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Sample records for 8-oxoguanine-repair-deficient mutator phenotype

  1. The new mutation theory of phenotypic evolution

    PubMed Central

    Nei, Masatoshi

    2007-01-01

    Recent studies of developmental biology have shown that the genes controlling phenotypic characters expressed in the early stage of development are highly conserved and that recent evolutionary changes have occurred primarily in the characters expressed in later stages of development. Even the genes controlling the latter characters are generally conserved, but there is a large component of neutral or nearly neutral genetic variation within and between closely related species. Phenotypic evolution occurs primarily by mutation of genes that interact with one another in the developmental process. The enormous amount of phenotypic diversity among different phyla or classes of organisms is a product of accumulation of novel mutations and their conservation that have facilitated adaptation to different environments. Novel mutations may be incorporated into the genome by natural selection (elimination of preexisting genotypes) or by random processes such as genetic and genomic drift. However, once the mutations are incorporated into the genome, they may generate developmental constraints that will affect the future direction of phenotypic evolution. It appears that the driving force of phenotypic evolution is mutation, and natural selection is of secondary importance. PMID:17640887

  2. A multiple phenotype predator-prey model with mutation

    NASA Astrophysics Data System (ADS)

    Abernethy, Gavin M.; Mullan, Rory; Glass, David H.; McCartney, Mark

    2017-01-01

    An existing multiple phenotype predator-prey model is expanded to include mutation amongst the predator phenotypes. Two unimodal maps are used for the underlying dynamics of the prey. A predation strategy is also defined which differs for each of the predators in the model. Results show that the introduction of predator mutation enhances predator survival both in terms of the number of phenotypes and total population for a range of values of the predation rate. In general, the dominant predator phenotype is the one which is most focused on the prey phenotype with the largest population.

  3. Cardiac sodium channel mutations: why so many phenotypes?

    PubMed Central

    Liu, Man; Yang, Kai-Chien; Dudley, Samuel C.

    2016-01-01

    Mutations of the cardiac sodium channel (Nav1.5) can induce gain or loss of channel function. Gain-of-function mutations can cause long QT syndrome type 3 and possibly atrial fibrillation, whereas loss-of-function mutations are associated with a variety of phenotypes, such as Brugada syndrome, cardiac conduction disease, sick sinus syndrome, and possibly dilated cardiomyopathy. The phenotypes produced by Nav1.5 mutations vary according to the direct effect of the mutation on channel biophysics, but also with age, sex, body temperature, and between regions of the heart. This phenotypic variability makes genotype–phenotype correlations difficult. In this Perspectives article, we propose that phenotypic variability not ascribed to mutation-dependent changes in channel function might be the result of additional modifiers of channel behaviour, such as other genetic variation and alterations in transcription, RNA processing, translation, post-translational modifications, and protein degradation. Consideration of these modifiers might help to improve genotype–phenotype correlations and lead to new therapeutic strategies. PMID:24958080

  4. IDH mutations: genotype-phenotype correlation and prognostic impact.

    PubMed

    Wang, Xiao-Wei; Ciccarino, Pietro; Rossetto, Marta; Boisselier, Blandine; Marie, Yannick; Desestret, Virginie; Gleize, Vincent; Mokhtari, Karima; Sanson, Marc; Labussière, Marianne

    2014-01-01

    IDH1/2 mutation is the most frequent genomic alteration found in gliomas, affecting 40% of these tumors and is one of the earliest alterations occurring in gliomagenesis. We investigated a series of 1305 gliomas and showed that IDH mutation is almost constant in 1p19q codeleted tumors. We found that the distribution of IDH1(R132H) , IDH1(nonR132H) , and IDH2 mutations differed between astrocytic, mixed, and oligodendroglial tumors, with an overrepresentation of IDH2 mutations in oligodendroglial phenotype and an overrepresentation of IDH1(nonR132H) in astrocytic tumors. We stratified grade II and grade III gliomas according to the codeletion of 1p19q and IDH mutation to define three distinct prognostic subgroups: 1p19q and IDH mutated, IDH mutated--which contains mostly TP53 mutated tumors, and none of these alterations. We confirmed that IDH mutation with a hazard ratio = 0.358 is an independent prognostic factor of good outcome. These data refine current knowledge on IDH mutation prognostic impact and genotype-phenotype associations.

  5. Weaver syndrome and EZH2 mutations: Clarifying the clinical phenotype.

    PubMed

    Tatton-Brown, Katrina; Murray, Anne; Hanks, Sandra; Douglas, Jenny; Armstrong, Ruth; Banka, Siddharth; Bird, Lynne M; Clericuzio, Carol L; Cormier-Daire, Valerie; Cushing, Tom; Flinter, Frances; Jacquemont, Marie-Line; Joss, Shelagh; Kinning, Esther; Lynch, Sally Ann; Magee, Alex; McConnell, Vivienne; Medeira, Ana; Ozono, Keiichi; Patton, Michael; Rankin, Julia; Shears, Debbie; Simon, Marleen; Splitt, Miranda; Strenger, Volker; Stuurman, Kyra; Taylor, Clare; Titheradge, Hannah; Van Maldergem, Lionel; Temple, I Karen; Cole, Trevor; Seal, Sheila; Rahman, Nazneen

    2013-12-01

    Weaver syndrome, first described in 1974, is characterized by tall stature, a typical facial appearance, and variable intellectual disability. In 2011, mutations in the histone methyltransferase, EZH2, were shown to cause Weaver syndrome. To date, we have identified 48 individuals with EZH2 mutations. The mutations were primarily missense mutations occurring throughout the gene, with some clustering in the SET domain (12/48). Truncating mutations were uncommon (4/48) and only identified in the final exon, after the SET domain. Through analyses of clinical data and facial photographs of EZH2 mutation-positive individuals, we have shown that the facial features can be subtle and the clinical diagnosis of Weaver syndrome is thus challenging, especially in older individuals. However, tall stature is very common, reported in >90% of affected individuals. Intellectual disability is also common, present in ~80%, but is highly variable and frequently mild. Additional clinical features which may help in stratifying individuals to EZH2 mutation testing include camptodactyly, soft, doughy skin, umbilical hernia, and a low, hoarse cry. Considerable phenotypic overlap between Sotos and Weaver syndromes is also evident. The identification of an EZH2 mutation can therefore provide an objective means of confirming a subtle presentation of Weaver syndrome and/or distinguishing Weaver and Sotos syndromes. As mutation testing becomes increasingly accessible and larger numbers of EZH2 mutation-positive individuals are identified, knowledge of the clinical spectrum and prognostic implications of EZH2 mutations should improve.

  6. Atypical phenotype in two patients with LAMA2 mutations.

    PubMed

    Marques, Joana; Duarte, Sofia T; Costa, Sónia; Jacinto, Sandra; Oliveira, Jorge; Oliveira, Márcia E; Santos, Rosário; Bronze-da-Rocha, Elsa; Silvestre, Ana Rita; Calado, Eulália; Evangelista, Teresinha

    2014-05-01

    Congenital muscular dystrophy type 1A is caused by mutations in the LAMA2 gene, which encodes the α2-chain of laminin. We report two patients with partial laminin-α2 deficiency and atypical phenotypes, one with almost exclusive central nervous system involvement (cognitive impairment and refractory epilepsy) and the second with marked cardiac dysfunction, rigid spine syndrome and limb-girdle weakness. Patients underwent clinical, histopathological, imaging and genetic studies. Both cases have two heterozygous LAMA2 variants sharing a potentially pathogenic missense mutation c.2461A>C (p.Thr821Pro) located in exon 18. Brain MRI was instrumental for the diagnosis, since muscular examination and motor achievements were normal in the first patient and there was a severe cardiac involvement in the second. The clinical phenotype of the patients is markedly different which could in part be explained by the different combination of mutations types (two missense versus a missense and a truncating mutation).

  7. Genotypes and phenotypes of 162 families with a glomulin mutation.

    PubMed

    Brouillard, P; Boon, L M; Revencu, N; Berg, J; Dompmartin, A; Dubois, J; Garzon, M; Holden, S; Kangesu, L; Labrèze, C; Lynch, S A; McKeown, C; Meskauskas, R; Quere, I; Syed, S; Vabres, P; Wassef, M; Mulliken, J B; Vikkula, M

    2013-04-01

    A decade ago, we identified a novel gene, glomulin (GLMN) in which mutations cause glomuvenous malformations (GVMs). GVMs are bluish-purple cutaneous vascular lesions with characteristic glomus cells in the walls of distended venous channels. The discovery of the genetic basis for GVMs allowed the definition of clinical features to distinguish GVMs from other venous anomalies. The variation in phenotype was also highlighted: from a single punctate blue dot to a large plaque-like lesion. In this study, we screened GLMN in a large cohort of patients to broaden the spectrum of mutations, define their frequency and search for possible genotype-phenotype correlations. Taking into account 6 families published by others, a mutation in GLMN has been found in 162 families. This represents 40 different mutations; the most frequent one being present in almost 45% of them. Expressivity varies largely, without a genotype/phenotype relationship. Among 381 individuals with a mutation, we discovered 37 unaffected carriers, implying a penetrance of 90%. As nonpenetrant individuals may transmit the disease to their descendants, knowledge on the mutational status is needed for appropriate genetic counseling.

  8. Genotypes and Phenotypes of 162 Families with a Glomulin Mutation

    PubMed Central

    Brouillard, P.; Boon, L.M.; Revencu, N.; Berg, J.; Dompmartin, A.; Dubois, J.; Garzon, M.; Holden, S.; Kangesu, L.; Labrèze, C.; Lynch, S.A.; McKeown, C.; Meskauskas, R.; Quere, I.; Syed, S.; Vabres, P.; Wassef, M.; Mulliken, J.B.; Vikkula, M.

    2013-01-01

    A decade ago, we identified a novel gene, glomulin (GLMN) in which mutations cause glomuvenous malformations (GVMs). GVMs are bluish-purple cutaneous vascular lesions with characteristic glomus cells in the walls of distended venous channels. The discovery of the genetic basis for GVMs allowed the definition of clinical features to distinguish GVMs from other venous anomalies. The variation in phenotype was also highlighted: from a single punctate blue dot to a large plaque-like lesion. In this study, we screened GLMN in a large cohort of patients to broaden the spectrum of mutations, define their frequency and search for possible genotype-phenotype correlations. Taking into account 6 families published by others, a mutation in GLMN has been found in 162 families. This represents 40 different mutations; the most frequent one being present in almost 45% of them. Expressivity varies largely, without a genotype/phenotype relationship. Among 381 individuals with a mutation, we discovered 37 unaffected carriers, implying a penetrance of 90%. As nonpenetrant individuals may transmit the disease to their descendants, knowledge on the mutational status is needed for appropriate genetic counseling. PMID:23801931

  9. CMT4D (NDRG1 mutation): genotype-phenotype correlations.

    PubMed

    Ricard, Emilie; Mathis, Stéphane; Magdelaine, Corinne; Delisle, Marie-Bernadette; Magy, Laurent; Funalot, Benoît; Vallat, Jean-Michel

    2013-09-01

    Charcot-Marie-Tooth (CMT) disease is a heterogeneous condition with a large number of clinical, electrophysiological and pathological phenotypes. More than 40 genes are involved. We report a child of gypsy origin with an autosomal recessive demyelinating phenotype. Clinical data, familial history, and electrophysiological studies were in favor of a CMT4 sub-type. The characteristic N-Myc downstream-regulated gene 1 (NDRG1) mutation responsible for this CMT4D phenotype was confirmed: p.R148X. The exact molecular function of the NDRG1 protein has yet to be elucidated.

  10. FOXL2 and BPES: mutational hotspots, phenotypic variability, and revision of the genotype-phenotype correlation.

    PubMed

    De Baere, Elfride; Beysen, Diane; Oley, Christine; Lorenz, Birgit; Cocquet, Julie; De Sutter, Paul; Devriendt, Koen; Dixon, Michael; Fellous, Marc; Fryns, Jean-Pierre; Garza, Arturo; Jonsrud, Christoffer; Koivisto, Pasi A; Krause, Amanda; Leroy, Bart P; Meire, Françoise; Plomp, Astrid; Van Maldergem, Lionel; De Paepe, Anne; Veitia, Reiner; Messiaen, Ludwine

    2003-02-01

    Blepharophimosis syndrome (BPES), an autosomal dominant syndrome in which an eyelid malformation is associated (type I) or not (type II) with premature ovarian failure (POF), has recently been ascribed to mutations in FOXL2, a putative forkhead transcription factor gene. We previously reported 22 FOXL2 mutations and suggested a preliminary genotype-phenotype correlation. Here, we describe 21 new FOXL2 mutations (16 novel ones) through sequencing of open reading frame, 5' untranslated region, putative core promoter, and fluorescence in situ hybridization analysis. Our study shows the existence of two mutational hotspots: 30% of FOXL2 mutations lead to polyalanine (poly-Ala) expansions, and 13% are a novel out-of-frame duplication. In addition, this is the first study to demonstrate intra- and interfamilial phenotypic variability (both BPES types caused by the same mutation). Furthermore, the present study allows a revision of the current genotype-phenotype correlation, since we found exceptions to it. We assume that for predicted proteins with a truncation before the poly-Ala tract, the risk for development of POF is high. For mutations leading to a truncated or extended protein containing an intact forkhead and poly-Ala tract, no predictions are possible, since some of these mutations lead to both types of BPES, even within the same family. Poly-Ala expansions may lead to BPES type II. For missense mutations, no correlations can be made yet. Microdeletions are associated with mental retardation. We conclude that molecular testing may be carefully used as a predictor for POF risk in a limited number of mutations.

  11. Novel SCN9A mutations underlying extreme pain phenotypes: unexpected electrophysiological and clinical phenotype correlations.

    PubMed

    Emery, Edward C; Habib, Abdella M; Cox, James J; Nicholas, Adeline K; Gribble, Fiona M; Woods, C Geoffrey; Reimann, Frank

    2015-05-20

    The importance of NaV1.7 (encoded by SCN9A) in the regulation of pain sensing is exemplified by the heterogeneity of clinical phenotypes associated with its mutation. Gain-of-function mutations are typically pain-causing and have been associated with inherited erythromelalgia (IEM) and paroxysmal extreme pain disorder (PEPD). IEM is usually caused by enhanced NaV1.7 channel activation, whereas mutations that alter steady-state fast inactivation often lead to PEPD. In contrast, nonfunctional mutations in SCN9A are known to underlie congenital insensitivity to pain (CIP). Although well documented, the correlation between SCN9A genotypes and clinical phenotypes is still unclear. Here we report three families with novel SCN9A mutations. In a multiaffected dominant family with IEM, we found the heterozygous change L245 V. Electrophysiological characterization showed that this mutation did not affect channel activation but instead resulted in incomplete fast inactivation and a small hyperpolarizing shift in steady-state slow inactivation, characteristics more commonly associated with PEPD. In two compound heterozygous CIP patients, we found mutations that still retained functionality of the channels, with two C-terminal mutations (W1775R and L1831X) exhibiting a depolarizing shift in channel activation. Two mutations (A1236E and L1831X) resulted in a hyperpolarizing shift in steady-state fast inactivation. To our knowledge, these are the first descriptions of mutations with some retained channel function causing CIP. This study emphasizes the complex genotype-phenotype correlations that exist for SCN9A and highlights the C-terminal cytoplasmic region of NaV1.7 as a critical region for channel function, potentially facilitating analgesic drug development studies.

  12. HRAS mutation analysis in Costello syndrome: genotype and phenotype correlation.

    PubMed

    Gripp, Karen W; Lin, Angela E; Stabley, Deborah L; Nicholson, Linda; Scott, Charles I; Doyle, Daniel; Aoki, Yoko; Matsubara, Yoichi; Zackai, Elaine H; Lapunzina, Pablo; Gonzalez-Meneses, Antonio; Holbrook, Jennifer; Agresta, Cynthia A; Gonzalez, Iris L; Sol-Church, Katia

    2006-01-01

    Costello syndrome is a rare condition comprising mental retardation, distinctive facial appearance, cardiovascular abnormalities (typically pulmonic stenosis, hypertrophic cardiomyopathy, and/or atrial tachycardia), tumor predisposition, and skin and musculoskeletal abnormalities. Recently mutations in HRAS were identified in 12 Japanese and Italian patients with clinical information available on 7 of the Japanese patients. To expand the molecular delineation of Costello syndrome, we performed mutation analysis in 34 North American and 6 European (total 40) patients with Costello syndrome, and detected missense mutations in HRAS in 33 (82.5%) patients. All mutations affected either codon 12 or 13 of the protein product, with G12S occurring in 30 (90.9%) patients of the mutation-positive cases. In two patients, we found a mutation resulting in an alanine substitution in position 12 (G12A), and in one patient, we detected a novel mutation (G13C). Five different HRAS mutations have now been reported in Costello syndrome, however genotype-phenotype correlation remains incomplete.

  13. Fragile X mutation and FG syndrome-like phenotype

    SciTech Connect

    Piussan, C.; Mathieu, M.; Berquin, P.

    1996-08-09

    We present data on 4 mentally retarded brothers, 2 of whom were dizygotic twins with congenital hypotonia, constipation, head size disproportionately large for length or height, and a combination of minor anomalies suggestive of FG syndrome. These brothers have a mentally retarded full sister with similar minor anomalies and an older half-brother with the Martin-Bell syndrome. The mother is mentally retarded; 4 of 7 individuals are positive for fragile X, but all have a CGG expansion ranging from 0.2-2 to 4 kb. Although the phenotype is not completely typical of the FG syndrome and the coincidence of the FMR1 mutation and segregation of the MCA/MR phenotype are highly unlikely, the FMR1 mutation may affect morphogenesis more extensively and differently than the Martin-Bell syndrome does to effect an FG syndrome-like phenotype in certain families. This phenotype does not appear to be a contiguous gene syndrome, but an effect of the FMR1 mutation on an adjacent gene must be considered. 18 refs., 4 figs.

  14. FKRP mutations, including a founder mutation, cause phenotype variability in Chinese patients with dystroglycanopathies.

    PubMed

    Fu, Xiaona; Yang, Haipo; Wei, Cuijie; Jiao, Hui; Wang, Shuo; Yang, Yanling; Han, Chunxi; Wu, Xiru; Xiong, Hui

    2016-12-01

    Mutations in the fukutin-related protein (FKRP) gene have been associated with dystroglycanopathies, which are common in Europe but rare in Asia. Our study aimed to retrospectively analyze and characterize the clinical, myopathological and genetic features of 12 Chinese patients with FKRP mutations. Three patients were diagnosed with congenital muscular dystrophy type 1C (MDC1C) and nine patients were diagnosed with limb girdle muscular dystrophy type 2I (LGMD2I). Three muscle biopsy specimens had dystrophic changes and reduced glycosylated α-dystroglycan staining, and two showed reduced expression of laminin α2. Two known and 13 novel mutations were identified in our single center cohort. Interestingly, the c.545A>G mutation was found in eight of the nine LGMD2I patients as a founder mutation and this founder mutation in Chinese patients differs from the one seen in European patients. Moreover, patients homozygous for the c.545A>G mutation were clinically asymptomatic, a less severe phenotype than in compound heterozygous patients with the c.545A>G mutation. The 13 novel mutations of FKRP significantly expanded the mutation spectrum of MDC1C and LGMD2I, and the different founder mutations indicate the ethnic difference in FKRP mutations.

  15. Phenotypic effect of mutations in evolving populations of RNA molecules

    PubMed Central

    2010-01-01

    Background The secondary structure of folded RNA sequences is a good model to map phenotype onto genotype, as represented by the RNA sequence. Computational studies of the evolution of ensembles of RNA molecules towards target secondary structures yield valuable clues to the mechanisms behind adaptation of complex populations. The relationship between the space of sequences and structures, the organization of RNA ensembles at mutation-selection equilibrium, the time of adaptation as a function of the population parameters, the presence of collective effects in quasispecies, or the optimal mutation rates to promote adaptation all are issues that can be explored within this framework. Results We investigate the effect of microscopic mutations on the phenotype of RNA molecules during their in silico evolution and adaptation. We calculate the distribution of the effects of mutations on fitness, the relative fractions of beneficial and deleterious mutations and the corresponding selection coefficients for populations evolving under different mutation rates. Three different situations are explored: the mutation-selection equilibrium (optimized population) in three different fitness landscapes, the dynamics during adaptation towards a goal structure (adapting population), and the behavior under periodic population bottlenecks (perturbed population). Conclusions The ratio between the number of beneficial and deleterious mutations experienced by a population of RNA sequences increases with the value of the mutation rate μ at which evolution proceeds. In contrast, the selective value of mutations remains almost constant, independent of μ, indicating that adaptation occurs through an increase in the amount of beneficial mutations, with little variations in the average effect they have on fitness. Statistical analyses of the distribution of fitness effects reveal that small effects, either beneficial or deleterious, are well described by a Pareto distribution. These results

  16. Genotype-Phenotype Correlations by Ethnicity and Mutation Location in BRCA Mutation Carriers.

    PubMed

    Bayraktar, Soley; Jackson, Michelle; Gutierrez-Barrera, Angelica M; Liu, Diane; Meric-Bernstam, Funda; Brandt, Amanda; Woodson, Ashley; Litton, Jennifer; Lu, Karen H; Valero, Vicente; Arun, Banu K

    2015-01-01

    The genotype-phenotype correlations of the specific BRCA1 and BRCA2 mutations in multi-ethnic populations in USA have not yet been fully investigated. This study was designed to evaluate the effects of ethnicity at specific mutation locations and breast/ovarian cancer phenotypes. Our cohort included 445 women with different ethnic backgrounds who underwent BRCA genetic testing between 1997 and 2010. Known clinical and pathologic characteristics were compared with Chi-Square Analysis or Fisher's Exact test as appropriate. The three most common mutation locations in BRCA1 (exons 2, 11, and 20) and BRCA2 (exons 10, 11, and 25) genes were chosen. Prevalence of BRCA1 exon 2 mutations were significantly higher in Ashkenazi Jewish (AJ) women compared to Caucasians (41% versus 15%; p = 0.001). Similarly, AJ women with breast cancer were more likely to have BRCA1 exon 2 mutation (47% positivity in AJ women versus 0-12.5% positivity in other ethnicities; p = 0.004). Women carrying the exon 20 BRCA1 mutation had the highest probability of having combined breast and ovarian cancers compared to women carrying other exon mutations (p = 0.05). The median age at initial cancer diagnosis, phenotypic features of breast cancer tumors, and overall survival did not vary significantly by ethnicity or mutation location. Our data suggest that ethnicity does not affect age of onset, overall survival or confer different risks of breast and ovarian cancer development in BRCA carriers. These results also suggest that women carrying the exon 20 BRCA1 mutation may warrant mutation-specific counseling and be more aggressively managed for risk reduction.

