšímalová, Soňa; Mazanec, Radim; Rautenstrauss, Bernd; Seeman, Pavel

    2012-08-01

    Charcot-Marie-Tooth neuropathies (CMT) are a group of clinically and genetically heterogeneous disorders of the peripheral nervous system. Selection of candidate disease genes for mutation analysis is sometimes difficult since more than 40 genes and loci are known to be associated with CMT neuropathies. Hence a Czech family Cz-CMT with demyelinating type of autosomal dominant CMT disease was investigated by genome-wide linkage analysis by means of single-nucleotide polymorphism (SNP) arrays. Among 35 regions with linkage, five carried known CMT genes. In the final result a novel early growth response 2 - missense mutation c.1235 A>G, p.Glu412Gly was found. Surprisingly, the more severely affected proband carried an additional heterozygous myelin protein zero variant p.Asp246Asn detected previously, which may modify the phenotype. However, this MPZ variant is benign in heterozygous state alone, because it is also carried by the patient's healthy father. PMID:22546699

  9. Impaired surface αβγ GABA(A) receptor expression in familial epilepsy due to a GABRG2 frameshift mutation.

    PubMed

    Tian, Mengnan; Mei, Davide; Freri, Elena; Hernandez, Ciria C; Granata, Tiziana; Shen, Wangzhen; Macdonald, Robert L; Guerrini, Renzo

    2013-02-01

    The purpose of the study was to explore the pathogenic mechanisms underlying generalized epilepsy and febrile seizures plus (GEFS+) in a family with a novel γ2 subunit gene (GABRG2) frameshift mutation. Four affected and one unaffected individuals carried a c.1329delC GABRG2 mutation resulting in a subunit [γ2S(S443delC)] with a modified and elongated carboxy-terminus that is different from that of the wildtype γ2S subunit. We expressed the wildtype γ2S subunit and the predicted mutant γ2S(S443delC) subunit cDNAs in HEK293T cells and performed immunoblotting, flow cytometry and electrophysiology studies. The mutant subunit was translated as a stable protein that was larger than the wildtype γ2S subunit and was retained in the ER and not expressed on the cell surface membrane, suggesting GABRG2 haploinsufficiency. Peak GABA-evoked currents recorded from cells cotransfected with wildtype α1 and β2 subunits and mutant γ2S subunits were significantly decreased and were comparable to α1β2 receptor currents. S443delC is the first GABR epilepsy mutation predicted to abolish the natural stop codon and produce a stop codon in the 3' UTR that leads to translation of an extended peptide. The GEFS+ phenotype observed in this family is likely caused by γ2S subunit loss-of-function and possibly to dominant-negative suppression of α1β2γ2 receptors. Many GABRG2 truncation mutations result in GEFS+, but the spectrum of phenotypic severity is wider, ranging from asymptomatic individuals to the Dravet syndrome. Mechanisms influencing the severity of the phenotype are therefore complex and difficult to correlate with its demonstrable functional effects.

  10. Expression of hepcidin and other iron-related genes in type 3 hemochromatosis due to a novel mutation in transferrin receptor-2

    PubMed Central

    Pelucchi, Sara; Mariani, Raffaella; Trombini, Paola; Coletti, Sabina; Pozzi, Matteo; Paolini, Valentina; Barisani, Donatella; Piperno, Alberto

    2009-01-01

    Transferrin receptor-2 (TFR2) regulates hepatic hepcidin secretion and when mutated causes type-3 hemochromatosis. No functional study is available in humans. We studied a 47 year-old woman with hemochromatosis. TFR2 DNA and its hepatic transcript were directly sequenced. Hepatic expression of hepcidin and other iron-related genes were measured by qRT-PCR. Urinary hepcidin was measured at baseline and after an oral iron challenge (ferrous sulfate, 65 mg) by SELDI-TOF-MS. A novel homozygous TFR2 mutation was identified in the splicing donor site of intron 4 (c.614+4 A>G) causing exon 4 skipping. Hepcidin and hemojuvelin expression were markedly reduced. Urinary hepcidin was lower than normal and further decreased after iron challenge. This is the first description of iron-related gene expression profiles in a TFR2 mutated patient. The decreased hepatic and urinary expression of hepcidin and lack of acute response to iron challenge confirms the primary role of TFR2 in iron homeostasis. PMID:19144662

  11. The application of minisatellite variant repeat mapping by PCR (MVR-PCR) in a paternity case showing false exclusion due to STR mutation.