  17. Mutator phenotype of MUTYH-null mouse embryonic stem cells.

    PubMed

    Hirano, Seiki; Tominaga, Yohei; Ichinoe, Akimasa; Ushijima, Yasuhiro; Tsuchimoto, Daisuke; Honda-Ohnishi, Yoko; Ohtsubo, Toshio; Sakumi, Kunihiko; Nakabeppu, Yusaku

    2003-10-03

    To evaluate the antimutagenic role of a mammalian mutY homolog, namely the Mutyh gene, which encodes adenine DNA glycosylase excising adenine misincorporated opposite 8-oxoguanine in the template DNA, we generated MUTYH-null mouse embryonic stem (ES) cells. In the MUTYH-null cells carrying no adenine DNA glycosylase activity, the spontaneous mutation rate increased 2-fold in comparison with wild type cells. The expression of wild type mMUTYH or mutant mMUTYH protein with amino acid substitutions at the proliferating cell nuclear antigen binding motif restored the increased spontaneous mutation rates of the MUTYH-null ES cells to the wild type level. The expression of a mutant mMUTYH protein with an amino acid substitution (G365D) that corresponds to a germ-line mutation (G382D) found in patients with multiple colorectal adenomas could not suppress the elevated spontaneous mutation rate of the MUTYH-null ES cells. Although the recombinant mMUTYH(G365D) purified from Escherichia coli cells had a substantial level of adenine DNA glycosylase activity as did wild type MUTYH, no adenine DNA glycosylase activity was detected in the MUTYH-null ES cells expressing the mMUTYH(G365D) mutant protein. The germ-line mutation (G382D) of the human MUTYH gene is therefore likely to be responsible for the occurrence of a mutator phenotype in these patients.

  18. Refining the phenotype associated with CASC5 mutation.

    PubMed

    Saadi, Abdelkrim; Verny, Florine; Siquier-Pernet, Karine; Bole-Feysot, Christine; Nitschke, Patrick; Munnich, Arnold; Abada-Dendib, Myriam; Chaouch, Malika; Abramowicz, Marc; Colleaux, Laurence

    2016-01-01

    Autosomal recessive primary microcephaly is a neurodevelopmental disorder characterized by congenitally reduced head circumference by at least two standard deviations (SD) below the mean for age and gender. It is associated with nonprogressive mental retardation of variable degree, minimal neurological deficit with no evidence of architectural anomalies of the brain. So far, 12 genetic loci (MCPH1-12) and corresponding genes have been identified. Most of these encode centrosomal proteins. CASC5 is one the most recently unravelled genes responsible for MCPH with mutations reported in three consanguineous families of Moroccan origin, all of whom harboured the same CASC5 homozygous mutation (c.6125G>A; p.Met2041Ile). Here, we report the identification, by whole exome sequencing, of the same missense mutation in a consanguineous Algerian family. All patients exhibited a similar clinical phenotype, including congenital microcephaly with head circumferences ranging from -3 to -4 standard deviations (SD) after age 5 years, moderate to severe cognitive impairment, short stature (adult height -3 SD), dysmorphic features included a sloping forehead, thick eyebrows, synophris and a low columella. Severe vermis hypoplasia and a large cyst of the posterior fossa were observed in one patient. Close microsatellite markers showed identical alleles in the Algerian the previously and Moroccan patients. This study confirms the involvement of CASC5 in autosomal recessive microcephaly and supports the hypothesis of a founder effect of the c.6125G>A mutation. In addition, this report refines the phenotype of this newly recognized form of primary microcephaly.

  19. Whole chromosome aneuploidy: big mutations drive adaptation by phenotypic leap

    PubMed Central

    Chen, Guangbo; Rubinstein, Boris; Li, Rong

    2012-01-01

    Despite its wide existence, the adaptive role of aneuploidy (the abnormal state of having unequal number of different chromosomes) has been a subject of debate. Cellular aneuploidy has been associated with enhanced resistance to stress, whereas on the organismal level it is detrimental to multi-cellular species. Certain aneuploid karyotypes are deleterious for specific environments, but karyotype diversity in a population potentiates adaptive evolution. To reconcile these paradoxical observations, this review distinguishes the role of aneuploidy in cellular versus organismal evolution. Further, it proposes a population genetics perspective to examine the behavior of aneuploidy on a populational versus individual level. By altering the copy number of a significant portion of the genome, aneuploidy introduces large phenotypic leap that enables small cell populations to explore a wide phenotypic landscape, from which adaptive traits can be selected. The production of chromosome number variation can be further increased by stress- or mutation-induced chromosomal instability, fueling rapid cellular adaptation. PMID:22926916

  20. EXOSC3 mutations in pontocerebellar hypoplasia type 1: novel mutations and genotype-phenotype correlations

    PubMed Central

    2014-01-01

    Background Pontocerebellar hypoplasia (PCH) represents a group of neurodegenerative disorders with prenatal onset. Eight subtypes have been described thus far (PCH1-8) based on clinical and genetic features. Common characteristics include hypoplasia and atrophy of the cerebellum, variable pontine atrophy, and severe mental and motor impairments. PCH1 is distinctly characterized by the combination with degeneration of spinal motor neurons. Recently, mutations in the exosome component 3 gene (EXOSC3) have been identified in approximately half of the patients with PCH subtype 1. Methods We selected a cohort of 99 PCH patients (90 families) tested negative for mutations in the TSEN genes, RARS2, VRK1 and CASK. Patients in this cohort were referred with a tentative diagnose PCH type 1, 2, 4, 7 or unclassified PCH. Genetic analysis of the EXOSC3 gene was performed using Sanger sequencing. Clinical data, MR images and autopsy reports of patients positive for EXOSC3 mutations were analyzed. Results EXOSC3 mutations were found in twelve families with PCH subtype 1, and were not found in patients with other PCH subtypes. Identified mutations included a large deletion, nonsense and missense mutations. Examination of clinical data reveals a prolonged disease course in patients with a homozygous p.D132A mutation. MRI shows variable pontine hypoplasia in EXOSC3 mediated PCH, where the pons is largely preserved in patients with a homozygous p.D132A mutation, but attenuated in patients with other mutations. Additionally, bilateral cerebellar cysts were found in patients compound heterozygous for a p.D132A mutation and a nonsense allele. Conclusions EXOSC3 mediated PCH shows clear genotype-phenotype correlations. A homozygous p.D132A mutation leads to PCH with possible survival into early puberty, and preservation of the pons. Compound heterozygosity for a p.D132A mutation and a nonsense or p.Y109N allele, a homozygous p.G31A mutation or a p.G135E mutation causes a more rapidly

  1. Amelogenesis Imperfecta: 1 Family, 2 Phenotypes, and 2 Mutated Genes.

    PubMed

    Prasad, M K; Laouina, S; El Alloussi, M; Dollfus, H; Bloch-Zupan, A

    2016-12-01

    Amelogenesis imperfecta (AI) is a clinically and genetically heterogeneous group of diseases characterized by enamel defects. The authors have identified a large consanguineous Moroccan family segregating different clinical subtypes of hypoplastic and hypomineralized AI in different individuals within the family. Using targeted next-generation sequencing, the authors identified a novel heterozygous nonsense mutation in COL17A1 (c.1873C>T, p.R625*) segregating with hypoplastic AI and a novel homozygous 8-bp deletion in C4orf26 (c.39_46del, p.Cys14Glyfs*18) segregating with hypomineralized-hypoplastic AI in this family. This study highlights the phenotypic and genotypic heterogeneity of AI that can exist even within a single consanguineous family. Furthermore, the identification of novel mutations in COL17A1 and C4orf26 and their correlation with distinct AI phenotypes can contribute to a better understanding of the pathophysiology of AI and the contribution of these genes to amelogenesis.

  2. The neuropathology and clinical phenotype of FTD with progranulin mutations.

    PubMed

    Mackenzie, Ian R A

    2007-07-01

    Mutations in the progranulin gene (PGRN), on chromosome 17q21, have recently been identified as a major cause of familial frontotemporal dementia (FTD). These cases have a characteristic pattern of neuropathology that is a distinct subtype of frontotemporal lobar degeneration with ubiquitinated inclusions (FTLD-U), with lentiform neuronal intranuclear inclusions being a consistent feature. There is no abnormal accumulation of PGRN protein in the brain and immunohistochemical and biochemical analysis indicates that the ubiquitinated pathological protein is TDP-43. In these families, FTD is inherited in an autosomal dominant fashion with high penetrance. The clinical phenotype is usually a combination of behavioural abnormality and language disturbance that is most often a form of primary progressive aphasia. Mild parkinsonism is common but motor neuron disease is notably rare. Marked variation in the disease course and clinical features are common, not only between families with different mutations, but also within individual families. This degree of clinical variability makes it difficult to predict which cases of familial FTD will turn out to have a PGRN mutation.

  3. Frameshift mutations in dentin phosphoprotein and dependence of dentin disease phenotype on mutation location.

    PubMed

    Nieminen, Pekka; Papagiannoulis-Lascarides, Lisa; Waltimo-Siren, Janna; Ollila, Päivi; Karjalainen, Sara; Arte, Sirpa; Veerkamp, Jaap; Tallon Walton, Victoria; Chimenos Küstner, Eduard; Siltanen, Tarja; Holappa, Heidi; Lukinmaa, Pirjo-Liisa; Alaluusua, Satu

    2011-04-01

    We describe results from a mutational analysis of the region of the dentin sialophosphoprotein (DSPP) gene encoding dentin phosphoprotein (DPP) in 12 families with dominantly inherited dentin diseases. In eight families (five mutations in the N-terminal third of DPP), the clinical and radiologic features were uniform and compatible with dentin dysplasia type II (DD-II) with major clinical signs in the deciduous dentition. In the other families (four mutations in the more C-terminal part), the permanent teeth also were affected, and the diseases could be classified as variants of dentinogenesis imperfecta. Attrition was not prominent, but periapical infections were common. Discoloring with varying intensity was evident, and pulps and root canals were obliterated in the permanent dentition. All mutations caused a frameshift that replaced the Ser-Ser-Asx repeat by a code for a hydrophobic downstream sequence of approximately original length. We conclude that frameshift mutations in DSPP explain a significant part of dentin diseases. Furthermore, we propose that the location of the mutation is reflected in the phenotypic features as a gradient from DD-II to more severe disease that does not conform to the classic definitions of DI-II.

  4. COMP and Col9A3 mutations and their relationship to the pseudoachondroplasia phenotype.

    PubMed

    Jung, Woon-Won; Balce, Gracia Cielo; Cho, Jae-Woo; Jung, Sung-Chul; Hong, Suk-Joo; Song, Hae-Ryong

    2010-12-01

    While pseudoachondroplasia (PSACH) is almost exclusively caused by cartilage oligomeric matrix protein (COMP) mutations, many patients identified with the PSACH phenotype do not have this mutation, suggesting gene and locus heterogeneity. In order to further characterize this entity, we studied 32 clinically and radiographically diagnosed PSACH patients, among 19 families. COMP and collagen (Col) IX (A1, A2 and A3) mutations, were determined. Patients who tested negative for pathological gene mutations but who were identified with the PSACH phenotype, were included. The phenotypes were characterized according to height deviation (cm) from normal, lower extremity mechanical axis deviation (MAD), cervical and thoracolumbar spine involvement, pelvic index, as well as hip, knee, ankle and hand involvement. We report an 81% mutation detection rate for PSACH, of which COMP+Col9A3 mutations were more prevalent (61%) than COMP mutations alone (30%). Of our PSACH patients, 19% tested negative for both COMP and Col9A3 mutations, and they presented with the greatest mean height deviations, but the least mean MADs. While all the PSACH mutations consistently produced the severe phenotype, the V426A mutation in Col9A3 produced the most severe. Mother-daughter and father-son phenotypic similarities were noted in the COMP+Col9A3 families. Col9A3 and gender play confounding roles in the phenotypic severity of PSACH. The presence of the PSACH phenotype in patients who tested negative for known mutations further confirms the genetic heterogeneity of this condition.

  5. Cardiopulmonary phenotype associated with human PHD2 mutation.

    PubMed

    Talbot, Nick P; Smith, Thomas G; Balanos, George M; Dorrington, Keith L; Maxwell, Patrick H; Robbins, Peter A

    2017-04-01

    Oxygen-dependent regulation of the erythropoietin gene is mediated by the hypoxia-inducible factor (HIF) family of transcription factors. When oxygen is plentiful, HIF undergoes hydroxylation by a family of oxygen-dependent prolyl hydroxylase domain (PHD) proteins, promoting its association with the von Hippel-Lindau (VHL) ubiquitin E3 ligase and subsequent proteosomal degradation. When oxygen is scarce, the PHD enzymes are inactivated, leading to HIF accumulation and upregulation not only of erythropoietin expression, but also the expression of hundreds of other genes, including those coordinating cardiovascular and ventilatory adaptation to hypoxia. Nevertheless, despite the identification of over 50 mutations in the PHD-HIF-VHL pathway in patients with previously unexplained congenital erythrocytosis, there are very few reports of associated cardiopulmonary abnormalities. We now report exaggerated pulmonary vascular and ventilatory responses to acute hypoxia in a 35-year-old man with erythrocytosis secondary to heterozygous mutation in PHD2, the most abundant of the PHD isoforms. We compare this phenotype with that reported in patients with the archetypal disorder of cellular oxygen sensing, Chuvash polycythemia, and discuss the possible clinical implications of our findings, particularly in the light of the emerging role for small molecule PHD inhibitors in clinical practice.

  6. Novel Mutations and Mutation Combinations of TMPRSS3 Cause Various Phenotypes in One Chinese Family with Autosomal Recessive Hearing Impairment

    PubMed Central

    Wang, Guo-Jian; Xu, Jin-Cao; Su, Yu

    2017-01-01

    Autosomal recessive hearing impairment with postlingual onset is rare. Exceptions are caused by mutations in the TMPRSS3 gene, which can lead to prelingual (DFNB10) as well as postlingual deafness (DFNB8). TMPRSS3 mutations can be classified as mild or severe, and the phenotype is dependent on the combination of TMPRSS3 mutations. The combination of two severe mutations leads to profound hearing impairment with a prelingual onset, whereas severe mutations in combination with milder TMPRSS3 mutations lead to a milder phenotype with postlingual onset. We characterized a Chinese family (number FH1523) with not only prelingual but also postlingual hearing impairment. Three mutations in TMPRSS3, one novel mutation c.36delC [p.(Phe13Serfs⁎12)], and two previously reported pathogenic mutations, c.916G>A (p.Ala306Thr) and c.316C>T (p.Arg106Cys), were identified. Compound heterozygous mutations of p.(Phe13Serfs⁎12) and p.Ala306Thr manifest as prelingual, profound hearing impairment in the patient (IV: 1), whereas the combination of p.Arg106Cys and p.Ala306Thr manifests as postlingual, milder hearing impairment in the patient (II: 2, II: 3, II: 5), suggesting that p.Arg106Cys mutation has a milder effect than p.(Phe13Serfs⁎12). We concluded that different combinations of TMPRSS3 mutations led to different hearing impairment phenotypes (DFNB8/DFNB10) in this family. PMID:28246597

  7. Complex phenotype in an Italian family with a novel mutation in SPG3A.

    PubMed

    de Leva, Maria Fulvia; Filla, Alessandro; Criscuolo, Chiara; Tessa, Alessandra; Pappatà, Sabina; Quarantelli, Mario; Bilo, Leonilda; Peluso, Silvio; Antenora, Antonella; Longo, Dario; Santorelli, Filippo M; De Michele, Giuseppe

    2010-03-01

    Mutations in the SPG3A gene represent a significant cause of autosomal dominant hereditary spastic paraplegia with early onset and pure phenotype. We describe an Italian family manifesting a complex phenotype, characterized by cerebellar involvement in the proband and amyotrophic lateral sclerosis-like syndrome in her father, in association with a new mutation in SPG3A. Our findings further widen the notion of clinical heterogeneity in SPG3A mutations.

  8. POMT2 mutation in a patient with 'MEB-like' phenotype.

    PubMed

    Mercuri, E; D'Amico, A; Tessa, A; Berardinelli, A; Pane, M; Messina, S; van Reeuwijk, J; Bertini, E; Muntoni, F; Santorelli, F M

    2006-07-01

    Mutations in POMT2 have so far only been reported in patients with Walker-Warburg phenotype. We report heterozygous POMT2 mutations in an a girl with a milder phenotype characterized by mental retardation, microcephaly, hypertrophy of the quadriceps and calf muscles, and structural brain changes mostly affecting the posterior fossa. Our findings suggest that, as previously reported for POMT1 and FKRP, mutations in the POMT2 can also be associated with clinical heterogeneity.

  9. Alzheimer's Disease Phenotypes and Genotypes Associated with Mutations in Presenilin 2

    ERIC Educational Resources Information Center

    Jayadev, Suman; Leverenz, James B.; Steinbart, Ellen; Stahl, Justin; Klunk, William; Yu, Cheng-En; Bird, Thomas D.

    2010-01-01

    Mutations in presenilin 2 are rare causes of early onset familial Alzheimer's disease. Eighteen presenilin 2 mutations have been reported, although not all have been confirmed pathogenic. Much remains to be learned about the range of phenotypes associated with these mutations. We have analysed our unique collection of 146 affected cases in 11…

  10. On genetic information uncertainty and the mutator phenotype in cancer.

    PubMed

    Chan, Jason Yongsheng

    2012-01-01

    Recent evidence supports the existence of a mutator phenotype in cancer cells, although the mechanistic basis remains unknown. In this paper, it is shown that this enhanced genetic instability is generated by an amplified measurement uncertainty on genetic information during DNA replication. At baseline, an inherent measurement uncertainty implies an imprecision of the recognition, replication and transfer genetic information, and forms the basis for an intrinsic genetic instability in all biological cells. Genetic information is contained in the sequence of DNA bases, each existing due to proton tunnelling, as a coherent superposition of quantum states composed of both the canonical and rare tautomeric forms until decoherence by interaction with DNA polymerase. The result of such a quantum measurement process may be interpreted classically as akin to a Bernoulli trial, whose outcome X is random and can be either of two possibilities, depending on whether the proton is tunnelled (X=1) or not (X=0). This inherent quantum uncertainty is represented by a binary entropy function and quantified in terms of Shannon information entropy H(X)=-P(X=1)log(2)P(X=1)-P(X=0)log(2)P(X=0). Enhanced genetic instability may either be directly derived from amplified uncertainty induced by increases in quantum and thermodynamic fluctuation, or indirectly arise from the loss of natural uncertainty reduction mechanisms.

  11. UNSTABLE MUTATIONS IN THE FMR1 GENE AND THE PHENOTYPES

    PubMed Central

    Loesch, Danuta; Hagerman, Randi

    2014-01-01

    Fragile X syndrome (FXS), a severe neurodevelopmental anomaly, and one of the earliest disorders linked to an unstable (‘dynamic’) mutation, is caused by the large (>200) CGG repeat expansions in the noncoding portion of the FMR1 (Fragile X Mental Retardation-1) gene. These expansions, termed full mutations, normally silence this gene's promoter through methylation, leading to a gross deficit of the Fragile X Mental Retardation Protein (FMRP) that is essential for normal brain development. Rare individuals with the expansion but with an unmethylated promoter (and thus, FMRP production), present a much less severe form of FXS. However, a unique feature of the relationship between the different sizes of CGG expanded tract and phenotypic changes is that smaller expansions (<200) generate a series of different clinical manifestations and/or neuropsychological changes. The major part of this chapter is devoted to those FMR1 alleles with small (55-200) CGG expansions, termed ‘premutations’, which have the potential for generating the full mutation alleles on mother-offspring transmission, on the one hand, and are associated with some phenotypic changes, on the other. Thus, the role of several factors known to determine the rate of CGG expansion in the premutation alleles is discussed first. Then, an account of various neurodevelopmental, congnitive, behavioural and physical changes reported in carriers of these small expansions is given, and possible association of these conditions with a toxicity of the elevated FMR1 gene's transcript (mRNA) is discussed. The next two sections are devoted to major and well defined clinical conditions associated with the premutation alleles. The first one is the late onset neurodegenerative disorder termed fragile X-associated tremor ataxia syndrome (FXTAS). The wide range of clinical and neuropsychological manifestations of this syndrome, and their relevance to elevated levels of the FMR1 mRNA, are described. Another distinct

  12. Do cell junction protein mutations cause an airway phenotype in mice or humans?

    PubMed

    Chang, Eugene H; Pezzulo, Alejandro A; Zabner, Joseph

    2011-08-01

    Cell junction proteins connect epithelial cells to each other and to the basement membrane. Genetic mutations of these proteins can cause alterations in some epithelia leading to varied phenotypes such as deafness, renal disease, skin disorders, and cancer. This review examines if genetic mutations in these proteins affect the function of lung airway epithelia. We review cell junction proteins with examples of disease mutation phenotypes in humans and in mouse knockout models. We also review which of these genes are expressed in airway epithelium by microarray expression profiling and immunocytochemistry. Last, we present a comprehensive literature review to find the lung phenotype when cell junction and adhesion genes are mutated or subject to targeted deletion. We found that in murine models, targeted deletion of cell junction and adhesion genes rarely result in a lung phenotype. Moreover, mutations in these genes in humans have no obvious lung phenotype. Our research suggests that simply because a cell junction or adhesion protein is expressed in an organ does not imply that it will exhibit a drastic phenotype when mutated. One explanation is that because a functioning lung is critical to survival, redundancy in the system is expected. Therefore mutations in a single gene might be compensated by a related function of a similar gene product. Further studies in human and animal models will help us understand the overlap in the function of cell junction gene products. Finally, it is possible that the human lung phenotype is subtle and has not yet been described.

  13. Germline mutation rates and the long-term phenotypic effects of mutation accumulation in wild-type laboratory mice and mutator mice

    PubMed Central

    Uchimura, Arikuni; Higuchi, Mayumi; Minakuchi, Yohei; Ohno, Mizuki; Toyoda, Atsushi; Fujiyama, Asao; Miura, Ikuo; Wakana, Shigeharu; Nishino, Jo; Yagi, Takeshi

    2015-01-01

    The germline mutation rate is an important parameter that affects the amount of genetic variation and the rate of evolution. However, neither the rate of germline mutations in laboratory mice nor the biological significance of the mutation rate in mammalian populations is clear. Here we studied genome-wide mutation rates and the long-term effects of mutation accumulation on phenotype in more than 20 generations of wild-type C57BL/6 mice and mutator mice, which have high DNA replication error rates. We estimated the base-substitution mutation rate to be 5.4 × 10−9 (95% confidence interval = 4.6 × 10−9–6.5 × 10−9) per nucleotide per generation in C57BL/6 laboratory mice, about half the rate reported in humans. The mutation rate in mutator mice was 17 times that in wild-type mice. Abnormal phenotypes were 4.1-fold more frequent in the mutator lines than in the wild-type lines. After several generations, the mutator mice reproduced at substantially lower rates than the controls, exhibiting low pregnancy rates, lower survival rates, and smaller litter sizes, and many of the breeding lines died out. These results provide fundamental information about mouse genetics and reveal the impact of germline mutation rates on phenotypes in a mammalian population. PMID:26129709

  14. Germline mutation rates and the long-term phenotypic effects of mutation accumulation in wild-type laboratory mice and mutator mice.

    PubMed

    Uchimura, Arikuni; Higuchi, Mayumi; Minakuchi, Yohei; Ohno, Mizuki; Toyoda, Atsushi; Fujiyama, Asao; Miura, Ikuo; Wakana, Shigeharu; Nishino, Jo; Yagi, Takeshi

    2015-08-01

    The germline mutation rate is an important parameter that affects the amount of genetic variation and the rate of evolution. However, neither the rate of germline mutations in laboratory mice nor the biological significance of the mutation rate in mammalian populations is clear. Here we studied genome-wide mutation rates and the long-term effects of mutation accumulation on phenotype in more than 20 generations of wild-type C57BL/6 mice and mutator mice, which have high DNA replication error rates. We estimated the base-substitution mutation rate to be 5.4 × 10(-9) (95% confidence interval = 4.6 × 10(-9)-6.5 × 10(-9)) per nucleotide per generation in C57BL/6 laboratory mice, about half the rate reported in humans. The mutation rate in mutator mice was 17 times that in wild-type mice. Abnormal phenotypes were 4.1-fold more frequent in the mutator lines than in the wild-type lines. After several generations, the mutator mice reproduced at substantially lower rates than the controls, exhibiting low pregnancy rates, lower survival rates, and smaller litter sizes, and many of the breeding lines died out. These results provide fundamental information about mouse genetics and reveal the impact of germline mutation rates on phenotypes in a mammalian population.

  15. A phenotype of atypical apraxia of speech in a family carrying SQSTM1 mutation.

    PubMed

    Boutoleau-Bretonnière, Claire; Camuzat, Agnès; Le Ber, Isabelle; Bouya-Ahmed, Kawtar; Guerreiro, Rita; Deruet, Anne-Laure; Evrard, Christelle; Bras, José; Lamy, Estelle; Auffray-Calvier, Elisabeth; Pallardy, Amandine; Hardy, John; Brice, Alexis; Derkinderen, Pascal; Vercelletto, Martine

    2015-01-01

    SQSTM1 mutations, coding for the p62 protein, were identified as a monogenic cause of Paget disease of bone and of amyotrophic lateral sclerosis. More recently, SQSTM1 mutations were identified in few families with frontotemporal dementia. We report a new family carrying SQSTM1 mutation and presenting with a clinical phenotype of speech apraxia or atypical behavioral disorders, associated with early visuo-contructional deficits. This study further supports the implication of SQSTM1 in frontotemporal dementia, and enlarges the phenotypic spectrum associated with SQSTM1 mutations.

  16. Novel MBTPS2 missense mutation causes a keratosis follicularis spinulosa decalvans phenotype: mutation update and review of the literature.

    PubMed

    Zhang, J; Wang, Y; Cheng, R; Ni, C; Liang, J; Li, M; Yao, Z

    2016-10-01

    Keratosis follicularis spinulosa decalvans (KFSD) is an X-linked condition characterized by keratotic follicular papules and progressive alopecia, which is caused by mutations in the MBTPS2 gene. We carried out a genetic study on a child who was suspected clinically to have KFSD. Sanger sequencing was performed to detect mutations in the entire coding region of MBTPS2. A novel missense mutation (c.599C>T) was identified in the patient, confirming a diagnosis of KFSD. We reviewed related cases with MBTPS2 mutations for evidence of genotype-phenotype correlations.

  17. A Novel Missense Mutation in POMT1 Modulates the Severe Congenital Muscular Dystrophy Phenotype Associated with POMT1 Nonsense Mutations

    PubMed Central

    Wallace, Stephanie E.; Conta, Jessie H.; Winder, Thomas L.; Willer, Tobias; Eskuri, Jamie M.; Haas, Richard; Patterson, Kathleen; Campbell, Kevin P.; Moore, Steven A.; Gospe, Sidney M.

    2014-01-01

    Mutations in POMT1 lead to a group of neuromuscular conditions ranging in severity from Walker-Warburg syndrome to limb girdle muscular dystrophy. We report two male siblings, ages 19 and 14, and an unrelated 6-year old female with early onset muscular dystrophy and intellectual disability with minimal structural brain anomalies and no ocular abnormalities. Compound heterozygous mutations in POMT1 were identified including a previously reported nonsense mutation (c.2167dupG; p.Asp723Glyfs*8) associated with Walker-Warburg syndrome and a novel missense mutation in a highly conserved region of the protein O-mannosyltransferase 1 protein (c.1958C>T; p.Pro653Leu). This novel variant reduces the phenotypic severity compared to patients with homozygous c.2167dupG mutations or compound heterozygous patients with a c.2167dupG mutation and a wide range of other mutant POMT1 alleles. PMID:24491487

  18. Phenotype-optimized sequence ensembles substantially improve prediction of disease-causing mutation in cystic fibrosis.

    PubMed

    Masica, David L; Sosnay, Patrick R; Cutting, Garry R; Karchin, Rachel

    2012-08-01

    Cystic fibrosis transmembrane conductance regulator (CFTR) mutation is associated with a phenotypic spectrum that includes cystic fibrosis (CF). The disease liability of some common CFTR mutations is known, but rare mutations are seen in too few patients to categorize unequivocally, making genetic diagnosis difficult. Computational methods can predict the impact of mutation, but prediction specificity is often below that required for clinical utility. Here, we present a novel supervised learning approach for predicting CF from CFTR missense mutation. The algorithm begins by constructing custom multiple sequence alignments called phenotype-optimized sequence ensembles (POSEs). POSEs are constructed iteratively, by selecting sequences that optimize predictive performance on a training set of CFTR mutations of known clinical significance. Next, we predict CF disease liability from a different set of CFTR mutations (test-set mutations). This approach achieves improved prediction performance relative to popular methods recently assessed using the same test-set mutations. Of clinical significance, our method achieves 94% prediction specificity. Because databases such as HGMD and locus-specific mutation databases are growing rapidly, methods that automatically tailor their predictions for a specific phenotype may be of immediate utility. If the performance achieved here generalizes to other systems, the approach could be an excellent tool to help establish genetic diagnoses.

  19. Autism Spectrum Phenotype in Males and Females with Fragile X Full Mutation and Premutation

    ERIC Educational Resources Information Center

    Clifford, Sally; Dissanayake, Cheryl; Bui, Quang M.; Huggins, Richard; Taylor, Annette K.; Loesch, Danuta Z.

    2007-01-01

    The behavioural phenotype of autism was assessed in individuals with full mutation and premutation fragile X syndrome (FXS) using the Autism Diagnostic Observation Scale-Generic (ADOS-G) and the Autism Diagnostic Interview (ADI-R). The participants, aged 5-80 years, comprised 33 males and 31 females with full mutation, 7 males and 43 females with…

  20. Novel PRRT2 mutations in paroxysmal dyskinesia patients with variant inheritance and phenotypes.

    PubMed

    Liu, X-R; Wu, M; He, N; Meng, H; Wen, L; Wang, J-L; Zhang, M-P; Li, W-B; Mao, X; Qin, J-M; Li, B-M; Tang, B; Deng, Y-H; Shi, Y-W; Su, T; Yi, Y-H; Tang, B-S; Liao, W-P

    2013-03-01

    Paroxysmal dyskinesias (PDs) are a group of episodic movement disorders with marked variability in clinical manifestation and potential association with epilepsy. PRRT2 has been identified as a causative gene for PDs, but the phenotypes and inheritance patterns of PRRT2 mutations need further clarification. In this study, 10 familial and 21 sporadic cases with PDs and PDs-related phenotypes were collected. Genomic DNA was screened for PRRT2 mutations by direct sequencing. Seven PRRT2 mutations were identified in nine (90.0%) familial cases and in six (28.6%) sporadic cases. Five mutations are novel: two missense mutations (c.647C>G/p.Pro216Arg and c.872C>T/p.Ala291Val) and three truncating mutations (c.117delA/p.Val41TyrfsX49, c.510dupT/p.Leu171SerfsX3 and c.579dupA/p.Glu194ArgfsX6). Autosomal dominant inheritance with incomplete penetrance was observed in most of the familial cases. In the sporadic cases, inheritance was heterogeneous including recessive inheritance with compound heterozygous mutations, inherited mutations with incomplete parental penetrance and de novo mutation. Variant phenotypes associated with PRRT2 mutations, found in 36.0% of the affected cases, included febrile convulsions, epilepsy, infantile non-convulsive seizures (INCS) and nocturnal convulsions (NC). All patients with INCS or NC, not reported previously, displayed abnormalities on electroencephalogram (EEG). No EEG abnormalities were recorded in patients with classical infantile convulsions and paroxysmal choreoathetosis (ICCA)/paroxysmal kinesigenic dyskinesia (PKD). Our study further confirms that PRRT2 mutations are the most common cause of familial PDs, displaying both dominant and recessive inheritance. Epilepsy may occasionally occur in ICCA/PKD patients with PRRT2 mutations. Variant phenotypes INCS or NC differ from classical ICCA/PKD clinically and electroencephalographically. They have some similarities with, but not identical to epilepsy, possibly represent an overlap between

  1. Strong mutator phenotype drives faster adaptation from growth on glucose to growth on acetate in Salmonella.

    PubMed

    Le Bars, Hervé; Bonnaure-Mallet, Martine; Barloy-Hubler, Frédérique; Jolivet-Gougeon, Anne; Bousarghin, Latifa

    2014-10-01

    The metabolic adaptation of strong mutator strains was studied to better understand the link between the strong mutator phenotype and virulence. Analysis of the growth curves of isogenic strains of Salmonella, which were previously grown in M63 glucose media, revealed that the exponential phase of growth was reached earlier in an M63 acetate medium with strong mutator strains (mutated in mutS or in mutL) than with normomutator strains (P<0.05). Complemented strains confirmed the direct role of the strong mutator phenotype in this faster metabolic adaptation to the assimilation of acetate. In a mixed cell population, proliferation of strong mutators over normomutators was observed when the carbon source was switched from glucose to acetate. These results add to the sparse body of knowledge about strong mutators and highlight the selective advantage conferred by the strong mutator phenotype to adapt to a switch of carbon source in the environment. This work may provide clinically useful information given that there is a high prevalence of strong mutators among pathogenic strains of Salmonella and that acetate is the principal short chain fatty acid of the human terminal ileum and colon where Salmonella infection is localized.

  2. Evidence of a Mild Mutator Phenotype in Cambodian Plasmodium falciparum Malaria Parasites.

    PubMed

    Lee, Andrew H; Fidock, David A

    2016-01-01

    Malaria control efforts have been continuously stymied by drug-resistant strains of Plasmodium falciparum, which typically originate in Southeast Asia prior to spreading into high-transmission settings in Africa. One earlier proposed explanation for Southeast Asia being a hotbed of resistance has been the hypermutability or "Accelerated Resistance to Multiple Drugs" (ARMD) phenotype, whereby multidrug-resistant Southeast Asian parasites were reported to exhibit 1,000-fold higher rates of resistance to unrelated antimalarial agents when compared to drug-sensitive parasites. However, three recent studies do not recapitulate this hypermutability phenotype. Intriguingly, genome sequencing of recently derived multidrug-resistant Cambodian isolates has identified a high proportion of DNA repair gene mutations in multidrug-resistant parasites, suggesting their potential role in shaping local parasite evolution. By adapting fluctuation assays for use in P. falciparum, we have examined the in vitro mutation rates of five recent Cambodian isolates and three reference laboratory strains. For these studies we also generated a knockout parasite line lacking the DNA repair factor Exonuclease I. In these assays, parasites were typed for their ability to acquire resistance to KAE609, currently in advanced clinical trials, yielding 13 novel mutations in the Na+/H+-ATPase PfATP4, the primary resistance determinant. We observed no evidence of hypermutability. Instead, we found evidence of a mild mutator (up to a 3.4-fold increase in mutation rate) phenotype in two artemisinin-resistant Cambodian isolates, which carry DNA repair gene mutations. We observed that one such mutation in the Mismatch Repair protein Mlh1 contributes to the mild mutator phenotype when modeled in yeast (scmlh1-P157S). Compared to basal rates of mutation, a mild mutator phenotype may provide a greater overall benefit for parasites in Southeast Asia in terms of generating drug resistance without incurring

  3. A missense mutation in PAX9 in a family with distinct phenotype of oligodontia.

    PubMed

    Lammi, Laura; Halonen, Katri; Pirinen, Sinikka; Thesleff, Irma; Arte, Sirpa; Nieminen, Pekka

    2003-11-01

    Mutations in PAX9 have been described for families in which inherited oligodontia characteristically involves permanent molars. Our study analysed one large family with dominantly inherited oligodontia clinically and genetically. In addition to permanent molars, some teeth were congenitally missing in the premolar, canine, and incisor regions. Measurements of tooth size revealed the reduced size of the proband's and his father's deciduous and permanent teeth. This phenotype is distinct from oligodontia phenotypes associated with mutations in PAX9. Sequencing of the PAX9 gene revealed a missense mutation in the beginning of the paired domain of the molecule, an arginine-to-tryptophan amino-acid change occurring in a position absolutely conserved in all sequenced paired box genes. A mutation of the homologous arginine of PAX6 has been shown to affect the target DNA specificity of PAX6. We suggest that a similar mechanism explains these distinct oligodontia phenotypes.

  4. System analysis of gene mutations and clinical phenotype in Chinese patients with autosomal-dominant polycystic kidney disease

    PubMed Central

    Jin, Meiling; Xie, Yuansheng; Chen, Zhiqiang; Liao, Yujie; Li, Zuoxiang; Hu, Panpan; Qi, Yan; Yin, Zhiwei; Li, Qinggang; Fu, Ping; Chen, Xiangmei

    2016-01-01

    Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disorder mainly caused by mutation in PKD1/PKD2. However, ethnic differences in mutations, the association between mutation genotype/clinical phenotype, and the clinical applicable value of mutation detection are poorly understood. We made systematically analysis of Chinese ADPKD patients based on a next-generation sequencing platform. Among 148 ADPKD patients enrolled, 108 mutations were detected in 127 patients (85.8%). Compared with mutations in Caucasian published previously, the PKD2 mutation detection rate was lower, and patients carrying the PKD2 mutation invariably carried the PKD1 mutation. The definite pathogenic mutation detection rate was lower, whereas the multiple mutations detection rate was higher in Chinese patients. Then, we correlated PKD1/PKD2 mutation data and clinical data: patients with mutation exhibited a more severe phenotype; patients with >1 mutations exhibited a more severe phenotype; patients with pathogenic mutations exhibited a more severe phenotype. Thus, the PKD1/PKD2 mutation status differed by ethnicity, and the PKD1/PKD2 genotype may affect the clinical phenotype of ADPKD. Furthermore, it makes sense to detect PKD1/PKD2 mutation status for early diagnosis and prognosis, perhaps as early as the embryo/zygote stage, to facilitate early clinical intervention and family planning. PMID:27782177

  5. Four Caucasian patients with mutations in the fukutin gene and variable clinical phenotype.

    PubMed

    Vuillaumier-Barrot, S; Quijano-Roy, S; Bouchet-Seraphin, C; Maugenre, S; Peudenier, S; Van den Bergh, P; Marcorelles, P; Avila-Smirnow, D; Chelbi, M; Romero, N B; Carlier, R Y; Estournet, B; Guicheney, P; Seta, N

    2009-03-01

    Fukuyama congenital muscular dystrophy (FCMD) is frequent in Japan, due to a founder mutation of the fukutin gene (FKTN). Outside Japan, FKTN mutations have only been reported in a few patients with a wide spectrum of phenotypes from Walker-Warburg syndrome to limb-girdle muscular dystrophy (LGMD2M). We studied four new Caucasian patients from three unrelated families. All showed raised serum CK initially isolated in one case and muscular dystrophy. Immunohistochemical studies and haplotype analysis led us to search for mutations in FKTN. Two patients (two sisters) presented with congenital muscular dystrophy, mental retardation, and posterior fossa malformation including cysts, and brain atrophy at Brain MRI. The other two patients had normal intelligence and brain MRI. Sequencing of the FKTN gene identified three previously described mutations and two novel missense mutations. Outside Japan, fukutinopathies are associated with a large spectrum of phenotypes from isolated hyperCKaemia to severe CMD, showing a clear overlap with that of FKRP.

  6. Expanding the phenotypic and mutational spectrum in microcephalic osteodysplastic primordial dwarfism type I.

    PubMed

    Abdel-Salam, Ghada M H; Abdel-Hamid, Mohamed S; Issa, Mahmoud; Magdy, Ahmed; El-Kotoury, Ahmed; Amr, Khalda

    2012-06-01

    Mutations in the RNU4ATAC gene cause microcephalic osteodysplastic primordial dwarfism type I. It encodes U4atac, a small nuclear RNA that is a component of the minor spliceosome. Six distinct mutations in 30 patients diagnosed as microcephalic osteodysplastic primordial dwarfism type I have been described. We report on three additional patients from two unrelated families presenting with a milder phenotype of microcephalic osteodysplastic primordial dwarfism type I and metopic synostosis. Patient 1 had two novel heterozygous mutations in the 3' prime stem-loop, g.66G > C and g.124G > A while Patients 2 and 3 had a homozygous mutation g.55G > A in the 5' prime stem-loop. Although they manifested the known spectrum of clinical features of microcephalic osteodysplastic primordial dwarfism type I, they lacked evidence of severe developmental delay and neurological symptoms. These findings expand the mutational and phenotypic spectrum of this syndrome.

  7. Novel TMEM67 Mutations and Genotype-phenotype Correlates in Meckelin-related Ciliopathies

    PubMed Central

    Iannicelli, Miriam; Brancati, Francesco; Mougou-Zerelli, Soumaya; Mazzotta, Annalisa; Thomas, Sophie; Elkhartoufi, Nadia; Travaglini, Lorena; Gomes, Céline; Ardissino, Gian Luigi; Bertini, Enrico; Boltshauser, Eugen; Castorina, Pierangela; D'Arrigo, Stefano; Fischetto, Rita; Leroy, Brigitte; Loget, Philippe; Bonnière, Maryse; Starck, Lena; Tantau, Julia; Gentilin, Barbara; Majore, Silvia; Swistun, Dominika; Flori, Elizabeth; Lalatta, Faustina; Pantaleoni, Chiara; Johannes.Penzien; Grammatico, Paola; Dallapiccola, Bruno; Gleeson, Joseph G.; Attie-Bitach, Tania; Valente, Enza Maria

    2010-01-01

    Human ciliopathies are hereditary conditions caused by defects of proteins expressed at the primary cilium. Among ciliopathies, Joubert syndrome and related disorders (JSRD), Meckel syndrome (MKS) and nephronophthisis (NPH) present clinical and genetic overlap, being allelic at several loci. One of the most interesting gene is TMEM67, encoding the transmembrane protein meckelin. We performed mutation analysis of TMEM67 in 341 probands, including 265 JSRD representative of all clinical subgroups and 76 MKS fetuses. We identified 33 distinct mutations, of which 20 were novel, in 8/10 (80%) JS with liver involvement (COACH phenotype) and 12/76 (16%) MKS fetuses. No mutations were found in other JSRD subtypes, confirming the strong association between TMEM67 mutations and liver involvement. Literature review of all published TMEM67 mutated cases was performed to delineate genotype-phenotype correlates. In particular, comparison of the types of mutations and their distribution along the gene in lethal versus non lethal phenotypes showed in MKS patients a significant enrichment of missense mutations falling in TMEM67 exons 8 to 15, especially when in combination with a truncating mutation. These exons encode for a region of unknown function in the extracellular domain of meckelin. PMID:20232449

  8. Novel motor phenotypes in patients with VRK1 mutations without pontocerebellar hypoplasia

    PubMed Central

    Stoll, Marion; Teoh, Hooiling; Lee, James; Reddel, Stephen; Zhu, Ying; Buckley, Michael; Sampaio, Hugo; Roscioli, Tony; Farrar, Michelle

    2016-01-01

    Objective: To describe the phenotypes in 2 families with vaccinia-related kinase 1 (VRK1) mutations including one novel VRK1 mutation. Methods: VRK1 mutations were found by whole exome sequencing in patients presenting with motor neuron disorders. Results: We identified pathogenic mutations in the VRK1 gene in the affected members of 2 families. In family 1, compound heterozygous mutations were identified in VRK1, c.356A>G; p.H119R, and c.1072C>T; p.R358*, in 2 siblings with adult onset distal spinal muscular atrophy (SMA). In family 2, a novel VRK1 mutation, c.403G>A; p.G135R and c.583T>G; p.L195V, were identified in a child with motor neuron disease. Conclusions: VRK1 mutations can produce adult-onset SMA and motor neuron disease in children without pontocerebellar hypoplasia. PMID:27281532

  9. An Organismal CNV Mutator Phenotype Restricted to Early Human Development.

    PubMed

    Liu, Pengfei; Yuan, Bo; Carvalho, Claudia M B; Wuster, Arthur; Walter, Klaudia; Zhang, Ling; Gambin, Tomasz; Chong, Zechen; Campbell, Ian M; Coban Akdemir, Zeynep; Gelowani, Violet; Writzl, Karin; Bacino, Carlos A; Lindsay, Sarah J; Withers, Marjorie; Gonzaga-Jauregui, Claudia; Wiszniewska, Joanna; Scull, Jennifer; Stankiewicz, Paweł; Jhangiani, Shalini N; Muzny, Donna M; Zhang, Feng; Chen, Ken; Gibbs, Richard A; Rautenstrauss, Bernd; Cheung, Sau Wai; Smith, Janice; Breman, Amy; Shaw, Chad A; Patel, Ankita; Hurles, Matthew E; Lupski, James R

    2017-02-23

    De novo copy number variants (dnCNVs) arising at multiple loci in a personal genome have usually been considered to reflect cancer somatic genomic instabilities. We describe a multiple dnCNV (MdnCNV) phenomenon in which individuals with genomic disorders carry five to ten constitutional dnCNVs. These CNVs originate from independent formation incidences, are predominantly tandem duplications or complex gains, exhibit breakpoint junction features reminiscent of replicative repair, and show increased de novo point mutations flanking the rearrangement junctions. The active CNV mutation shower appears to be restricted to a transient perizygotic period. We propose that a defect in the CNV formation process is responsible for the "CNV-mutator state," and this state is dampened after early embryogenesis. The constitutional MdnCNV phenomenon resembles chromosomal instability in various cancers. Investigations of this phenomenon may provide unique access to understanding genomic disorders, structural variant mutagenesis, human evolution, and cancer biology.