    PubMed

    Yamamoto, T; Tamaki, K; Huang, X L; Yoshimoto, T; Mizutani, M; Uchihi, R; Katsumata, Y; Jeffreys, A J

    2001-03-01

    A boy and a girl with their mother brought a paternity suit against an alleged but deceased father. We tested six conventional genetic markers, the AmpliType PM+ DQA1 and twelve STR loci the children and mother together with the alleged paternal grandparents. We also DNA typed the bloodstain found later in the alleged father's medical record. Only the result at D3S1358 in a nineplex STR system excluded the alleged father from parentage of the boy, whereas all markers were inclusive for the girl. Accordingly, we performed sequence analysis at D3S1358 to confirm the presence of a paternal exclusion or mutation. The sequence analysis indicated that the boy's allele 17 could have originated from either of the alleged father's allele 16 or 18 by a single-step mutation associated with slippage mutation in STR loci. We carried out minisatellite variant repeat mapping by PCR (MVR-PCR) at loci D1S8 (MS32) and D7S21 (MS31A) and mapped allele haplotypes of all individuals except the deceased alleged father. The MVR-PCR analysis showed that the boy has no inconsistency with the relationship between the alleged grandparents, and was very effective at increasing the paternity index (PI) value. We conclude that there is biological relationship between not only the girl but also the boy and the alleged father. PMID:11305445

  12. Adrenocorticotropin-dependent precocious puberty of testicular origin in a boy with X-linked adrenal hypoplasia congenita due to a novel mutation in the DAX1 gene.

    PubMed

    Domenice, S; Latronico, A C; Brito, V N; Arnhold, I J; Kok, F; Mendonca, B B

    2001-09-01

    Primary adrenal insufficiency is a rare condition in pediatric age, and its association with precocious sexual development is very uncommon. We report a 2-yr-old Brazilian boy with DAX1 gene mutation whose first clinical manifestation was isosexual gonadotropin-independent precocious puberty. He presented with pubic hair, enlarged penis and testes, and advanced bone age. T levels were elevated, whereas basal and GnRH-stimulated LH levels were compatible with a prepubertal pattern. Chronic GnRH agonist therapy did not reduce T levels, supporting the diagnosis of gonadotropin-independent precocious puberty. Testotoxicosis was ruled out after normal sequencing of exon 11 of the LH receptor gene. At age 3 yr he developed clinical and hormonal features of severe primary adrenal insufficiency. The entire coding region of the DAX1 gene was analyzed through direct sequencing. A nucleotide G insertion between nucleotides 430 and 431 in exon 1, resulting in a novel frameshift mutation and a premature stop codon at position 71 of DAX-1, was identified. Surprisingly, steroid replacement therapy induced a clear decrease in testicular size and T levels to the prepubertal range. These findings suggest that chronic excessive ACTH levels resulting from adrenal insufficiency may stimulate Leydig cells and lead to gonadotropin-independent precocious puberty in some boys with DAX1 gene mutations. PMID:11549627

  13. Maternal Hypercalcemia Due to Failure of 1,25-Dihydroxyvitamin-D3 Catabolism in a Patient With CYP24A1 Mutations

    PubMed Central

    Hsiao, Edward C.; O'Donnell, Betsy; Salmeen, Kirsten; Nussbaum, Robert; Krebs, Michael; Baumgartner-Parzer, Sabina; Kaufmann, Martin; Jones, Glenville; Bikle, Daniel D.; Wang, YongMei; Mathew, Allen S.; Shoback, Dolores; Block-Kurbisch, Ingrid

    2015-01-01

    Context: Calcium metabolism changes in pregnancy and lactation to meet fetal needs, with increases in 1,25-dihydroxyvitamin D [1,25-(OH)2D] during pregnancy playing an important role. However, these changes rarely cause maternal hypercalcemia. When maternal hypercalcemia occurs, further investigation is essential, and disorders of 1,25-(OH)2D catabolism should be carefully considered in the differential diagnosis. Case: A patient with a childhood history of recurrent renal stone disease and hypercalciuria presented with recurrent hypercalcemia and elevated 1,25-(OH)2D levels during pregnancy. Laboratory tests in the fourth pregnancy showed suppressed PTH, elevated 1,25-(OH)2D, and high-normal 25-hydroxyvitamin D levels, suggesting disordered vitamin D metabolism. Analysis revealed low 24,25-dihydroxyvitamin D3 and high 25-hydroxyvitamin D3 levels, suggesting loss of function of CYP24A1 (25-hydroxyvitamin-D3-24-hydroxylase). Gene sequencing confirmed that she was a compound heterozygote with the E143del and R396W mutations in CYP24A1. Conclusions: This case broadens presentations of CYP24A1 mutations and hypercalcemia in pregnancy. Furthermore, it illustrates that patients with CYP24A1 mutations can maintain normal calcium levels during the steady state but can develop hypercalcemia when challenged, such as in pregnancy when 1,25-(OH)2D levels are physiologically elevated. PMID:26097993

  14. Human Preosteoblastic Cell Culture from a Patient with Severe Tumoral Calcinosis-Hyperphosphatemia Due to a New GALNT3 Gene Mutation: Study of In Vitro Mineralization.