  10. New insights into genotype–phenotype correlation for GLI3 mutations

    PubMed Central

    Démurger, Florence; Ichkou, Amale; Mougou-Zerelli, Soumaya; Le Merrer, Martine; Goudefroye, Géraldine; Delezoide, Anne-Lise; Quélin, Chloé; Manouvrier, Sylvie; Baujat, Geneviève; Fradin, Mélanie; Pasquier, Laurent; Megarbané, André; Faivre, Laurence; Baumann, Clarisse; Nampoothiri, Sheela; Roume, Joëlle; Isidor, Bertrand; Lacombe, Didier; Delrue, Marie-Ange; Mercier, Sandra; Philip, Nicole; Schaefer, Elise; Holder, Muriel; Krause, Amanda; Laffargue, Fanny; Sinico, Martine; Amram, Daniel; André, Gwenaelle; Liquier, Alain; Rossi, Massimiliano; Amiel, Jeanne; Giuliano, Fabienne; Boute, Odile; Dieux-Coeslier, Anne; Jacquemont, Marie-Line; Afenjar, Alexandra; Van Maldergem, Lionel; Lackmy-Port-Lis, Marylin; Vincent- Delorme, Catherine; Chauvet, Marie-Liesse; Cormier-Daire, Valérie; Devisme, Louise; Geneviève, David; Munnich, Arnold; Viot, Géraldine; Raoul, Odile; Romana, Serge; Gonzales, Marie; Encha-Razavi, Ferechte; Odent, Sylvie; Vekemans, Michel; Attie-Bitach, Tania

    2015-01-01

    The phenotypic spectrum of GLI3 mutations includes autosomal dominant Greig cephalopolysyndactyly syndrome (GCPS) and Pallister–Hall syndrome (PHS). PHS was first described as a lethal condition associating hypothalamic hamartoma, postaxial or central polydactyly, anal atresia and bifid epiglottis. Typical GCPS combines polysyndactyly of hands and feet and craniofacial features. Genotype–phenotype correlations have been found both for the location and the nature of GLI3 mutations, highlighting the bifunctional nature of GLI3 during development. Here we report on the molecular and clinical study of 76 cases from 55 families with either a GLI3 mutation (49 GCPS and 21 PHS), or a large deletion encompassing the GLI3 gene (6 GCPS cases). Most of mutations are novel and consistent with the previously reported genotype–phenotype correlation. Our results also show a correlation between the location of the mutation and abnormal corpus callosum observed in some patients with GCPS. Fetal PHS observations emphasize on the possible lethality of GLI3 mutations and extend the phenotypic spectrum of malformations such as agnathia and reductional limbs defects. GLI3 expression studied by in situ hybridization during human development confirms its early expression in target tissues. PMID:24736735

  11. New insights into genotype-phenotype correlation for GLI3 mutations.

    PubMed

    Démurger, Florence; Ichkou, Amale; Mougou-Zerelli, Soumaya; Le Merrer, Martine; Goudefroye, Géraldine; Delezoide, Anne-Lise; Quélin, Chloé; Manouvrier, Sylvie; Baujat, Geneviève; Fradin, Mélanie; Pasquier, Laurent; Megarbané, André; Faivre, Laurence; Baumann, Clarisse; Nampoothiri, Sheela; Roume, Joëlle; Isidor, Bertrand; Lacombe, Didier; Delrue, Marie-Ange; Mercier, Sandra; Philip, Nicole; Schaefer, Elise; Holder, Muriel; Krause, Amanda; Laffargue, Fanny; Sinico, Martine; Amram, Daniel; André, Gwenaelle; Liquier, Alain; Rossi, Massimiliano; Amiel, Jeanne; Giuliano, Fabienne; Boute, Odile; Dieux-Coeslier, Anne; Jacquemont, Marie-Line; Afenjar, Alexandra; Van Maldergem, Lionel; Lackmy-Port-Lis, Marylin; Vincent-Delorme, Catherine; Chauvet, Marie-Liesse; Cormier-Daire, Valérie; Devisme, Louise; Geneviève, David; Munnich, Arnold; Viot, Géraldine; Raoul, Odile; Romana, Serge; Gonzales, Marie; Encha-Razavi, Ferechte; Odent, Sylvie; Vekemans, Michel; Attie-Bitach, Tania

    2015-01-01

    The phenotypic spectrum of GLI3 mutations includes autosomal dominant Greig cephalopolysyndactyly syndrome (GCPS) and Pallister-Hall syndrome (PHS). PHS was first described as a lethal condition associating hypothalamic hamartoma, postaxial or central polydactyly, anal atresia and bifid epiglottis. Typical GCPS combines polysyndactyly of hands and feet and craniofacial features. Genotype-phenotype correlations have been found both for the location and the nature of GLI3 mutations, highlighting the bifunctional nature of GLI3 during development. Here we report on the molecular and clinical study of 76 cases from 55 families with either a GLI3 mutation (49 GCPS and 21 PHS), or a large deletion encompassing the GLI3 gene (6 GCPS cases). Most of mutations are novel and consistent with the previously reported genotype-phenotype correlation. Our results also show a correlation between the location of the mutation and abnormal corpus callosum observed in some patients with GCPS. Fetal PHS observations emphasize on the possible lethality of GLI3 mutations and extend the phenotypic spectrum of malformations such as agnathia and reductional limbs defects. GLI3 expression studied by in situ hybridization during human development confirms its early expression in target tissues.

  12. Mutations in CEP120 cause Joubert syndrome as well as complex ciliopathy phenotypes

    PubMed Central

    Romani, Marta; Isrie, Mala; Rosti, Rasim Ozgur; Micalizzi, Alessia; Musaev, Damir; Mazza, Tommaso; Al-gazali, Lihadh; Altunoglu, Umut; Boltshauser, Eugen; D'Arrigo, Stefano; De Keersmaecker, Bart; Kayserili, Hülya; Brandenberger, Sarah; Kraoua, Ichraf; Mark, Paul R; McKanna, Trudy; Van Keirsbilck, Joachim; Moerman, Philippe; Poretti, Andrea; Puri, Ratna; Van Esch, Hilde; Gleeson, Joseph G; Valente, Enza Maria

    2016-01-01

    Background Ciliopathies are an extensive group of autosomal recessive or X-linked disorders with considerable genetic and clinical overlap, which collectively share multiple organ involvement and may result in lethal or viable phenotypes. In large numbers of cases the genetic defect remains yet to be determined. The aim of this study is to describe the mutational frequency and phenotypic spectrum of the CEP120 gene. Methods Exome sequencing was performed in 145 patients with Joubert syndrome (JS), including 15 children with oral-facial-digital syndrome type VI (OFDVI) and 21 Meckel syndrome (MKS) fetuses. Moreover, exome sequencing was performed in one fetus with tectocerebellar dysraphia with occipital encephalocele (TCDOE), molar tooth sign and additional skeletal abnormalities. As a parallel study, 346 probands with a phenotype consistent with JS or related ciliopathies underwent next-generation sequencing-based targeted sequencing of 120 previously described and candidate ciliopathy genes. Results We present six probands carrying nine distinct mutations (of which eight are novel) in the CEP120 gene, previously found mutated only in Jeune asphyxiating thoracic dystrophy (JATD). The CEP120-associated phenotype ranges from mild classical JS in four patients to more severe conditions in two fetuses, with overlapping features of distinct ciliopathies that include TCDOE, MKS, JATD and OFD syndromes. No obvious correlation is evident between the type or location of identified mutations and the ciliopathy phenotype. Conclusion Our findings broaden the spectrum of phenotypes caused by CEP120 mutations that account for nearly 1% of patients with JS as well as for more complex ciliopathy phenotypes. The lack of clear genotype–phenotype correlation highlights the relevance of comprehensive genetic analyses in the diagnostics of ciliopathies. PMID:27208211

  13. Single amino acid mutations in the capsid switch the neutralization phenotype of porcine circovirus 2.

    PubMed

    Saha, Dipongkor; Lefebvre, David J; Ooms, Karen; Huang, Liping; Delputte, Peter L; Van Doorsselaere, Jan; Nauwynck, Hans J

    2012-07-01

    Porcine circovirus 2 (PCV2) is the causative agent of porcine circovirus-associated diseases in pigs. Previously, it was demonstrated that mAbs 16G12, 38C1, 63H3 and 94H8 directed against the PCV2 capsid protein recognize PCV2 strains Stoon-1010 (PCV2a), 48285 (PCV2b), 1121 (PCV2a), 1147 (PCV2b) and II9F (PCV2b), but only neutralize Stoon-1010 and 48285. This points to the existence of two distinct PCV2 neutralization phenotypes: phenotype α (mAb recognition with neutralization; Stoon-1010 and 48285) and phenotype β (mAb recognition without neutralization; 1121, 1147 and II9F). In the present study, amino acids that are important in determining the neutralization phenotype were identified in the capsid. Mutation of T at position 190 to A in strain 48285 (phenotype α) resulted in a capsid resembling that of strain 1147 (phenotype β) and caused a loss of neutralization (switch from α to β). Mutations of P at position 151 to T and A at position 190 to T in strain II9F (phenotype β) resulted in a capsid resembling that of strain 48285 (phenotype α) and gave a gain of neutralization (switch from β to α). Mutations of T at position 131 to P and of E at position 191 to R in Stoon-1010 (phenotype α) changed the capsid into that of 1121 (phenotype β) and reduced neutralization (switch from α to β). This study demonstrated that single amino acid changes in the capsid result in a phenotypic switch from α to β or β to α.

  14. A distinctive oral phenotype points to FAM20A mutations not identified by Sanger sequencing.

    PubMed

    Poulter, James A; Smith, Claire E L; Murrillo, Gina; Silva, Sandra; Feather, Sally; Howell, Marianella; Crinnion, Laura; Bonthron, David T; Carr, Ian M; Watson, Christopher M; Inglehearn, Chris F; Mighell, Alan J

    2015-11-01

    Biallelic FAM20A mutations cause two conditions where Amelogenesis Imperfecta (AI) is the presenting feature: Amelogenesis Imperfecta and Gingival Fibromatosis Syndrome; and Enamel Renal Syndrome. A distinctive oral phenotype is shared in both conditions. On Sanger sequencing of FAM20A in cases with that phenotype, we identified two probands with single, likely pathogenic heterozygous mutations. Given the recessive inheritance pattern seen in all previous FAM20A mutation-positive families and the potential for renal disease, further screening was carried out to look for a second pathogenic allele. Reverse transcriptase-PCR on cDNA was used to determine transcript levels. CNVseq was used to screen for genomic insertions and deletions. In one family, FAM20A cDNA screening revealed only a single mutated FAM20A allele with the wild-type allele not transcribed. In the second family, CNV detection by whole genome sequencing (CNVseq) revealed a heterozygous 54.7 kb duplication encompassing exons 1 to 4 of FAM20A. This study confirms the link between biallelic FAM20A mutations and the characteristic oral phenotype. It highlights for the first time examples of FAM20A mutations missed by the most commonly used mutation screening techniques. This information informed renal assessment and ongoing clinical care.

  15. A structure-function study of MID1 mutations associated with a mild Opitz phenotype.

    PubMed

    Mnayer, Laila; Khuri, Sawsan; Merheby, Hassan Al-Ali; Meroni, Germana; Elsas, Louis J

    2006-03-01

    The X-linked form of Opitz syndrome (OS) affects midline structures and produces a characteristic, but heterogeneous, phenotype that may include severe mental retardation, hypertelorism, broad nasal bridge, widow's peak, cleft lip/cleft palate, congenital heart disease, laryngotracheal defects, and hypospadias. The MID1 gene was implicated in OS by linkage to Xp22. It encodes a 667 amino acid protein that contains a RING finger motif, two B-box zinc fingers, a coiled-coil, a fibronectin type III (FNIII) domain, and a B30.2 domain. Several mutations in MID1 are associated with severe OS. Here, we describe an intelligent male with a milder phenotype characterized by hypertelorism, broad nasal bridge, widow's peak, mild hypospadias, pectus excavatum, and a surgically corrected tracheo-esophageal fistula. He has an above average intelligence and no cleft lip/palate or heart disease. We identified a novel mutation in MID1 (P441L) which is in exon 8 and functionally associated with the FNIII domain. While OS phenotypes have been attributed to mutations in the C-terminal part of MID1, little is currently known about the structure-function relationships of MID1 mutations, and how they affect phenotype. We find from a literature review that missense mutations within the FNIII domain of MID1 are associated with a milder presentation of OS than missense mutations elsewhere in MID1. All truncating mutations (frameshift, insertions/deletions) lead to severe OS. We used homology analysis of the MID1 FNIII domain to investigate structure-function changes caused by our missense mutation. This and other missense mutations probably cause disruption of protein-protein interactions, either within MID1 or between MID1 and other proteins. We correlate these protein structure-function findings to the absence of CNS or palatal changes and conclude that the FNIII domain of the MID1 protein may be involved in midline differentiation after neural tube and palatal structures are completed.

  16. De novo SHANK3 mutation causes Rett syndrome-like phenotype in a female patient.

    PubMed

    Hara, Munetsugu; Ohba, Chihiro; Yamashita, Yushiro; Saitsu, Hirotomo; Matsumoto, Naomichi; Matsuishi, Toyojiro

    2015-07-01

    Rett syndrome (RTT) is a neurodevelopmental disorder predominantly affecting females. Females with the MECP2 mutations exhibit a broad spectrum of clinical manifestations ranging from classical Rett syndrome to asymptomatic carriers. Mutations of genes encoding cyclin-dependent kinase-like 5 (CDKL5) and forkhead box G1 (FOXG1) are also found in early onset RTT variants. Here, we present the first report of a female patient with RTT-like phenotype caused by SHANK3 (SH3 and multiple ankylin repeat domain 3) mutation, indicating that the clinical spectrum of SHANK3 mutations may extend to RTT-like phenotype in addition to (severe) developmental delay, absence of expressive speech, autistic behaviors and intellectual disability.

  17. Somatic mosaicism and the phenotypic expression of COL2A1 mutations.

    PubMed

    Nagendran, Sonali; Richards, Allan J; McNinch, Annie; Sandford, Richard N; Snead, Martin P

    2012-05-01

    Mutations in COL2A1, the gene for type II-collagen, can result in a wide variety of phenotypes depending upon the nature of the mutation. Dominant negative mutations tend to result in severe and often lethal skeletal dysplasias such as achondrogenesis type 2, Kniest dysplasia, and spondyloepiphyseal dysplasia congenita. Stickler syndrome, a condition characterized by ophthalmological and orofacial features, deafness and arthritis, usually, but not exclusively, results from haploinsufficiency. Overlapping features of all these disorders can also be seen in the same family. Rare reports have demonstrated that phenotypic variability can be explained in some families by somatic mosaicism. Here, we describe five further examples of somatic mosaicism of COL2A1 mutations illustrating the importance of detailed clinical evaluation and molecular testing even in clinically normal parents of affected individuals.

  18. Genotype-phenotype correlations analysis of mutations in the phenylalanine hydroxylase (PAH) gene.

    PubMed

    Bercovich, Dani; Elimelech, Arava; Zlotogora, Joel; Korem, Sigal; Yardeni, Tal; Gal, Nurit; Goldstein, Nurit; Vilensky, Bela; Segev, Roni; Avraham, Smadar; Loewenthal, Ron; Schwartz, Gerard; Anikster, Yair

    2008-01-01

    The aims of our research were to define the genotype-phenotype correlations of mutations in the phenylalanine hydroxylase (PAH) gene that cause phenylketonuria (PKU) among the Israeli population. The mutation spectrum of the PAH gene in PKU patients in Israel is described, along with a discussion on genotype-phenotype correlations. By using polymerase chain reaction/denaturing high-performance liquid chromatography (PCR/dHPLC) and DNA sequencing, we screened all exons of the PAH gene in 180 unrelated patients with four different PKU phenotypes [classic PKU, moderate PKU, mild PKU, and mild hyperphenylalaninemia (MHP)]. In 63.2% of patient genotypes, the metabolic phenotype could be predicted, though evidence is also found for both phenotypic inconsistencies among subjects with more than one type of mutation in the PAH gene. Data analysis revealed that about 25% of patients could participate in the future in (6R)-L: -erythro-5, 6, 7, 8-tetrahydrobiopterin (BH4) treatment trials according to their mutation genotypes. This study enables us to construct a national database in Israel that will serve as a valuable tool for genetic counseling and a prognostic evaluation of future cases of PKU.

  19. Phenotypes of craniofrontonasal syndrome in patients with a pathogenic mutation in EFNB1

    PubMed Central

    van den Elzen, M E P; Twigg, S R F; Goos, J A C; Hoogeboom, A J M; van den Ouweland, A M W; Wilkie, A O M; Mathijssen, I M J

    2014-01-01

    Craniofrontonasal syndrome (CFNS) is an X-linked developmental malformation, caused by mutations in the EFNB1 gene, which have only been described since 2004. A genotype–phenotype correlation seems not to be present. As it is of major importance to adequately counsel patients with EFNB1 mutations and their parents, and to improve diagnosis of new patients, more information about the phenotypic features is needed. This study included 23 patients (2 male, 21 female) with confirmed EFNB1 mutations. All patients underwent a thorough physical examination and photographs were taken. If available, radiological images were also consulted. Hypertelorism, longitudinal ridging and/or splitting of nails, a (mild) webbed neck and a clinodactyly of one or more toes were the only consistent features observed in all patients. Frequently observed phenotypic features were bifid tip of the nose (91%), columellar indentation (91%) and low implantation of breasts (90%). In comparison with anthropometric data of facial proportions, patients with CFNS had a significantly different face in multiple respects. An overview of all phenotypic features is shown. Patients with EFNB1 mutations have a clear phenotype. This study will facilitate genetic counseling of parents and patients, and contribute to the diagnostic and screening process of patients with suspected CFNS. PMID:24281372

  20. Mutation spectrum of phenylketonuria in Syrian population: genotype-phenotype correlation.

    PubMed

    Murad, Hossam; Dabboul, Amir; Moassas, Faten; Alasmar, Diana; Al-Achkar, Walid

    2013-10-10

    Characterization of the molecular basis of phenylketonuria (PKU) in Syria has been accomplished through the analysis of 78 unrelated chromosomes from 39 Syrian patients with PKU. Phenylalanine hydroxylase (PAH) gene mutations have been analyzed by using molecular detection methods based on the restriction fragment length polymorphism (RFLP), artificial constructed restriction sites (ACRS) PCR and direct DNA sequencing. 56.4% of the patients had cPKU. A mutation detection rate of 79.49% was achieved and sixteen different mutations were found: missense 56.25%, splice site 37.5%, and frameshift 6.25%. The predominant mutation in this population sample was p.R261Q G>A, p.F55>Lfs and p.R243Q G>A. No mutation in six PKU patients was observed. In 57.9% of patient genotypes, the metabolic phenotype could be predicted. The identification of the mutations in the PAH gene and the genotype-phenotype correlation should facilitate the evaluation of metabolic phenotypes, diagnosis, implementation of optimal dietary therapy, and determination of prognosis in the patients and genetic counseling for the patient's relatives.

  1. DLX3 mutation in a new family and its phenotypic variations.

    PubMed

    Lee, S-K; Lee, Z H; Lee, S-J; Ahn, B-D; Kim, Y-J; Lee, S-H; Kim, J-W

    2008-04-01

    Tricho-dento-osseous syndrome (TDO) is an autosomal-dominant disease characterized by curly hair at birth, enamel hypoplasia, taurodontism, and a thick cortical bone. A common DLX3 gene mutation (c.571_574delGGGG) has been identified in multiple families with variable clinical phenotypes. Recently, another DLX3 gene mutation (c.561_562delCT) was reported to cause amelogenesis imperfecta with taurodontism (AIHHT). We identified a Korean family with overlapping phenotypes of TDO and AIHHT. We performed mutational analysis to discover its genetic etiology. The identified mutation was c.561_562delCT mutation in the DLX3 gene. The enamel was hypomature and hypoplastic. The characteristic taurodontic features were not identified. Increased bone density or thickness could not be revealed by cephalometric, hand-wrist, and panoramic radiographs. Affected individuals reported that their nails were brittle, and they had curly hair at birth. This study clearly showed that the c.561_562delCT mutation had not only enamel defects, but also other clinical phenotypes resembling those of TDO syndrome.

  2. Phenotypic Suppression of Streptomycin Resistance by Mutations in Multiple Components of the Translation Apparatus

    PubMed Central

    Carr, Jennifer F.; Lee, Hannah J.; Jaspers, Joshua B.; Dahlberg, Albert E.; Jogl, Gerwald

    2015-01-01

    ABSTRACT The bacterial ribosome and its associated translation factors are frequent targets of antibiotics, and antibiotic resistance mutations have been found in a number of these components. Such mutations can potentially interact with one another in unpredictable ways, including the phenotypic suppression of one mutation by another. These phenotypic interactions can provide evidence of long-range functional interactions throughout the ribosome and its functional complexes and potentially give insights into antibiotic resistance mechanisms. In this study, we used genetics and experimental evolution of the thermophilic bacterium Thermus thermophilus to examine the ability of mutations in various components of the protein synthesis apparatus to suppress the streptomycin resistance phenotypes of mutations in ribosomal protein S12, specifically those located distant from the streptomycin binding site. With genetic selections and strain constructions, we identified suppressor mutations in EF-Tu or in ribosomal protein L11. Using experimental evolution, we identified amino acid substitutions in EF-Tu or in ribosomal proteins S4, S5, L14, or L19, some of which were found to also relieve streptomycin resistance. The wide dispersal of these mutations is consistent with long-range functional interactions among components of the translational machinery and indicates that streptomycin resistance can result from the modulation of long-range conformational signals. IMPORTANCE The thermophilic bacterium Thermus thermophilus has become a model system for high-resolution structural studies of macromolecular complexes, such as the ribosome, while its natural competence for transformation facilitates genetic approaches. Genetic studies of T. thermophilus ribosomes can take advantage of existing high-resolution crystallographic information to allow a structural interpretation of phenotypic interactions among mutations. Using a combination of genetic selections, strain constructions

  3. The hemoglobin O mutation in Indonesia: distribution and phenotypic expression.

    PubMed

    Daud, D; Harahap, A; Setianingsih, I; Nainggolan, I; Tranggana, S; Pakasi, R; Marzuki, S

    2001-01-01

    We have investigated hemoglobin O Indonesia (HbOIna) in related ethnic populations of the Indonesian archipelago: 1725 individuals of the five ethnic populations of South Sulawesi (Bugis, Toraja, Makassar, Mandar, and Kajang) and 959 individuals of the neighboring islands, who were divided into five phylogenetic groups: (a) Batak; (b) Malay from Padang, Pakanbaru, and Palembang in the island of Sumatra; (c) Javanese-related populations (Java, Tengger, and Bali) from the islands of Java and Bali; (d) populations of the Lesser Sunda Islands of Lombok, Sumba, and Sumbawa; and (e) the Papuan-languagespeaking population of Alor Island. Nineteen individuals heterozygous for HbO(Ina) were identified from the Bugis, Toraja, Makassar, and Kajang ethnic populations, but none from the other populations. In all cases, the underlying mutation was found to be in codon 116 (GAG to AAG) of the alpha1-globin gene, resulting in the Glull6Lys amino acid change. The level of HbO in the 17 individuals plus 12 additional family members carrying the mutation was found to be 11.6 +/- 1.0%, significantly lower than the expected 17%-22%, indicating the instability of HbO.

  4. Inactivating Mutations in ESCO2 Cause SC Phocomelia and Roberts Syndrome: No Phenotype-Genotype Correlation

    PubMed Central

    Schüle, Birgitt; Oviedo, Angelica; Johnston, Kathreen; Pai, Shashidhar; Francke, Uta

    2005-01-01

    The rare, autosomal recessive Roberts syndrome (RBS) is characterized by tetraphocomelia, profound growth deficiency of prenatal onset, craniofacial anomalies, microcephaly, and mental deficiency. SC phocomelia (SC) has a milder phenotype, with a lesser degree of limb reduction and with survival to adulthood. Since heterochromatin repulsion (HR) is characteristic for both disorders and is not complemented in somatic-cell hybrids, it has been hypothesized that the disorders are allelic. Recently, mutations in ESCO2 (establishment of cohesion 1 homolog 2) on 8p21.1 have been reported in RBS. To determine whether ESCO2 mutations are also responsible for SC, we studied three families with SC and two families in which variable degrees of limb and craniofacial abnormalities, detected by fetal ultrasound, led to pregnancy terminations. All cases were positive for HR. We identified seven novel mutations in exons 3–8 of ESCO2. In two families, affected individuals were homozygous—for a 5-nucleotide deletion in one family and a splice-site mutation in the other. In three nonconsanguineous families, probands were compound heterozygous for a single-nucleotide insertion or deletion, a nonsense mutation, or a splice-site mutation. Abnormal splice products were characterized at the RNA level. Since only protein-truncating mutations were identified, regardless of clinical severity, we conclude that genotype does not predict phenotype. Having established that RBS and SC are caused by mutations in the same gene, we delineated the clinical phenotype of the tetraphocomelia spectrum that is associated with HR and ESCO2 mutations and differentiated it from other types of phocomelia that are negative for HR. PMID:16380922

  5. KCNT1 mutations in seizure disorders: the phenotypic spectrum and functional effects.

    PubMed

    Lim, Chiao Xin; Ricos, Michael G; Dibbens, Leanne M; Heron, Sarah E

    2016-04-01

    Mutations in the sodium-gated potassium channel subunit gene KCNT1 have recently emerged as a cause of several different epileptic disorders. This review describes the mutational and phenotypic spectrum associated with the gene and discusses the comorbidities found in patients, which include intellectual disability and psychiatric features. The gene may also be linked with cardiac disorders. KCNT1 missense mutations have been found in 39% of patients with the epileptic encephalopathy malignant migrating focal seizures of infancy (MMFSI), making it the most significant MMFSI disease-causing gene identified to date. Mutations in KCNT1 have also been described in eight unrelated cases of sporadic and familial autosomal-dominant nocturnal frontal lobe epilepsy (ADNFLE). These patients have a high frequency of associated intellectual disability and psychiatric features. Two mutations in KCNT1 have been associated with both ADNFLE and MMFSI, suggesting that the genotype-phenotype relationship for KCNT1 mutations is not straightforward. Mutations have also been described in several patients with infantile epileptic encephalopathies other than MMFSI. Notably, all mutations in KCNT1 described to date are missense mutations, and electrophysiological studies have shown that they result in increased potassium current. Together, these genetic and electrophysiological studies raise the possibility of delivering precision medicine by treating patients with KCNT1 mutations using drugs that alter the action of potassium channels to specifically target the biological effects of their disease-causing mutation. Such trials are now in progress. Better understanding of the mechanisms underlying KCNT1-related disease will produce further improvements in treatment of the associated severe seizure disorders.

  6. Complex Inheritance of ABCA4 Disease: Four Mutations in a Family with Multiple Macular Phenotypes

    PubMed Central

    Lee, Winston; Xie, Yajing (Angela); Zernant, Jana; Yuan, Bo; Bearelly, Srilaxmi; Tsang, Stephen H.; Lupski, James R.; Allikmets, Rando

    2015-01-01

    Over 800 mutations in the ABCA4 gene cause autosomal recessive Stargardt disease. Due to extensive genetic heterogeneity, observed variant-associated phenotypes can manifest tremendous variability of expression. Furthermore, the high carrier frequency of pathogenic ABCA4 alleles in the general population (~1:20) often results in pseudo-dominant inheritance patterns further complicating the diagnosis and characterization of affected individuals. This study describes a genotype/phenotype analysis of an unusual family with multiple macular disease phenotypes spanning across two generations and segregating four distinct ABCA4 mutant alleles. Complete sequencing of ABCA4 discovered two known missense mutations, p.C54Y and p.G1961E. Array comparative genomic hybridization revealed a large novel deletion combined with a small insertion, c.6148-698_c.6670del/insTGTGCACCTCCCTAG, and complete sequencing of the entire ABCA4 genomic locus uncovered a new deep intronic variant, c.302+68C>T. Patients with the p.G1961E mutation had the mildest, confined maculopathy phenotype with peripheral flecks while those with all other mutant allele combinations exhibited a more advanced stage of generalized retinal and choriocapillaris atrophy. This family epitomizes the clinical and genetic complexity of ABCA4-associated diseases. It contained variants from all classes of mutations, in the coding region, deep intronic, both single nucleotide variants (SNV) and copy number variants (CNV) that accounted for varying phenotypes segregating in an apparent dominant fashion. Unequivocally defining disease-associated alleles in the ABCA4 locus requires a multifaceted approach that includes advanced mutation detection methods and a thorough analysis of clinical phenotypes. PMID:26527198

  7. Correlation between connexin 32 gene mutations and clinical phenotype in X-linked dominant Charcot-Marie-Tooth neuropathy

    SciTech Connect

    Ionasescu, V.; Ionasescu, R.; Searby, C.

    1996-06-14

    We studied the relationship between the genotype and clinical phenotype in 27 families with dominant X-linked Charcot-Marie-Tooth (CMTX1) neuropathy. Twenty-two families showed mutations in the coding region of the connexin32 (cx32) gene. The mutations include four nonsense mutations, eight missense mutations, two medium size deletions, and one insertion. Most missense mutations showed a mild clinical phenotype (five out of eight), whereas all nonsense mutations, the larger of the two deletions, and the insertion that produced frameshifts showed severe phenotypes. Five CMTX1 families with mild clinical phenotype showed no point mutations of the cx32 gene coding region. Three of these families showed positive genetic linkage with the markers of the Xq13.1 region. The genetic linkage of the remaining two families could not be evaluated because of their small size. 25 refs., 1 fig., 1 tab.

  8. Genetic testing in familial AD and FTD: mutation and phenotype spectrum in a Danish cohort.

    PubMed

    Lindquist, S G; Schwartz, M; Batbayli, M; Waldemar, G; Nielsen, J E

    2009-08-01

    Autosomal dominantly transmitted Alzheimer's disease (AD) and frontotemporal dementia (FTD) are genetically heterogeneous disorders. To date, three genes have been identified in which mutations cause early-onset autosomal dominant inherited AD: APP, PSEN1, and PSEN2. Mutations in two genes on chromosome 17, the MAPT and the PGRN genes, are associated with autosomal dominant inherited FTD. The aim of this study was to characterize the mutation spectrum and describe genotype-phenotype correlations in families with inherited dementia. The identification of novel mutations and/or atypical genotype-phenotype correlations contributes to further characterizing the disorders. DNA-samples from the 90 index cases from a Danish referral-based cohort representing families with presumed autosomal dominant inherited AD or FTD were screened for mutations in the known genes with sequencing, denaturing high-performance liquid chromatography (DHPLC) and multiplex ligation-dependent probe amplification (MLPA) techniques. Seven presumed pathogenic mutations (two PSEN1, one PSEN2, one APP, one MAPT, and two PGRN) were identified, including a novel PSEN2 mutation (V393M). No dosage aberrations were identified.

  9. Oncogenic mutations produce similar phenotypes in Drosophila tissues of diverse origins

    PubMed Central

    Stickel, Stefanie; Su, Tin Tin

    2014-01-01

    ABSTRACT An emerging interest in oncology is to tailor treatment to particular cancer genotypes, i.e. oncogenic mutations present in the tumor, and not the tissue of cancer incidence. Integral to such a practice is the idea that the same oncogenic mutation(s) produces similar outcomes in different tissues. To test this idea experimentally, we studied tumors driven by a combination of RasV12 and scrib1 mutations in Drosophila larvae. We found that tumors induced in tissues of neural ectodermal and mesodermal origins behaved similarly in every manner examined: cell cycle checkpoints, apoptosis, cellular morphology, increased aneuploidy and response to Taxol. We conclude that oncogenic effects override tissue-specific differences, at least for the mutations, tissues, and phenotypes studied herein. PMID:24570398

  10. Mutations in RIT1 cause Noonan syndrome – additional functional evidence and expanding the clinical phenotype

    PubMed Central

    Koenighofer, Martin; Hung, Christina Y.; McCauley, Jacob L.; Dallman, Julia; Back, Emma J.; Mihalek, Ivana; Gripp, Karen W.; Sol-Church, Katia; Rusconi, Paolo; Zhang, Zhaiyi; Shi, Geng-Xian; Andres, Douglas A.; Bodamer, Olaf A.

    2015-01-01

    RASopathies are a clinically heterogeneous group of conditions caused by mutations in one of sixteen proteins in the RAS-MAPK pathway. Recently, mutations in RIT1 were identified as a novel cause for Noonan syndrome. Here we provide additional functional evidence for a causal role of RIT1 mutations and expand the associated phenotypic spectrum. We identified two de novo missense variants p.Met90Ile and, p.Ala57Gly. Both variants resulted in increased MEK-ERK signaling compared to wild-type, underscoring gain-of-function as the primary functional mechanism. Introduction of p.Met90Ile and p.Ala57Gly into zebrafish embryos reproduced not only aspects of the human phenotype but also revealed abnormalities of eye development, emphasizing the importance of RIT1 for spatial and temporal organization of the growing organism. In addition, we observed severe lymphedema of the lower extremity and genitalia in one patient. We provide additional evidence for a causal relationship between pathogenic mutations in RIT1, increased RAS-MAPK/MEK-ERK signaling and the clinical phenotype. The mutant RIT1 protein may possess reduced GTPase activity or a diminished ability to interact with cellular GTPase activating proteins, however the precise mechanism remains unknown. The phenotypic spectrum is likely to expand and includes lymphedema of the lower extremities in addition to nuchal hygroma. PMID:25959749

  11. Mutations in the gene for X-linked adrenoleukodystrophy in patients with different clinical phenotypes

    SciTech Connect

    Braun, A.; Ambach, H.; Kammerer, S.; Rolinski, B.; Roscher, A.; Rabl, W.; Stoeckler, S.; Gaertner, J.; Zierz, S.

    1995-04-01

    Recently, the gene for the most common peroxisomal disorder, X-linked adrenoleukodystrophy (X-ALD), has been described encoding a peroxisomal membrane transporter protein. We analyzed the entire protein-coding sequence of this gene by reverse-transcription PCR, SSCP, and DNA sequencing in five patients with different clinical expressions were cerebral childhood ALD, adrenomyecloneuropathy (AMN), and {open_quotes}Addison disease only{close_quotes} (AD) phenotype. In the three patients exhibiting the classical picture of severe childhood ALD we identified in the 5{prime} portion of the X-ALD gene a 38-bp deletion that causes a frameshift mutation, a 3-bp deletion leading to a deletion of an amino acid in the ATP-binding domain of the ALD protein, and a missense mutation. In the patient with the clinical phenotype of AMN, a nonsense mutation in codon 212, along with a second site mutation at codon 178, was observed. Analysis of the patient with the ADO phenotype revealed a further missense mutation at a highly conserved position in the ALDP/PMP70 comparison. The disruptive nature of two mutations (i.e., the frameshift and the nonsense mutation) in patients with biochemically proved childhood ALD and AMN further strongly supports the hypothesis that alterations in this gene play a crucial role in the pathogenesis of X-ALD. Since the current biochemical techniques for X-ALD carrier detection in affected families lack sufficient reliability, our procedure described for systematic mutation scanning is also capable of improving genetic counseling and prenatal diagnosis. 19 refs., 6 figs., 3 tabs.

  12. Insights into genotype-phenotype correlation in pachyonychia congenita from the human intermediate filament mutation database.

    PubMed

    McLean, W H Irwin; Smith, Frances J D; Cassidy, Andrew J

    2005-10-01

    Keratins are the intermediate filament proteins specifically expressed by epithelial cells. The Human Genome Project has uncovered a total of 54 functional keratin genes that are differentially expressed in specific epithelial structures of the body, many of which involve the epidermis and its appendages. Pachyonychia congenita (PC) is a group of autosomal dominant genodermatoses affecting the nails, thick skin and other ectodermal structures, according to specific sub-type. The major clinical variants of the disorder (PC-1 and PC-2) are known to be caused by dominant-negative mutations in one of four differentiation-specific keratins: K6a, K6b, K16, and K17. A total of 20 human keratin genes are currently linked to single-gene disorders or are predisposing factors in complex traits. In addition, a further six intermediate filament genes have been linked to other non-epithelial genetic disorders. We have established a comprehensive mutation database that catalogs all published independent occurrences of intermediate filament mutations (http://www.interfil.org), with details of phenotypes, published papers, patient support groups and other information. Here, we review the genotype-phenotype trends emerging from the spectrum of mutations in these genes and apply these correlations to make predictions about PC phenotypes based on the site of mutation and keratin pair involved.

  13. Variability in dentofacial phenotypes in four families with WNT10A mutations

    PubMed Central

    Vink, Christian P; Ockeloen, Charlotte W; ten Kate, Sietske; Koolen, David A; Ploos van Amstel, Johannes Kristian; Kuijpers-Jagtman, Anne-Marie; van Heumen, Celeste C; Kleefstra, Tjitske; Carels, Carine E L

    2014-01-01

    This article describes the inter- and intra-familial phenotypic variability in four families with WNT10A mutations. Clinical characteristics of the patients range from mild to severe isolated tooth agenesis, over mild symptoms of ectodermal dysplasia, to more severe syndromic forms like odonto-onycho-dermal dysplasia (OODD) and Schöpf–Schulz–Passarge syndrome (SSPS). Recurrent WNT10A mutations were identified in all affected family members and the associated symptoms are presented with emphasis on the dentofacial phenotypes obtained with inter alia three-dimensional facial stereophotogrammetry. A comprehensive overview of the literature regarding WNT10A mutations, associated conditions and developmental defects is presented. We conclude that OODD and SSPS should be considered as variable expressions of the same WNT10A genotype. In all affected individuals, a dished-in facial appearance was observed which might be helpful in the clinical setting as a clue to the underlying genetic etiology. PMID:24398796

  14. Exploring the Phenotypic Space and the Evolutionary History of a Natural Mutation in Drosophila melanogaster.

    PubMed

    Ullastres, Anna; Petit, Natalia; González, Josefa

    2015-07-01

    A major challenge of modern Biology is elucidating the functional consequences of natural mutations. Although we have a good understanding of the effects of laboratory-induced mutations on the molecular- and organismal-level phenotypes, the study of natural mutations has lagged behind. In this work, we explore the phenotypic space and the evolutionary history of a previously identified adaptive transposable element insertion. We first combined several tests that capture different signatures of selection to show that there is evidence of positive selection in the regions flanking FBti0019386 insertion. We then explored several phenotypes related to known phenotypic effects of nearby genes, and having plausible connections to fitness variation in nature. We found that flies with FBti0019386 insertion had a shorter developmental time and were more sensitive to stress, which are likely to be the adaptive effect and the cost of selection of this mutation, respectively. Interestingly, these phenotypic effects are not consistent with a role of FBti0019386 in temperate adaptation as has been previously suggested. Indeed, a global analysis of the population frequency of FBti0019386 showed that climatic variables explain well the FBti0019386 frequency patterns only in Australia. Finally, although FBti0019386 insertion could be inducing the formation of heterochromatin by recruiting HP1a (Heterochromatin Protein 1a) protein, the insertion is associated with upregulation of sra in adult females. Overall, our integrative approach allowed us to shed light on the evolutionary history, the relevant fitness effects, and the likely molecular mechanisms of an adaptive mutation and highlights the complexity of natural genetic variants.

  15. Analysis of phenotypic features and FGFR2 mutations in Apert syndrome.

    PubMed Central

    Park, W J; Theda, C; Maestri, N E; Meyers, G A; Fryburg, J S; Dufresne, C; Cohen, M M; Jabs, E W

    1995-01-01

    A phenotypic and genotypic survey was conducted on 36 Apert syndrome patients. In all but one patient, an FGFR2 mutation, either S252W or P253R, was found in exon IIIa (exon U or 7). The frequency was 71% and 26%, for the mutations S252W and P253R, respectively. These mutations occur in the linker region between immunoglobulin-like domains II and III, which are involved in activation of the receptor by ligand binding and dimerization. The fact that one patient did not have a mutation in the same exon suggests further genetic heterogeneity in Apert syndrome. The frequencies of occurrence or means for measurements of 29 different clinical features (including severity of craniofacial features, syndactyly of the hands and feet, and multisystem involvement) were determined for all patients and for the two subgroups defined by their mutations. Comparison between the subgroups for the different clinical features was performed and suggested no statistically significant differences. These results are not unexpected, because the two common mutations for Apert syndrome alter FGFR2 at adjacent amino acids that are likely to have similar biological, and therefore phenotypic, consequences. Images Figure 2 Figure 3 Figure 4 PMID:7668257

  16. Identification of novel KIF11 mutations in patients with familial exudative vitreoretinopathy and a phenotypic analysis

    PubMed Central

    Li, Jia-Kai; Fei, Ping; Li, Yian; Huang, Qiu-Jing; Zhang, Qi; Zhang, Xiang; Rao, Yu-Qing; Li, Jing; Zhao, Peiquan

    2016-01-01

    KIF11 gene mutations cause a rare autosomal dominant inheritable disease called microcephaly with or without chorioretinopathy, lymphedema, or mental retardation (MCLMR). Recently, such mutations were also found to be associated with familial exudative vitreoretinopathy (FEVR). Here, we report 7 novel KIF11 mutations identified by targeted gene capture in a cohort of 142 probands with FEVR who were diagnosed in our clinic between March 2015 and November 2015. These mutations were: p.L171V, c.790-2A>C, p.Q525*, p.Q842*, p.S936*, p.L983fs and p.R1025G. Phenotypic analysis revealed that all of the affected probands had advanced FEVR (stage 4 or above). Three had microcephaly, and one had chorioretinopathy, which indicated a phenotypic overlap with MCLMR. Two mutations were also found in the families of the affected probands. One parent with a p.R1025G mutation had an avascular peripheral retina and abnormal looping vessels. However, one parent with p.L983fs had normal retina, which indicated incomplete penetration of the genotype. Our results further confirmed that KIF11 is causative of FEVR in an autosomal dominant manner. We also suggest the examination of MCLMR-like features, such as microcephaly, chorioretinopathy, for patients with FEVR and wide-field fundus photography for patients with MCLMR in future practice. PMID:27212378

  17. Analysis of phenotypic features and FGFR2 mutations in Apert syndrome

    SciTech Connect

    Park, Woo-Jin; Theda, C.; Maestri, N.E.

    1995-08-01

    A phenotypic and genotypic survey was conducted on 36 Apert syndrome patients. In all but one patient, an FGFR2 mutation, either S252W or P253R, was found in exon IIIa (exon U or 7). The frequency was 71% and 26% for the mutations S252W and P253R, respectively. These mutations occur in the linker region between immunoglobulin-like domains II and III, which are involved in activation of the receptor by ligand binding and dimerization. The fact that one patient did not have a mutation in the same exon suggests further genetic heterogeneity in Apert syndrome. The frequencies of occurrence or means for measurements of 29 different clinical features (including severity of craniofacial features, syndactyly of the hands and feet, and multisystem involvement) were determined for all patients and for the two subgroups defined by their mutations. Comparison between the subgroups for the different clinical features was performed and suggested no statistically significant differences. These results are not unexpected, because the two common mutations for Apert syndrome alter FGFR2 at adjacent amino acids that are likely to have similar biological, and therefore phenotypic, consequences. 34 refs., 4 figs., 1 tab.

  18. BMP9 mutations cause a vascular-anomaly syndrome with phenotypic overlap with hereditary hemorrhagic telangiectasia.

    PubMed

    Wooderchak-Donahue, Whitney L; McDonald, Jamie; O'Fallon, Brendan; Upton, Paul D; Li, Wei; Roman, Beth L; Young, Sarah; Plant, Parker; Fülöp, Gyula T; Langa, Carmen; Morrell, Nicholas W; Botella, Luisa M; Bernabeu, Carmelo; Stevenson, David A; Runo, James R; Bayrak-Toydemir, Pinar

    2013-09-05

    Hereditary hemorrhagic telangiectasia (HHT), the most common inherited vascular disorder, is caused by mutations in genes involved in the transforming growth factor beta (TGF-β) signaling pathway (ENG, ACVRL1, and SMAD4). Yet, approximately 15% of individuals with clinical features of HHT do not have mutations in these genes, suggesting that there are undiscovered mutations in other genes for HHT and possibly vascular disorders with overlapping phenotypes. The genetic etiology for 191 unrelated individuals clinically suspected to have HHT was investigated with the use of exome and Sanger sequencing; these individuals had no mutations in ENG, ACVRL1, and SMAD4. Mutations in BMP9 (also known as GDF2) were identified in three unrelated probands. These three individuals had epistaxis and dermal lesions that were described as telangiectases but whose location and appearance resembled lesions described in some individuals with RASA1-related disorders (capillary malformation-arteriovenous malformation syndrome). Analyses of the variant proteins suggested that mutations negatively affect protein processing and/or function, and a bmp9-deficient zebrafish model demonstrated that BMP9 is involved in angiogenesis. These data confirm a genetic cause of a vascular-anomaly syndrome that has phenotypic overlap with HHT.