    PubMed

    Masi, L; Beltrami, G; Ottanelli, S; Franceschelli, F; Gozzini, A; Zonefrati, R; Galli, G; Ciuffi, S; Mavilia, C; Giusti, F; Marcucci, G; Cioppi, F; Colli, E; Fossi, C; Franchi, A; Casentini, C; Capanna, R; Brandi, Maria Luisa

    2015-05-01

    Human disorders of phosphate (Pi) handling and skeletal mineralization represent a group of rare bone diseases. One of these disease is tumoral calcinosis (TC). In this study, we present the case of a patient with TC with a new GALNT3 gene mutation. We also performed functional studies using an in vitro cellular model. Genomic DNA was extracted from peripheral blood collected from a teenage Caucasian girl affected by TC, and from her parents. A higher capability to form mineralization nodules in vitro was found in human preosteoblastic cells of mutant when compared to wild-type controls. We found a novel homozygous inactivating splice site mutation in intron I (c.516-2a>g). A higher capability to form mineralization nodules in vitro was found in the mutant cells in human preosteoblastic cells when compared to wild-type controls. Understanding the functional significance and molecular physiology of this novel mutation will help to define the role of FGF23 in the control of Pi homeostasis in normal and in pathological conditions. PMID:25899975

  15. Rapid in vitro selection of human immunodeficiency virus type 1 resistant to 3'-thiacytidine inhibitors due to a mutation in the YMDD region of reverse transcriptase.

    PubMed Central

    Tisdale, M; Kemp, S D; Parry, N R; Larder, B A

    1993-01-01

    Resistant variants of human immunodeficiency virus type 1 (HIV-1) have been selected by limited passage in MT4 cells of both wild-type and 3'-azido-3'-deoxythymidine (AZT, zidovudine)-resistant strains with the nucleoside analogues (-)-2'-deoxy-3'-thiacytidine (3TC) and (-)-2'-deoxy-5-fluoro-3'-thiacytidine (FTC). Virus variants selected independently were crossresistant to both inhibitors. This rapid in vitro selection of resistant virus has not previously been seen with nucleoside analogues but is reminiscent of that observed with the nonnucleoside reverse transcriptase inhibitors. However, passage of wild-type virus with a combination of AZT and FTC appreciably delayed emergence of FTC-resistant virus. DNA sequence analysis of the reverse transcriptase coding region from FTC-resistant virus revealed changes at codon 184 in the highly conserved Tyr, Met, Asp, Asp (YMDD) region. When the mutation Met184-->Val was introduced into the infectious clone HXB2, this change alone accounted for the resistance (> 1000-fold) seen with both 3TC and FTC, and for a 5- to 15-fold reduction in sensitivity to their (+) enantiomers. It had no effect on susceptibility to AZT or nevirapine and minimal effect on susceptibility to 2',3'-dideoxyinosine and 2',3'-dideoxycytidine. To determine the influence of this mutation in a background of mutations conferring resistance to AZT and nonnucleoside reverse transcriptase inhibitors, a series of HIV-1 variants were created by site-directed mutagenesis. All mutants with Met184-->Val were cross-resistant to 3TC and FTC. The Met184-->Val mutation did not influence nevirapine resistance, but resistance to AZT was suppressed. Similar suppression of AZT resistance was seen with Tyr181-->Cys. Interestingly, when both Met184-->Val and Tyr181-->Cys substitutions were present, highly resistant virus reverted to complete AZT sensitivity. Assessment of the interactive effects of multiple drug-resistance mutations may help to establish a rationale for

  16. Bladder Cancer and Genetic Mutations.

    PubMed

    Zhang, Xiaoying; Zhang, Yangde

    2015-09-01

    The most common type of urinary bladder cancer is called as transitional cell carcinoma. The major risk factors for bladder cancer are environmental, tobacco smoking, exposure to toxic industrial chemicals and gases, bladder inflammation due to microbial and parasitic infections, as well as some adverse side-effects of medications. The genetic mutations in some chromosomal genes, such as FGFR3, RB1, HRAS, TP53, TSC1, and others, occur which form tumors in the urinary bladder. These genes play an important role in the regulation of cell division which prevents cells from dividing too quickly. The changes in the genes of human chromosome 9 are usually responsible for tumor in bladder cancer, but the genetic mutation of chromosome 22 can also result in bladder cancer. The identification of p53 gene mutation has been studied at NIH, Washington, DC, USA, in urine samples of bladder cancer patients. The invasive blad