  19. Phenotypic consequences of somatic mutations in the ataxia-telangiectasia mutated gene in non-small cell lung cancer

    PubMed Central

    Weber, Anika Maria; Drobnitzky, Neele; Devery, Aoife Maire; Bokobza, Sivan Mili; Adams, Richard A.; Maughan, Timothy S.; Ryan, Anderson Joseph

    2016-01-01

    Mutations in the Ataxia-telangiectasia mutated (ATM) gene are frequently found in human cancers, including non-small cell lung cancer (NSCLC). Loss of ATM function confers sensitivity to ionising radiation (IR) and topoisomerase inhibitors and may thus define a subset of cancer patients that could get increased benefit from these therapies. In this study, we evaluated the phenotypic consequences of ATM missense changes reported in seven NSCLC cell lines with regard to radiosensitivity and functionality of ATM signalling. Our data demonstrate that only 2/7 NSCLC cell lines (H1395 and H23) harbouring ATM missense mutations show a functional impairment of ATM signalling following IR-exposure. In these two cell lines, the missense mutations caused a significant reduction in ATM protein levels, impairment of ATM signalling and marked radiosensitivity. Of note, only cell lines with homozygous mutations in the ATM gene showed significant impairment of ATM function. Based on these observations, we developed an immunohistochemistry-based assay to identify patients with loss or reduction of ATM protein expression in a clinical setting. In a set of 137 NSCLC and 154 colorectal cancer specimens we identified tumoral loss of ATM protein expression in 9.5% and 3.9% of cases, respectively, demonstrating the potential utility of this method. PMID:27602502

  20. CASK mutations are frequent in males and cause X-linked nystagmus and variable XLMR phenotypes.

    PubMed

    Hackett, Anna; Tarpey, Patrick S; Licata, Andrea; Cox, James; Whibley, Annabel; Boyle, Jackie; Rogers, Carolyn; Grigg, John; Partington, Michael; Stevenson, Roger E; Tolmie, John; Yates, John Rw; Turner, Gillian; Wilson, Meredith; Futreal, Andrew P; Corbett, Mark; Shaw, Marie; Gecz, Jozef; Raymond, F Lucy; Stratton, Michael R; Schwartz, Charles E; Abidi, Fatima E

    2010-05-01

    Mutations of the calcium/calmodulin-dependent serine protein kinase (CASK) gene have recently been associated with X-linked mental retardation (XLMR) with microcephaly, optic atrophy and brainstem and cerebellar hypoplasia, as well as with an X-linked syndrome having some FG-like features. Our group has recently identified four male probands from 358 probable XLMR families with missense mutations (p.Y268H, p.P396S, p.D710G and p.W919R) in the CASK gene. Congenital nystagmus, a rare and striking feature, was present in two of these families. We screened a further 45 probands with either nystagmus or microcephaly and mental retardation (MR), and identified two further mutations, a missense mutation (p.Y728C) and a splice mutation (c.2521-2A>T) in two small families with nystagmus and MR. Detailed clinical examinations of all six families, including an ophthalmological review in four families, were undertaken to further characterise the phenotype. We report on the clinical features of 24 individuals, mostly male, from six families with CASK mutations. The phenotype was variable, ranging from non-syndromic mild MR to severe MR associated with microcephaly and dysmorphic facial features. Carrier females were variably affected. Congenital nystagmus was found in members of four of the families. Our findings reinforce the CASK gene as a relatively frequent cause of XLMR in females and males. We further define the phenotypic spectrum and demonstrate that affected males with missense mutations or in-frame deletions in CASK are frequently associated with congenital nystagmus and XLMR, a striking feature not previously reported.

  1. Interplay between DMD Point Mutations and Splicing Signals in Dystrophinopathy Phenotypes

    PubMed Central

    Juan-Mateu, Jonàs; González-Quereda, Lidia; Rodríguez, Maria José; Verdura, Edgard; Lázaro, Kira; Jou, Cristina; Nascimento, Andrés; Jiménez-Mallebrera, Cecilia; Colomer, Jaume; Monges, Soledad; Lubieniecki, Fabiana; Foncuberta, Maria Eugenia; Pascual-Pascual, Samuel Ignacio; Molano, Jesús; Baiget, Montserrat; Gallano, Pia

    2013-01-01

    DMD nonsense and frameshift mutations lead to severe Duchenne muscular dystrophy while in-frame mutations lead to milder Becker muscular dystrophy. Exceptions are found in 10% of cases and the production of alternatively spliced transcripts is considered a key modifier of disease severity. Several exonic mutations have been shown to induce exon-skipping, while splice site mutations result in exon-skipping or activation of cryptic splice sites. However, factors determining the splicing pathway are still unclear. Point mutations provide valuable information regarding the regulation of pre-mRNA splicing and elements defining exon identity in the DMD gene. Here we provide a comprehensive analysis of 98 point mutations related to clinical phenotype and their effect on muscle mRNA and dystrophin expression. Aberrant splicing was found in 27 mutations due to alteration of splice sites or splicing regulatory elements. Bioinformatics analysis was performed to test the ability of the available algorithms to predict consequences on mRNA and to investigate the major factors that determine the splicing pathway in mutations affecting splicing signals. Our findings suggest that the splicing pathway is highly dependent on the interplay between splice site strength and density of regulatory elements. PMID:23536893

  2. KCNC3: phenotype, mutations, channel biophysics-a study of 260 familial ataxia patients.

    PubMed

    Figueroa, Karla P; Minassian, Natali A; Stevanin, Giovanni; Waters, Michael; Garibyan, Vartan; Forlani, Sylvie; Strzelczyk, Adam; Bürk, Katrin; Brice, Alexis; Dürr, Alexandra; Papazian, Diane M; Pulst, Stefan M

    2010-02-01

    We recently identified KCNC3, encoding the Kv3.3 voltage-gated potassium channel, as the gene mutated in SCA13. One g.10684G>A (p.Arg420His) mutation caused late-onset ataxia resulting in a nonfunctional channel subunit with dominant-negative properties. A French early-onset pedigree with mild mental retardation segregated a g.10767T>C (p.Phe448Leu) mutation. This mutation changed the relative stability of the channel's open conformation. Coding exons were amplified and sequenced in 260 autosomal-dominant ataxia index cases of European descent. Functional analyses were performed using expression in Xenopus oocytes. The previously identified p.Arg420His mutation occurred in three families with late-onset ataxia. A novel mutation g.10693G>A (p.Arg423His) was identified in two families with early-onset. In one pedigree, a novel g.10522G>A (p.Arg366His) sequence variant was seen in one index case but did not segregate with affected status in the respective family. In a heterologous expression system, the p.Arg423His mutation exhibited dominant-negative properties. The p.Arg420His mutation, which results in a nonfunctional channel subunit, was recurrent and associated with late-onset progressive ataxia. In two families the p.Arg423His mutation was associated with early-onset slow-progressive ataxia. Despite a phenotype reminiscent of the p.Phe448Leu mutation, segregating in a large early-onset French pedigree, the p.Arg423His mutation resulted in a nonfunctional subunit with a strong dominant-negative effect.

  3. Multiple Phenotypes Resulting from a Mutagenesis Screen for Pharynx Muscle Mutations in Caenorhabditis elegans

    PubMed Central

    Ferrier, Andrew; Charron, Alexandra; Sadozai, Yama; Switaj, Lynn; Szutenbach, Anneliese; Smith, Pliny A.

    2011-01-01

    We describe a novel screen to isolate pharyngeal cell morphology mutants in Caenorhabditis elegans using myo-2::GFP to rapidly identify abnormally shaped pharynxes in EMS (Ethyl Methanesulfonate) mutagenized worms. We observed over 83 C. elegans lines with distinctive pharyngeal phenotypes in worms surviving to the L1 larval stage, with phenotypes ranging from short pharynx, unattached pharynx, missing cells, asymmetric morphology, and non-adherent pharynx cells. Thirteen of these mutations have been chromosomally mapped using Single Nucleotide Polymorphisms (SNPs) and deficiency strain complementation. Our studies have focused on genetically mapping and functionally testing two phenotypes, the short pharynx and the loss of muscle cohesion phenotypes. We have also identified new alleles of sma-1, and our screen suggests many genes directing pharynx assembly and structure may be either pharynx specific or less critical in other tissues. PMID:22073173

  4. Multiple phenotypes resulting from a mutagenesis screen for pharynx muscle mutations in Caenorhabditis elegans.

    PubMed

    Ferrier, Andrew; Charron, Alexandra; Sadozai, Yama; Switaj, Lynn; Szutenbach, Anneliese; Smith, Pliny A

    2011-01-01

    We describe a novel screen to isolate pharyngeal cell morphology mutants in Caenorhabditis elegans using myo-2::GFP to rapidly identify abnormally shaped pharynxes in EMS (Ethyl Methanesulfonate) mutagenized worms. We observed over 83 C. elegans lines with distinctive pharyngeal phenotypes in worms surviving to the L1 larval stage, with phenotypes ranging from short pharynx, unattached pharynx, missing cells, asymmetric morphology, and non-adherent pharynx cells. Thirteen of these mutations have been chromosomally mapped using Single Nucleotide Polymorphisms (SNPs) and deficiency strain complementation. Our studies have focused on genetically mapping and functionally testing two phenotypes, the short pharynx and the loss of muscle cohesion phenotypes. We have also identified new alleles of sma-1, and our screen suggests many genes directing pharynx assembly and structure may be either pharynx specific or less critical in other tissues.

  5. Alzheimer’s disease phenotypes and genotypes associated with mutations in presenilin 2

    PubMed Central

    Jayadev, Suman; Leverenz, James B.; Steinbart, Ellen; Stahl, Justin; Klunk, William; Yu, Cheng-En

    2010-01-01

    Mutations in presenilin 2 are rare causes of early onset familial Alzheimer’s disease. Eighteen presenilin 2 mutations have been reported, although not all have been confirmed pathogenic. Much remains to be learned about the range of phenotypes associated with these mutations. We have analysed our unique collection of 146 affected cases in 11 Volga German families, 101 who are likely to have the same N141I mutation in presenilin 2 (54 genotyped confirmed). We have also assessed the detailed neuropathologic findings in 18 autopsies from these families and reviewed the world’s literature on other presenilin 2 mutations; presenting a novel mutation that is predicted to lead to a premature truncation codon. Seven presenilin 2 mutations reported in the literature have strong evidence for pathogenicity whereas others may be benign polymorphisms. One hundred and one affected persons, with sufficient historical information from the Volga German pedigrees (N141I mutation), had a mean onset age of 53.7 years ± 7.8 (range 39–75) and mean age at death of 64.2 years ± 9.8 (range 43–88). These figures overlap with and generally fall between the results from the subjects in our centre who have late onset familial Alzheimer’s disease or mutations in presenilin 1. Seizures were noted in 20 (30%) of 64 subjects with detailed medical records. Two mutation carriers lived beyond age 80 without developing dementia, representing uncommon examples of decreased penetrance. Two persons had severe amyloid angiopathy and haemorrhagic stroke. Eighteen cases had detailed histopathology available and analysed at our institution. Braak stage was five or six, amyloid angiopathy and neuritic plaques were common and more than 75% had Lewy bodies in the amygdala. TAR DNA-binding protein-43 inclusions were uncommon. In addition, a 58-year-old female with a 2 year course of cognitive decline and no family history of dementia has abnormal fludeoxyglucose-positron emission tomography imaging

  6. Alzheimer's disease phenotypes and genotypes associated with mutations in presenilin 2.

    PubMed

    Jayadev, Suman; Leverenz, James B; Steinbart, Ellen; Stahl, Justin; Klunk, William; Yu, Cheng-En; Bird, Thomas D

    2010-04-01

    Mutations in presenilin 2 are rare causes of early onset familial Alzheimer's disease. Eighteen presenilin 2 mutations have been reported, although not all have been confirmed pathogenic. Much remains to be learned about the range of phenotypes associated with these mutations. We have analysed our unique collection of 146 affected cases in 11 Volga German families, 101 who are likely to have the same N141I mutation in presenilin 2 (54 genotyped confirmed). We have also assessed the detailed neuropathologic findings in 18 autopsies from these families and reviewed the world's literature on other presenilin 2 mutations; presenting a novel mutation that is predicted to lead to a premature truncation codon. Seven presenilin 2 mutations reported in the literature have strong evidence for pathogenicity whereas others may be benign polymorphisms. One hundred and one affected persons, with sufficient historical information from the Volga German pedigrees (N141I mutation), had a mean onset age of 53.7 years+/-7.8 (range 39-75) and mean age at death of 64.2 years+/-9.8 (range 43-88). These figures overlap with and generally fall between the results from the subjects in our centre who have late onset familial Alzheimer's disease or mutations in presenilin 1. Seizures were noted in 20 (30%) of 64 subjects with detailed medical records. Two mutation carriers lived beyond age 80 without developing dementia, representing uncommon examples of decreased penetrance. Two persons had severe amyloid angiopathy and haemorrhagic stroke. Eighteen cases had detailed histopathology available and analysed at our institution. Braak stage was five or six, amyloid angiopathy and neuritic plaques were common and more than 75% had Lewy bodies in the amygdala. TAR DNA-binding protein-43 inclusions were uncommon. In addition, a 58-year-old female with a 2 year course of cognitive decline and no family history of dementia has abnormal fludeoxyglucose-positron emission tomography imaging and a novel

  7. FOXL2 mutations lead to different ovarian phenotypes in BPES patients: Case Report.

    PubMed

    Méduri, Géri; Bachelot, Anne; Duflos, Catherine; Bständig, Bettina; Poirot, Catherine; Genestie, Catherine; Veitia, Reiner; De Baere, Elfride; Touraine, Philippe

    2010-01-01

    FOXL2 mutations cause the autosomal dominant Blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) that may be associated with premature ovarian failure (POF). However, little is known about the molecular mechanisms of FOXL2 actions in the human ovary. We conducted an extensive clinical, hormonal and ovarian histological study in two patients carrying a FOXL2 mutation associated with the typical eyelid malformations and infertility. This observational study was conducted at referral centres for POF. Histological and immunohistological studies were conducted on ovarian biopsies from two women with POF carrying a FOXL2 mutation resulting in putative polyalanine expansions of the protein. Abnormalities similar to those observed in mice with FOXL2 gene inactivation were present in the first patient's ovary, although the ovarian histology of the second patient was apparently normal. Different ovarian phenotypes, follicular defects and distribution of FOXL2 protein were observed in two patients carrying a FOXL2 mutation.

  8. Mutations of the Wiskott-Aldrich Syndrome Protein affect protein expression and dictate the clinical phenotypes.

    PubMed

    Ochs, Hans D

    2009-01-01

    Mutations of the Wiskott-Aldrich Syndrome Protein (WASP) are responsible for classic Wiskott-Aldrich Syndrome (WAS), X-linked thrombocytopenia (XLT), and in rare instances congenital X-linked neutropenia (XLN). WASP is a regulator of actin polymerization in hematopoietic cells with well-defined functional domains that are involved in cell signaling and cell locomotion, immune synapse formation, and apoptosis. Mutations of WASP are located throughout the gene and either inhibit or disregulate normal WASP function. Analysis of a large patient population demonstrates a strong phenotype-genotype correlation. Classic WAS occurs when WASP is absent, XLT when mutated WASP is expressed and XLN when missense mutations occur in the Cdc42-binding site. However, because there are exceptions to this rule it is difficult to predict the long-term prognosis of a given affected boy solely based on the analysis of WASP expression.

  9. Indian-subcontinent NBIA: unusual phenotypes, novel PANK2 mutations, and undetermined genetic forms.

    PubMed

    Aggarwal, Annu; Schneider, Susanne A; Houlden, Henry; Silverdale, Monty; Paudel, Reema; Paisan-Ruiz, Coro; Desai, Shrinivas; Munshi, Mihir; Sanghvi, Darshana; Hardy, John; Bhatia, Kailash P; Bhatt, Mohit

    2010-07-30

    Neurodegeneration with brain iron accumulation (NBIA) is etiologically, clinically, and by imaging a heterogeneous group including NBIA types 1 [pantothenate kinase-associated neurodegeneration (PKAN)] and 2 (PLA2G6-associated neurodegeneration), neuroferritinopathy, and aceruloplasminaemia. Data on genetically defined Indian-subcontinent NBIA cases are limited. We report 6 patients from the Indian-subcontinent with a movement disorder and MRI basal ganglia iron deposition, compatible with diagnosis of an NBIA syndrome. All patients were screened for abnormalities in serum ceruloplasmin and ferritin levels and mutations in NBIA-associated genes [pantothenate kinase 2 (PANK2), PLA2G6 and ferritin light chain (exon 4)]. We present clinical, imaging and genetic data correlating phenotype-genotype relations. Four patients carried PANK2 mutations, two of these were novel. The clinical phenotype was mainly dystonic with generalized dystonia and marked orobulbar features in the 4 adolescent-onset cases. One of the four had a late-onset (age 37) unilateral jerky postural tremor. His mutation, c.1379C>T, appears associated with a milder phenotype. Interestingly, he developed the eye-of-the-tiger sign only 10 years after onset. Two of the six presented with adult-onset levodopa (L-dopa)-responsive asymmetric re-emergent rest tremor, developing L-dopa-induced dyskinesias, and good benefit to deep brain stimulation (in one), thus resembling Parkinson's disease (PD). Both had an eye-of-the-tiger sign on MRI but were negative for known NBIA-associated genes, suggesting the existence of further genetic or sporadic forms of NBIA syndromes. In conclusion, genetically determined NBIA cases from the Indian subcontinent suggest presence of unusual phenotypes of PANK2 and novel mutations. The phenotype of NBIA of unknown cause includes a PD-like presentation.

  10. Mutations in the BLOC-1 Subunits Dysbindin and Muted Generate Divergent and Dosage-dependent Phenotypes*

    PubMed Central

    Larimore, Jennifer; Zlatic, Stephanie A.; Gokhale, Avanti; Tornieri, Karine; Singleton, Kaela S.; Mullin, Ariana P.; Tang, Junxia; Talbot, Konrad; Faundez, Victor

    2014-01-01

    Post-mortem analysis has revealed reduced levels of the protein dysbindin in the brains of those suffering from the neurodevelopmental disorder schizophrenia. Consequently, mechanisms controlling the cellular levels of dysbindin and its interacting partners may participate in neurodevelopmental processes impaired in that disorder. To address this question, we studied loss of function mutations in the genes encoding dysbindin and its interacting BLOC-1 subunits. We focused on BLOC-1 mutants affecting synapse composition and function in addition to their established systemic pigmentation, hematological, and lung phenotypes. We tested phenotypic homogeneity and gene dosage effects in the mouse null alleles muted (Bloc1s5mu/mu) and dysbindin (Bloc1s8sdy/sdy). Transcripts of NMDA receptor subunits and GABAergic interneuron markers, as well as expression of BLOC-1 subunit gene products, were affected differently in the brains of Bloc1s5mu/mu and Bloc1s8sdy/sdy mice. Unlike Bloc1s8sdy/sdy, elimination of one or two copies of Bloc1s5 generated indistinguishable pallidin transcript phenotypes. We conclude that monogenic mutations abrogating the expression of a protein complex subunit differentially affect the expression of other complex transcripts and polypeptides as well as their downstream effectors. We propose that the genetic disruption of different subunits of protein complexes and combinations thereof diversifies phenotypic presentation of pathway deficiencies, contributing to the wide phenotypic spectrum and complexity of neurodevelopmental disorders. PMID:24713699

  11. 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

  12. Mutations in chromatin regulators functionally link Cornelia de Lange syndrome and clinically overlapping phenotypes.

    PubMed

    Parenti, Ilaria; Teresa-Rodrigo, María E; Pozojevic, Jelena; Ruiz Gil, Sara; Bader, Ingrid; Braunholz, Diana; Bramswig, Nuria C; Gervasini, Cristina; Larizza, Lidia; Pfeiffer, Lutz; Ozkinay, Ferda; Ramos, Feliciano; Reiz, Benedikt; Rittinger, Olaf; Strom, Tim M; Watrin, Erwan; Wendt, Kerstin; Wieczorek, Dagmar; Wollnik, Bernd; Baquero-Montoya, Carolina; Pié, Juan; Deardorff, Matthew A; Gillessen-Kaesbach, Gabriele; Kaiser, Frank J

    2017-03-01

    The coordinated tissue-specific regulation of gene expression is essential for the proper development of all organisms. Mutations in multiple transcriptional regulators cause a group of neurodevelopmental disorders termed "transcriptomopathies" that share core phenotypical features including growth retardation, developmental delay, intellectual disability and facial dysmorphism. Cornelia de Lange syndrome (CdLS) belongs to this class of disorders and is caused by mutations in different subunits or regulators of the cohesin complex. Herein, we report on the clinical and molecular characterization of seven patients with features overlapping with CdLS who were found to carry mutations in chromatin regulators previously associated to other neurodevelopmental disorders that are frequently considered in the differential diagnosis of CdLS. The identified mutations affect the methyltransferase-encoding genes KMT2A and SETD5 and different subunits of the SWI/SNF chromatin-remodeling complex. Complementary to this, a patient with Coffin-Siris syndrome was found to carry a missense substitution in NIPBL. Our findings indicate that mutations in a variety of chromatin-associated factors result in overlapping clinical phenotypes, underscoring the genetic heterogeneity that should be considered when assessing the clinical and molecular diagnosis of neurodevelopmental syndromes. It is clear that emerging molecular mechanisms of chromatin dysregulation are central to understanding the pathogenesis of these clinically overlapping genetic disorders.

  13. Mutation in collagen II alpha 1 isoforms delineates Stickler and Wagner syndrome phenotypes

    PubMed Central

    Tran-Viet, Khanh-Nhat; Soler, Vincent; Quiette, Valencia; Powell, Caldwell; Yanovitch, Tammy; Metlapally, Ravikanth; Luo, Xiaoyan; Katsanis, Nicholas; Nading, Erica

    2013-01-01

    Purpose Stickler syndrome is an arthro-ophthalmopathy with phenotypic overlap with Wagner syndrome. The common Stickler syndrome type I is inherited as an autosomal dominant trait, with causal mutations in collagen type II alpha 1 (COL2A1). Wagner syndrome is associated with mutations in versican (VCAN), which encodes for a chondroitin sulfate proteoglycan. A three-generation Caucasian family variably diagnosed with either syndrome was screened for sequence variants in the COL2A1 and VCAN genes. Methods Genomic DNA samples derived from saliva were collected from all family members (six affected and four unaffected individuals). Complete sequencing of COL2A1 and VCAN was performed on two affected individuals. Direct sequencing of remaining family members was conducted if the discovered variants followed segregation. Results A base-pair substitution (c.258C>A) in exon 2 of COL2A1 cosegregated with familial disease status. This known mutation occurs in a highly conserved site that causes a premature stop codon (p.C86X). The mutation was not seen in 1,142 ethnically matched control DNA samples. Conclusions Premature stop codons in COL2A1 exon 2 lead to a Stickler syndrome type I ocular-only phenotype with few or no systemic manifestations. Mutation screening of COL2A1 exon 2 in families with autosomal dominant vitreoretinopathy is important for accurate clinical diagnosis. PMID:23592912

  14. Narrative review: Thrombocytosis, polycythemia vera, and JAK2 mutations: The phenotypic mimicry of chronic myeloproliferation.

    PubMed

    Spivak, Jerry L

    2010-03-02

    The myeloproliferative disorders polycythemia vera, essential thrombocytosis, and primary myelofibrosis are clonal disorders arising in a pluripotent hematopoietic stem cell, causing an unregulated increase in the number of erythrocytes, leukocytes, or platelets, alone or in combination; eventual marrow dominance by the progeny of the involved stem cell; and a tendency to arterial or venous thrombosis, marrow fibrosis, splenomegaly, or transformation to acute leukemia, albeit at widely varying frequencies. The discovery of an activating mutation (V617F) in the gene for JAK2 (Janus kinase 2), a tyrosine kinase utilized by hematopoietic cell receptors for erythropoietin, thrombopoietin, and granulocyte colony-stimulating factor, provided an explanation for the shared clinical features of these 3 disorders. Constitutive JAK2 activation provides a growth and survival advantage to the hematopoietic cells of the affected clone. Because signaling by the mutated kinase utilizes normal pathways, the result is overproduction of morphologically normal blood cells, an often indolent course, and (in essential thrombocytosis) usually a normal life span. Because the erythropoietin, thrombopoietin, and granulocyte colony-stimulating factor receptors are all constitutively activated, polycythemia vera is the potential ultimate clinical phenotype of the JAK2 V617F mutation and, as a corollary, is the most common of the 3 disorders. The number of cells expressing the JAK2 V617F mutation (the allele burden) seems to correlate with the clinical phenotype. Preliminary results of clinical trials with agents that inhibit the mutated kinase indicate a reduction in splenomegaly and alleviation of night sweats, fatigue, and pruritus.

  15. Augmentation of phenotype in a transgenic Parkinson mouse heterozygous for a Gaucher mutation.

    PubMed

    Fishbein, Ianai; Kuo, Yien-Ming; Giasson, Benoit I; Nussbaum, Robert L

    2014-12-01

    The involvement of the protein α-synuclein (SNCA) in the pathogenesis of Parkinson's disease is strongly supported by the facts that (i) missense and copy number mutations in the SNCA gene can cause inherited Parkinson's disease; and (ii) Lewy bodies in sporadic Parkinson's disease are largely composed of aggregated SNCA. Unaffected heterozygous carriers of Gaucher disease mutations have an increased risk for Parkinson's disease. As mutations in the GBA gene encoding glucocerebrosidase (GBA) are known to interfere with lysosomal protein degradation, GBA heterozygotes may demonstrate reduced lysosomal SNCA degradation, leading to increased steady-state SNCA levels and promoting its aggregation. We have created mouse models to investigate the interaction between GBA mutations and synucleinopathies. We investigated the rate of SNCA degradation in cultured primary cortical neurons from mice expressing wild-type mouse SNCA, wild-type human SNCA, or mutant A53T SNCA, in a background of either wild-type Gba or heterozygosity for the L444P GBA mutation associated with Gaucher disease. We also tested the effect of this Gaucher mutation on motor and enteric nervous system function in these transgenic animals. We found that human SNCA is stable, with a half-life of 61 h, and that the A53T mutation did not significantly affect its half-life. Heterozygosity for a naturally occurring Gaucher mutation, L444P, reduced GBA activity by 40%, reduced SNCA degradation and triggered accumulation of the protein in culture. This mutation also resulted in the exacerbation of motor and gastrointestinal deficits found in the A53T mouse model of Parkinson's disease. This study demonstrates that heterozygosity for a Gaucher disease-associated mutation in Gba interferes with SNCA degradation and contributes to its accumulation, and exacerbates the phenotype in a mouse model of Parkinson's disease.

  16. The Spectrum of CHM Gene Mutations in Choroideremia and Their Relationship to Clinical Phenotype

    PubMed Central

    Simunovic, Matthew P.; Jolly, Jasleen K.; Xue, Kanmin; Edwards, Thomas L.; Groppe, Markus; Downes, Susan M.; MacLaren, Robert E.

    2016-01-01

    Purpose We report the underlying genotype and explore possible genotypic-phenotypic correlations in a large cohort of choroideremia patients. Methods We studied prospectively a cohort of 79 patients diagnosed within a tertiary referral service for patients with retinal dystrophies. Phenotypic evaluation consisted of clinical examination, including visual acuity and residual retinal area by fundus autofluorescence (FAF). Genotype was established by sequencing. We also investigated whether particular genotypes were associated with more severe phenotypes by performing analysis of covariance (ANCOVA), with visual acuity and FAF as the dependent variables and age as the covariant. Results A total of 74 (94%) of patients in our cohort had causative mutations by sequencing, the majority of which were anticipated to be null. Of these, 35 (47%) had insertions and deletions, 13 (18%) had mutations predicted to affect splicing, and 26 (35%) had single point mutations. In the latter case, 13 of 21 (62%) pedigrees with single point mutations were C to T transitions at C-phosphate-G (CpG) dinucleotides. These mutations were spread across 5 of only 24 CpG dinucleotides in the entire CHM cDNA. Furthermore, these 5 locations are the only sites at which C to T transitions result in a stop codon. No clear evidence was found for genotype–phenotype correlation except in the instance of a patient with a large deletion involving neighbouring sequences. Conclusions In patients with a diagnosis of choroideremia made by a specialty service, there is a high likelihood of establishing a genetic diagnosis. The majority of causative mutations appear to be null and, therefore, may benefit from gene replacement therapy. A disproportionate number of single point mutations observed were C to T transitions, consistent with the evolutionary decay of CpG dinucleotides through methylation and subsequent deamination. Hence, the development of choroideremia in such patients may represent the unwanted

  17. Bilateral frontoparietal polymicrogyria: a novel GPR56 mutation and an unusual phenotype.

    PubMed

    Santos-Silva, Rita; Passas, Armanda; Rocha, Carla; Figueiredo, Rita; Mendes-Ribeiro, Jose; Fernandes, Susana; Biskup, Saskia; Leão, Miguel

    2015-04-01

    Loss of function of GPR56 causes a specific brain malformation called the bilateral frontoparietal polymicrogyria (BFPP), which has typical clinical and neuroradiological findings. So far, 35 families and 26 independent mutations have been described.We present a Portuguese 5-year-old boy, born from nonconsanguineous parents, with BFPP. This patient has a novel GPR56 mutation (R271X) and an unusual phenotype, because he presents hot water epilepsy.To the best of our knowledge, this is the first reported case of BFPP evolving hot water epilepsy.

  18. A rare CYP21A2 mutation in a congenital adrenal hyperplasia kindred displaying genotype-phenotype nonconcordance.

    PubMed

    Khattab, Ahmed; Yuen, Tony; Al-Malki, Sultan; Yau, Mabel; Kazmi, Diya; Sun, Li; Harbison, Madeleine; Haider, Shozeb; Zaidi, Mone; New, Maria I

    2016-01-01

    Congenital adrenal hyperplasia (CAH) owing to 21-hydroxylase deficiency is caused by the autosomal recessive inheritance of mutations in the gene CYP21A2. CYP21A2 mutations lead to variable impairment of the 21-hydroxylase enzyme, which, in turn, is associated with three clinical phenotypes, namely, salt wasting, simple virilizing, and nonclassical CAH. However, it is known that a given mutation can associate with different clinical phenotypes, resulting in a high rate of genotype-phenotype nonconcordance. We aimed to study the genotype-phenotype nonconcordance in a family with three siblings affected with nonclassical CAH. All had hormonal evidence of nonclassical CAH, but this phenotype could not be explained by the genotype obtained from commercial CYP21A2 genetic testing, which revealed heterozygosity for the maternal 30 kb deletion mutation. We performed Sanger sequencing of the entire CYP21A2 gene in this family to search for a rare mutation that was not covered by commercial testing and found in the three siblings a second, rare c.1097G>A (p.R366H) mutation in exon 8. Computational modeling confirmed that this was a mild mutation consistent with nonclassical CAH. We recommend that sequencing of entire genes for rare mutations should be carried out when genotype-phenotype nonconcordance is observed in patients with autosomal recessive monogenic disorders, including CAH.

  19. Novel truncating mutations in PKP1 and DSP cause similar skin phenotypes in two Brazilian families.

    PubMed

    Tanaka, A; Lai-Cheong, J E; Café, M E M; Gontijo, B; Salomão, P R; Pereira, L; McGrath, J A

    2009-03-01

    Inherited mutations in components of desmosomes result in a spectrum of syndromes characterized by variable abnormalities in the skin and its appendages, including blisters and erosions, palmoplantar hyperkeratosis, woolly hair or hypotrichosis and, in some cases, extracutaneous features such as cardiomyopathy. We investigated the molecular basis of two Brazilian patients presenting with clinical features consistent with ectodermal dysplasia-skin fragility syndrome. In patient 1 we identified a homozygous nonsense mutation, p.R672X, in the PKP1 gene (encoding plakophilin 1). This particular mutation has not been reported previously but is similar to the molecular pathology underlying other cases of this syndrome. In patient 2 we found compound heterozygosity for two frameshift mutations, c.2516del4 and c.3971del4, in the DSP gene (encoding desmoplakin). Although there was considerable clinical overlap in the skin and hair abnormalities in these two cases, patient 2 also had early-onset cardiomyopathy. The mutation c.3971del4 occurs in the longer desmoplakin-I isoform (which is the major cardiac transcript) but not in the more ubiquitous desmoplakin-II. In contrast, PKP1 is not expressed in the heart, which accounts for the lack of cardiomyopathy in patient 1. Collectively, these cases represent the first desmosomal genodermatoses to be reported from Brazil and add to genotype-phenotype correlation in this group of inherited disorders. Loss-of-function mutations in the DSP gene can result in a phenotype similar to ectodermal dysplasia-skin fragility syndrome resulting from PKP1 mutations but only DSP pathology is associated with cardiac disease.

  20. A cohort study of MFN2 mutations and phenotypic spectrums in Charcot-Marie-Tooth disease 2A patients.

    PubMed

    Choi, B-O; Nakhro, K; Park, H J; Hyun, Y S; Lee, J H; Kanwal, S; Jung, S-C; Chung, K W

    2015-06-01

    Charcot-Marie-Tooth disease 2A (CMT2A) is the most common axonal form of peripheral neuropathy caused by a defect in the mitofusin 2 (MFN2) gene, which encodes an outer mitochondrial membrane GTPase. MFN2 mutations result in a large range of phenotypes. This study analyzed the prevalence of MFN2 mutation in Korean families with their assorted phenotypes (607 CMT families and 160 CMT2 families). Direct sequencing of the MFN2 coding exons or whole-exome sequencing has been applied to identify causative mutations. A total of 21 mutations were found in 36 CMT2 families. Comparative genotype-phenotype correlations impacting severity, onset age, and specific symptoms were assessed. Most mutations were seen in the GTPase domain (∼86%). A deletion mutation found in the transmembrane helices is reported for the first time, as well as five novel mutations at other domains. MFN2 mutations made up 5.9% of total CMT families, whereas 22.9% in CMT2 families, of which 27.8% occurred de novo. Interestingly, patient phenotypes ranged from mild to severe even for the same mutation, suggesting other factors influenced phenotype and penetrance. This CMT2A cohort study will be useful for molecular diagnosis and treatment of axonal neuropathy.

  1. 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

  2. Polysaccharide storage myopathy phenotype in quarter horse-related breeds is modified by the presence of an RYR1 mutation.

    PubMed

    McCue, M E; Valberg, S J; Jackson, M; Borgia, L; Lucio, M; Mickelson, J R

    2009-01-01

    In this study we examined a family of Quarter Horses with Polysaccharide Storage Myopathy (PSSM) with a dominant mutation in the skeletal muscle glycogen synthase (GYS1) gene. A subset of horses within this family had a more severe and occasionally fatal PSSM phenotype. The purpose of this study was to identify a modifying gene(s) for the severe clinical phenotype. A genetic association analysis was used to identify RYR1 as a candidate modifying gene. A rare, known equine RYR1 mutation, associated with malignant hyperthermia (MH), was found to segregate in this GYS1 PSSM family. Retrospective analysis of patient records (n=179) demonstrated that horses with both the GYS1 and RYR1 mutations had a more severe clinical phenotype than horses with the GYS1 mutation alone. A treadmill trial (n=8) showed that serum creatine kinase activity was higher and exercise intolerance greater in horses with both mutations compared to the GYS1 mutation alone.

  3. 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

  4. Choline Acetyltransferase Mutations Causing Congenital Myasthenic Syndrome: Molecular Findings and Genotype-Phenotype Correlations.

    PubMed

    Arredondo, Juan; Lara, Marian; Gospe, Sídney M; Mazia, Claudio G; Vaccarezza, Maria; Garcia-Erro, Marcela; Bowe, Constance M; Chang, Celia H; Mezei, Michelle M; Maselli, Ricardo A

    2015-09-01

    Choline acetyltransferase catalyzes the synthesis of acetylcholine at cholinergic nerves. Mutations in human CHAT cause a congenital myasthenic syndrome due to impaired synthesis of ACh; this severe variant of the disease is frequently associated with unexpected episodes of potentially fatal apnea. The severity of this condition varies remarkably, and the molecular factors determining this variability are poorly understood. Furthermore, genotype-phenotype correlations have been difficult to establish in patients with biallelic mutations. We analyzed the protein expression of phosphorylated ChAT of seven CHAT mutations, p.Val136Met, p.Arg207His, p.Arg186Trp, p.Val194Leu, p.Pro211Ala, p.Arg566Cys, and p.Ser694Cys, in HEK-293 cells to phosphorylated ChAT, determined their enzyme kinetics and thermal stability, and examined their structural changes. Three mutations, p.Arg207His, p.Arg186Trp, and p.Arg566Cys, are novel, and p.Val136Met and p.Arg207His are homozygous in three families and associated with severe disease. The characterization of mutants showed a decrease in the overall catalytic efficiency of ChAT; in particular, those located near the active-site tunnel produced the most seriously disruptive phenotypic effects. On the other hand, p.Val136Met, which is located far from both active and substrate-binding sites, produced the most drastic reduction of ChAT expression. Overall, CHAT mutations producing low enzyme expression and severe kinetic effects are associated with the most severe phenotypes.

  5. Choline acetyltransferase mutations causing congenital myasthenic syndrome: molecular findings and genotype-phenotype correlations

    PubMed Central

    Arredondo, Juan; Lara, Marian; Gospe, Sídney M.; Mazia, Claudio G.; Vaccarezza, Maria; Garcia-Erro, Marcela; Bowe, Constance; Chang, Celia; Mezei, Michelle; Maselli, Ricardo A.

    2015-01-01

    Choline acetyltransferase catalyzes the synthesis of acetylcholine at cholinergic nerves. Mutations in human CHAT cause a congenital myasthenic syndrome (CMS) due to impaired synthesis of ACh; this severe variant of the disease is frequently associated with unexpected episodes of potentially fatal apnea. The severity of this condition varies remarkably, and the molecular factors determining this variability are poorly understood. Furthermore, genotype–phenotype correlations have been difficult to establish in patients with biallelic mutations. We analyzed the protein expression of seven ChAT mutations, p.Val136Met, p.Arg207His, p.Arg186Trp, p.Val194Leu, p.Pro211Ala, p.Arg566Cys and p.Ser694Cys, in HEK-293 cells to phosphorylated ChAT, determined their enzyme kinetics and thermal instability, and examined their structural changes. Three mutations, p.Arg207His, p.Arg186Trp and p.Arg566Cys, are novel, and p.Val136Met and p.Arg207His are homozygous in three families and associated with severe disease. The characterization of mutants showed a decrease in the overall catalytic efficiency of ChAT; in particular, those located near the active-site tunnel produced the most seriously disruptive phenotypic effects. On the other hand, p.Val136Met is located far from both active and substrate-binding sites produced the most drastic reduction of ChAT expression. Overall, CHAT mutations producing low enzyme expression and severe kinetic effects are associated with the most severe phenotypes. PMID:26080897

  6. Phenotypic Variability of Osteogenesis Imperfecta Type V Caused by an IFITM5 Mutation

    PubMed Central

    Shapiro, Jay R; Lietman, Caressa; Grover, Monica; Lu, James T; Nagamani, Sandesh CS; Dawson, Brian C; Baldridge, Dustin M; Bainbridge, Matthew N; Cohn, Dan H; Blazo, Maria; Roberts, Timothy T; Brennen, Feng-Shu; Wu, Yimei; Gibbs, Richard A; Melvin, Pamela; Campeau, Philippe M; Lee, Brendan H

    2013-01-01

    In a large cohort of osteogenesis imperfecta type V (OI type V) patients (17 individuals from 12 families), we identified the same mutation in the 5′ untranslated region (5′UTR) of the interferon-induced transmembrane protein 5 (IFITM5) gene by whole exome and Sanger sequencing (IFITM5 c.–14C > T) and provide a detailed description of their phenotype. This mutation leads to the creation of a novel start codon adding five residues to IFITM5 and was recently reported in several other OI type V families. The variability of the phenotype was quite large even within families. Whereas some patients presented with the typical calcification of the forearm interosseous membrane, radial head dislocation and hyperplastic callus (HPC) formation following fractures, others had only some of the typical OI type V findings. Thirteen had calcification of interosseous membranes, 14 had radial head dislocations, 10 had HPC, 9 had long bone bowing, 11 could ambulate without assistance, and 1 had mild unilateral mixed hearing loss. The bone mineral density varied greatly, even within families. Our study thus highlights the phenotypic variability of OI type V caused by the IFITM5 mutation. PMID:23408678

  7. Non-truncating LIFR mutation: causal for prominent congenital pain insensitivity phenotype with progressive vertebral destruction?

    PubMed

    Elsaid, M F; Chalhoub, N; Kamel, H; Ehlayel, M; Ibrahim, N; Elsaid, A; Kumar, P; Khalak, H; Ilyin, V A; Suhre, K; Abdel Aleem, A

    2016-02-01

    We present a Qatari family with two children who displayed a characteristic phenotype of congenital marked pain insensitivity with hypohidrosis and progressive aseptic destruction of joints and vertebrae resembling that of hereditary sensory and autonomic neuropathies (HSANs). The patients, aged 10 and 14, remained of uncertain genetic diagnosis until whole genome sequencing was pursued. Genome sequencing identified a novel homozygous C65S mutation in the LIFR gene that is predicted to markedly destabilize and alter the structure of a particular domain and consequently to affect the functionality of the whole multi-domain LIFR protein. The C65S mutant LIFR showed altered glycosylation and an elevated expression level that might be attributed to a slow turnover of the mutant form. LIFR mutations have been reported in Stüve-Wiedemann syndrome (SWS), a severe autosomal recessive skeletal dysplasia often resulting in early death. Our patients share some clinical features of rare cases of SWS long-term survivors; however, they also phenocopy HSAN due to the marked pain insensitivity phenotype and progressive bone destruction. Screening for LIFR mutations might be warranted in genetically unresolved HSAN phenotypes.

  8. Characterization of spectrum, de novo rate and genotype-phenotype correlation of dominant GJB2 mutations in Chinese hans.

    PubMed

    Pang, Xiuhong; Chai, Yongchuan; Sun, Lianhua; Chen, Dongye; Chen, Ying; Zhang, Zhihua; Wu, Hao; Yang, Tao

    2014-01-01

    Dominant mutations in GJB2 may lead to various degrees of sensorineural hearing impairment and/or hyperproliferative epidermal disorders. So far studies of dominant GJB2 mutations were mostly limited to case reports of individual patients and families. In this study, we identified 7 families, 11 subjects with dominant GJB2 mutations by sequencing of GJB2 in 2168 Chinese Han probands with sensorineural hearing impairment and characterized the associated spectrum, de novo rate and genotype-phenotype correlation. We identified p.R75Q, p.R75W and p.R184Q as the most frequent dominant GJB2 mutations among Chinese Hans, which had a very high de novo rate (71% of probands). A majority (10/11) of subjects carrying dominant GJB2 mutations exhibited palmoplantar keratoderma in addition to hearing impairment. In two families segregated with additional c.235delC or p.V37I mutations of GJB2, family members with the compound heterozygous mutations exhibited more severe phenotype than those with single dominant GJB2 mutation. Our study suggested that the high de novo mutation rate gives rise to a significant portion of dominant GJB2 mutations. The severity of the hearing and epidermal phenotypes associated with dominant GJB2 mutations may be modified by additional recessive mutations of GJB2.

  9. ADAMTSL4-associated isolated ectopia lentis: Further patients, novel mutations and a detailed phenotype description.

    PubMed

    Neuhann, Teresa M; Stegerer, Annette; Riess, Angelika; Blair, Edward; Martin, Thomas; Wieser, Stefanie; Kläs, Rüdiger; Bouman, Arjan; Kuechler, Alma; Rittinger, Olaf

    2015-10-01

    ADAMTSL4 mutations seem to be the most common cause of isolated ectoplia lentis (EL) and thus are important concerning the differential diagnosis of connective tissue syndromes with EL as main feature. In this study, we describe an additional cohort of patients with apparently isolated EL. All underwent a detailed clinical exam with cardiac evaluation combined with ADAMTSL4 mutation analysis. Mutations were identified in 12/15 patients with EL. Besides the European founder mutation p. (Gln256Profs*38) we identified five further mutations not yet described in the literature: p. (Leu249Tyrfs*21), p. (Ala388Glyfs*8), p. (Arg746His), p. (Gly592Ser), and p. (Arg865His). Clinical evaluation showed common additional ocular features such as high myopia, but no major systemic findings. In particular: no dilatation of the aortic root was reported on. This report increases the total number of patients with ADAMTSL4 mutations reported on today and reviews in detail the clinical findings in all patients reported on to date demonstrate, that these patients have a mainly ocular phenotype. There are no consistent systemic findings. The differentiation between syndromic and isolated EL is crucial for the further surveillance, treatment, and counseling of these patients, especially in young children.

  10. SCN4A mutation as modifying factor of myotonic dystrophy type 2 phenotype.

    PubMed

    Bugiardini, E; Rivolta, I; Binda, A; Soriano Caminero, A; Cirillo, F; Cinti, A; Giovannoni, R; Botta, A; Cardani, R; Wicklund, M P; Meola, G

    2015-04-01

    In myotonic dystrophy type 2 (DM2), an association has been reported between early and severe myotonia and recessive chloride channel (CLCN1) mutations. No DM2 cases have been described with sodium channel gene (SCN4A) mutations. The aim is to describe a DM2 patient with severe and early onset myotonia and co-occurrence of a novel missense mutation in SNC4A. A 26-year-old patient complaining of hand cramps and difficulty relaxing her hands after activity was evaluated at our department. Neurophysiology and genetic analysis for DM1, DM2, CLCN1 and SCN4A mutations were performed. Genetic testing was positive for DM2 (2650 CCTG repeat) and for a variant c.215C>T (p.Pro72Leu) in the SCN4A gene. The variation affects the cytoplasmic N terminus domain of Nav1.4, where mutations have never been reported. The biophysical properties of the mutant Nav1.4 channels were evaluated by whole-cell voltage-clamp analysis of heterologously expressed mutant channel in tsA201 cells. Electrophysiological studies of the P72L variant showed a hyperpolarizing shift (-5 mV) of the voltage dependence of activation that may increase cell excitability. This case suggests that SCN4A mutations may enhance the myotonic phenotype of DM2 patients and should be screened for atypical cases with severe myotonia.

  11. PCR assay confirms diagnosis in syndrome with variably expressed phenotype: mutation detection in Stickler syndrome.

    PubMed Central

    Ahmad, N N; McDonald-McGinn, D M; Dixon, P; Zackai, E H; Tasman, W S

    1996-01-01

    Stickler syndrome is an autosomal dominant disease with ocular (severe myopia, vitreal degeneration, and retinal detachment) and other systemic manifestations (hearing loss, cleft palate, epiphyseal dysplasia, and premature osteoarthritis). As with other dominantly inherited conditions, the clinical phenotype of Stickler syndrome varies considerably. To date, all mutations have been located in the type II procollagen (COL2A1) gene. Analysis of a C-->T mutation we had identified previously, in COL2A1 gene in exon 40, in a three generation pedigree showed the loss of a cleavage site for the TaqI restriction enzyme. We designed a rapid PCR based restriction enzyme assay to detect this mutation and used it to establish the diagnosis in a neonate from the same pedigree, presenting with the first occurrence of the Pierre-Robin sequence in the family and minimal ocular findings. These results underline the potential diagnostic value of many as yet undetected DNA mutations in families affected with Stickler syndrome, since the variability of the phenotype can impede accurate diagnosis, appropriate genetic counselling, and effective intervention and prophylactic treatment for affected people. Images PMID:8863161

  12. Telomere phenotypes in females with heterozygous mutations in the dyskeratosis congenita 1 (DKC1) gene.

    PubMed

    Alder, Jonathan K; Parry, Erin M; Yegnasubramanian, Srinivasan; Wagner, Christa L; Lieblich, Lawrence M; Auerbach, Robert; Auerbach, Arleen D; Wheelan, Sarah J; Armanios, Mary

    2013-11-01

    Dyskeratosis congenita (DC) is a telomere-mediated syndrome defined by mucocutaneous features. The X-linked mode of inheritance accounts for half the cases, and is thought to predominantly manifest in childhood as bone marrow failure. We identified two male probands who presented in the fifth decade with idiopathic pulmonary fibrosis and cancer. Their pedigrees displayed consecutively affected generations. Five of six females (83%) manifested mucocutaneous features of DC, and two had wound-healing complications. No mutations in autosomal dominant telomere genes were present, but exome sequencing revealed novel variants in the X-chromosome DKC1 gene that predicted missense mutations in conserved residues, p.Thr49Ser and p.Pro409Arg. Variants segregated with the telomere phenotype, and affected females were heterozygotes, showing skewed X-inactivation. Telomerase RNA levels were compromised in cells from DKC1 mutation carriers, consistent with their pathogenic role. These findings indicate that females with heterozygous DKC1 mutations may be at increased risk for developing penetrant telomere phenotypes that, at times, may be associated with clinical morbidity.

  13. Telomere phenotypes in females with heterozygous mutations in the dyskeratosis congenita 1 (DKC1) gene

    PubMed Central

    Alder, Jonathan K.; Parry, Erin M.; Yegnasubramanian, Srinivasan; Wagner, Christa L.; Lieblich, Lawrence M.; Auerbach, Robert; Auerbach, Arleen D.; Wheelan, Sarah J.; Armanios, Mary

    2013-01-01

    Dyskeratosis congenita is a telomere-mediated syndrome defined by mucocutaneous features. The X-linked mode of inheritance accounts for half the cases, and is thought to predominantly manifest in childhood as bone marrow failure. We identified two male probands who presented in the fifth decade with idiopathic pulmonary fibrosis and cancer. Their pedigrees displayed consecutively affected generations. Five of six females (83%) manifested mucocutaneous features of dyskeratosis congenita, and two had wound-healing complications. No mutations in autosomal dominant telomere genes were present, but exome sequencing revealed novel variants in the X-chromosome DKC1 gene that predicted missense mutations in conserved residues, p.Thr49Ser and p.Pro409Arg. Variants segregated with the telomere phenotype, and affected females were heterozygotes showing skewed X-inactivation. Telomerase RNA levels were compromised in cells from DKC1 mutation carriers, consistent with their pathogenic role. These findings indicate that females with heterozygous DKC1 mutations may be at increased risk for developing telomere phenotypes that, at times, may be associated with clinical morbidity. PMID:23946118

  14. Single Synonymous Mutations in KRAS Cause Transformed Phenotypes in NIH3T3 Cells

    PubMed Central

    Waters, Andrew M.; Bagni, Rachel; Portugal, Franklin; Hartley, James L.

    2016-01-01

    Synonymous mutations in the KRAS gene are clustered at G12, G13, and G60 in human cancers. We constructed 9 stable NIH3T3 cell lines expressing KRAS, each with one of these synonymous mutations. Compared to the negative control cell line expressing the wild type human KRAS gene, all the synonymous mutant lines expressed more KRAS protein, grew more rapidly and to higher densities, and were more invasive in multiple assays. Three of the cell lines showed dramatic loss of contact inhibition, were more refractile under phase contrast, and their refractility was greatly reduced by treatment with trametinib. Codon usage at these glycines is highly conserved in KRAS compared to HRAS, indicating selective pressure. These transformed phenotypes suggest that synonymous mutations found in driver genes such as KRAS may play a role in human cancers. PMID:27684555

  15. Four novel point mutations in the PMP22 gene with phenotypes of HNPP and Dejerine-Sottas neuropathy.

    PubMed

    Brožková, Dana; Mazanec, Radim; Rychlý, Zdeněk; Haberlová, Jana; Böhm, Jiří; Staněk, Jan; Plevová, Pavlína; Lisoňová, Jana; Sabová, Jana; Sakmaryová, Iva; Seeman, Pavel

    2011-11-01

    We report four novel point mutations in the PMP22 gene with two different phenotypes: mutation p.Ser79Thr arose de novo in a patient with the Dejerine-Sottas neuropathy (DSN) phenotype; and mutations c.78+5 G>A, c.320-1 G>C, and p.Trp140Stop segregated with HNPP in 5 families.Our findings show that point mutations in PMP22 may be more likely in HNPP patients than in CMT1 patients after exclusion of CMT1A/HNPP.

  16. The molecular basis of variable phenotypic severity among common missense mutations causing Rett syndrome.

    PubMed

    Brown, Kyla; Selfridge, Jim; Lagger, Sabine; Connelly, John; De Sousa, Dina; Kerr, Alastair; Webb, Shaun; Guy, Jacky; Merusi, Cara; Koerner, Martha V; Bird, Adrian

    2016-02-01

    Rett syndrome is caused by mutations in the X-linked MECP2 gene, which encodes a chromosomal protein that binds to methylated DNA. Mouse models mirror the human disorder and therefore allow investigation of phenotypes at a molecular level. We describe an Mecp2 allelic series representing the three most common missense Rett syndrome (RTT) mutations, including first reports of Mecp2[R133C] and Mecp2[T158M] knock-in mice, in addition to Mecp2[R306C] mutant mice. Together these three alleles comprise ∼25% of all RTT mutations in humans, but they vary significantly in average severity. This spectrum is mimicked in the mouse models; R133C being least severe, T158M most severe and R306C of intermediate severity. Both R133C and T158M mutations cause compound phenotypes at the molecular level, combining compromised DNA binding with reduced stability, the destabilizing effect of T158M being more severe. Our findings contradict the hypothesis that the R133C mutation exclusively abolishes binding to hydroxymethylated DNA, as interactions with DNA containing methyl-CG, methyl-CA and hydroxymethyl-CA are all reduced in vivo. We find that MeCP2[T158M] is significantly less stable than MeCP2[R133C], which may account for the divergent clinical impact of the mutations. Overall, this allelic series recapitulates human RTT severity, reveals compound molecular aetiologies and provides a valuable resource in the search for personalized therapeutic interventions.

  17. Genome-wide annotation of mutations in a phenotyped mutant library provides an efficient platform for discovery of casual gene mutations

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Ethyl methanesulfonate (EMS) efficiently generates high-density mutations in genomes. Conventionally, these mutations are identified by techniques that can detect single-nucleotide mismatches in heteroduplexes of individual PCR amplicons. We applied whole-genome sequencing to 256-phenotyped mutant l...

  18. A novel distinctive cerebrovascular phenotype is associated with heterozygous Arg179 ACTA2 mutations

    PubMed Central

    Munot, Pinki; Saunders, Dawn E.; Milewicz, Dianna M.; Regalado, Ellen S.; Ostergaard, John R.; Braun, Kees P.; Kerr, Timothy; Lichtenbelt, Klaske D.; Philip, Sunny; Rittey, Christopher; Jacques, Thomas S.; Cox, Timothy C.

    2012-01-01

    Mutations in the ACTA2 gene lead to diffuse and diverse vascular diseases; the Arg179His mutation is associated with an early onset severe phenotype due to global smooth muscle dysfunction. Cerebrovascular disease associated with ACTA2 mutations has been likened to moyamoya disease, but appears to have distinctive features. This study involved the analysis of neuroimaging of 13 patients with heterozygous missense mutations in ACTA2 disrupting Arg179. All patients had persistent ductus arteriosus and congenital mydriasis, and variable presentation of pulmonary hypertension, bladder and gastrointestinal problems associated with this mutation. Distinctive cerebrovascular features were dilatation of proximal internal carotid artery, occlusive disease of terminal internal carotid artery, an abnormally straight course of intracranial arteries, and absent basal ‘moyamoya’ collaterals. Patterns of brain injury supported both large and small vessel disease. Key differences from moyamoya disease were more widespread arteriopathy, the combination of arterial ectasia and stenosis and, importantly, absence of the typical basal ‘moyamoya’ collaterals. Evaluation of previously published cases suggests some of these features are also seen in the ACTA2 mutations disrupting Arg258. The observation that transition from dilated to normal/stenotic arterial calibre coincides with where the internal carotid artery changes from an elastic to muscular artery supports the hypothesis that abnormal smooth muscle cell proliferation caused by ACTA2 mutations is modulated by arterial wall components. Patients with persistent ductus arteriosus or congenital mydriasis with a label of ‘moyamoya’ should be re-evaluated to ensure the distinctive neuroimaging features of an ACTA2 mutation have not been overlooked. This diagnosis has prognostic and genetic implications, and mandates surveillance of other organ systems, in particular the aorta, to prevent life-threatening aortic dissection

  19. Longitudinal imaging in C9orf72 mutation carriers: Relationship to phenotype.

    PubMed

    Floeter, Mary Kay; Bageac, Devin; Danielian, Laura E; Braun, Laura E; Traynor, Bryan J; Kwan, Justin Y

    2016-01-01

    Expansion mutations in the C9orf72 gene may cause amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), or mixtures of the two clinical phenotypes. Different imaging findings have been described for C9orf72-associated diseases in comparison with sporadic patients with the same phenotypes, but it is uncertain whether different phenotypes have a common genotype-associated imaging signature. To address this question, 27 unrelated C9orf72 expansion mutation carriers (C9 +) with varied phenotypes, 28 age-matched healthy controls and 22 patients with sporadic ALS (sALS) underwent 3T MRI scanning and clinical phenotyping. Measures of brain volumes and cortical thickness were extracted from T1 images. Compared to healthy controls and sALS patients, symptomatic C9 + subjects had greater ventricular volume loss and thalamic atrophy for age, with diffuse, patchy cortical thinning. Asymptomatic carriers did not differ from controls. C9 + ALS and ALS-FTD patients had less thinning of the motor cortex than sALS patients, but more thinning in extramotor regions, particularly in frontal and temporal lobes. C9 + ALS patients differed from sporadic ALS patients in the thickness of the superior frontal gyrus and lateral orbitofrontal cortex. Thickness of the precentral gyrus was weakly correlated with the revised ALS functional rating scale. Thickness of many cortical regions, including several frontal and temporal regions, was moderately correlated with letter fluency scores. Letter fluency scores were weakly correlated with ventricular and thalamic volume. To better understand how imaging findings are related to disease progression, nineteen C9 + subjects and 23 healthy controls were scanned approximately 6 months later. Ventricular volume increased in C9 + patients with FTD and ALS-FTD phenotypes and remained stable in asymptomatic C9 + subjects. We conclude that diffuse atrophy is a common underlying feature of disease associated with C9orf72 mutations

  20. ABCA12 mutations and autosomal recessive congenital ichthyosis: a review of genotype/phenotype correlations and of pathogenetic concepts.

    PubMed

    Akiyama, Masashi

    2010-10-01

    Mutations in ABCA12 have been described in autosomal recessive congenital ichthyoses (ARCI) including harlequin ichthyosis (HI), congenital ichthyosiform erythroderma (CIE), and lamellar ichthyosis (LI). HI shows the most severe phenotype. CIE and LI are clinically characterized by fine, whitish scales on a background of erythematous skin, and large, thick, dark scales over the entire body without serious background erythroderma, respectively. To date, a total of 56 ABCA12 mutations have been reported in 66 ARCI families including 48 HI, 10 LI, and 8 CIE families of African, European, Pakistani/Indian, and Japanese origin (online database: http://www.derm-hokudai.jp/ABCA12/). A total of 62.5% of reported ABCA12 mutations are expected to lead to truncated proteins. Most mutations in HI are truncation mutations and homozygous or compound heterozygous truncation mutations always results in HI phenotype. In CIE families, at least one mutation on each allele is typically a missense mutation. Combinations of missense mutations in the first ATP-binding cassette of ABCA12 underlie the LI phenotype. ABCA12 is a keratinocyte lipid transporter associated with lipid transport in lamellar granules, and loss of ABCA12 function leads to a defective lipid barrier in the stratum corneum, resulting in an ichthyotic phenotype. Recent work using mouse models confirmed ABCA12 roles in skin barrier formation.

  1. Genotype-phenotype correlations emerging from the identification of missense mutations in MBTPS2.

    PubMed

    Bornholdt, Dorothea; Atkinson, T Prescott; Bouadjar, Bakar; Catteau, Benoit; Cox, Helen; De Silva, Deepthi; Fischer, Judith; Gunasekera, Chalukya N; Hadj-Rabia, Smaïl; Happle, Rudolf; Holder-Espinasse, Muriel; Kaminski, Elke; König, Arne; Mégarbané, André; Mégarbané, Hala; Neidel, Ulrike; Oeffner, Frank; Oji, Vinzenz; Theos, Amy; Traupe, Heiko; Vahlquist, Anders; van Bon, Bregje W; Virtanen, Marie; Grzeschik, Karl-Heinz

    2013-04-01

    Missense mutations affecting membrane-bound transcription factor protease site 2 (MBTPS2) have been associated with Ichthyosis Follicularis with Atrichia and Photophobia (IFAP) syndrome with or without BRESHECK syndrome, with keratosis follicularis spinulosa decalvans, and Olmsted syndrome. This metalloprotease activates, by intramembranous trimming in conjunction with the protease MBTPS1, regulatory factors involved in sterol control of transcription and in cellular stress response. In this study, 11 different MBTPS2 missense mutations detected in patients from 13 unrelated families were correlated with the clinical phenotype, with their effect on cellular growth in media without lipids, and their potential role for sterol control of transcription. Seven variants were novel [c.774C>G (p.I258M); c.758G>C (p.G253A); c.686T>C (p.F229S); c.1427T>C (p.L476S); c.1430A>T (p.D477V); c.1499G>A (p.G500D); c.1538T>C (p.L513P)], four had previously been reported in unrelated sibships [c.261G>A (p.M87I); c.1286G>A (p.R429H); c.1424T>C (p.F475S); c.1523A>G (p.N508S)]. In the enzyme, the mutations cluster in transmembrane domains. Amino-acid exchanges near the active site are more detrimental to functionality of the enzyme and, clinically, associated with more severe phenotypes. In male patients, a genotype-phenotype correlation begins to emerge, linking the site of the mutation in MBTPS2 with the clinical outcome described as IFAP syndrome with or without BRESHECK syndrome, keratosis follicularis spinulosa decalvans, X-linked, Olmsted syndrome, or possibly further X-linked traits with an oculocutaneous component.

  2. Thomsen or Becker myotonia? A novel autosomal recessive nonsense mutation in the CLCN1 gene associated with a mild phenotype.

    PubMed

    Gurgel-Giannetti, Juliana; Senkevics, Adriano S; Zilbersztajn-Gotlieb, Dinorah; Yamamoto, Lydia U; Muniz, Viviane P; Pavanello, Rita C M; Oliveira, Acary B; Zatz, Mayana; Vainzof, Mariz

    2012-02-01

    We describe a large Brazilian consanguineous kindred with 3 clinically affected patients with a Thomsen myotonia phenotype. They carry a novel homozygous nonsense mutation in the CLCN1 gene (K248X). None of the 6 heterozygote carriers show any sign of myotonia on clinical evaluation or electromyography. These findings confirm the autosomal recessive inheritance of the novel mutation in this family, as well as the occurrence of phenotypic variability in the autosomal recessive forms of myotonia.

  3. Rare familial TSC2 gene mutation associated with atypical phenotype presentation of Tuberous Sclerosis Complex.

    PubMed

    Fox, Jonah; Ben-Shachar, Shay; Uliel, Shimrit; Svirsky, Ran; Saitsu, Hirotomo; Matsumoto, Naomichi; Fattal-Valevski, Aviva

    2017-03-01

    Tuberous sclerosis complex (TSC) is a neurocutaneous disorder that results from mutations within either the TSC1 gene or the TSC2 gene. Diagnosis is based on well-established clinical criteria or genetic criteria. We describe an 18-month-old boy who presented with seizures and a single hypopigmented macule. He did not meet consensus criteria for the clinical diagnosis of TSC. Exome sequencing revealed a heterozygous TSC2 mutation (c.5138G>A (p.Arg1713His)) in the patient. This heterozygous alteration was detected in his mother as well as several other maternal family members. The mother and other family members with the mutation were asymptomatic except for the presence of hypopigmented macules. The phenotypic characteristics of the individuals in this family were not suggestive of a TSC2 mutation as none satisfied the clinical criteria for even a diagnosis of possible TSC. This case provides evidence for a unique TSC2 mutation that resulted in an atypical clinical presentation and indicates potential shortcomings of the current diagnostic criteria for TSC. These findings may have implications for genetic counseling and screening. © 2017 Wiley Periodicals, Inc.

  4. Mutations in MC1R gene determine black coat color phenotype in Chinese sheep.

    PubMed

    Yang, Guang-Li; Fu, Dong-Li; Lang, Xia; Wang, Yu-Tao; Cheng, Shu-Ru; Fang, Su-Li; Luo, Yu-Zhu

    2013-01-01

    The melanocortin receptor 1 (MC1R) plays a central role in regulation of animal coat color formation. In this study, we sequenced the complete coding region and parts of the 5'- and 3'-untranslated regions of the MC1R gene in Chinese sheep with completely white (Large-tailed Han sheep), black (Minxian Black-fur sheep), and brown coat colors (Kazakh Fat-Rumped sheep). The results showed five single nucleotide polymorphisms (SNPs): two non-synonymous mutations previously associated with coat color (c.218 T>A, p.73 Met>Lys. c.361 G>A, p.121 Asp>Asn) and three synonymous mutations (c.429 C>T, p.143 Tyr>Tyr; c.600 T>G, p.200 Leu>Leu. c.735 C>T, p.245 Ile>Ile). Meanwhile, all mutations were detected in Minxian Black-fur sheep. However, the two nonsynonymous mutation sites were not in all studied breeds (Large-tailed Han, Small-tailed Han, Gansu Alpine Merino, and China Merino breeds), all of which are in white coat. A single haplotype AATGT (haplotype3) was uniquely associated with black coat color in Minxian Black-fur breed (P = 9.72E - 72, chi-square test). The first and second A alleles in this haplotype 3 represent location at 218 and 361 positions, respectively. Our results suggest that the mutations of MC1R gene are associated with black coat color phenotype in Chinese sheep.

  5. Genotype-phenotype relationship in 12 patients carrying cystic fibrosis mutation R334W.

    PubMed Central

    Antiñolo, G; Borrego, S; Gili, M; Dapena, J; Alfageme, I; Reina, F

    1997-01-01

    We present a phenotype-genotype correlation analysis in 12 patients with cystic fibrosis (CF) carrying the mutation R334W in the CFTR gene. The clinical data obtained for this group were compared with the clinical data of deltaF508/deltaF508 patients. Current age and age at diagnosis were significantly higher in the R334W mutation group (p=0.028 and p=0.0001). We found a lower rate of Pseudomonas aeruginosa colonisation in patients carrying the R334W mutation, although the difference was not found to be statistically significant. However, we found a statistically significant higher age of onset of Pseudomonas aeruginosa colonisation (p=0.0036) in the group of patients with the R334W mutation. Thirty three percent of R334W patients were pancreatic insufficient, significantly lower than the deltaF508/deltaF508 patients (p=0.004). We also found that the weight expressed as a percentage of ideal weight for height was significantly higher in patients with the R334W mutation (p=0.0028). PMID:9039981

  6. Mice homozygous for c.451C>T mutation in Cln1 gene recapitulate INCL phenotype

    PubMed Central

    Bouchelion, Ashleigh; Zhang, Zhongjian; Li, Yichao; Qian, Haohua; Mukherjee, Anil B

    2014-01-01

    Objective Nonsense mutations account for 5–70% of all genetic disorders. In the United States, nonsense mutations in the CLN1/PPT1 gene underlie >40% of the patients with infantile neuronal ceroid lipofuscinosis (INCL), a devastating neurodegenerative lysosomal storage disease. We sought to generate a reliable mouse model of INCL carrying the most common Ppt1 nonsense mutation (c.451C>T) found in the United States patient population to provide a platform for evaluating nonsense suppressors in vivo. Methods We knocked-in c.451C>T nonsense mutation in the Ppt1 gene in C57 embryonic stem (ES) cells using a targeting vector in which LoxP flanked the Neo cassette, which was removed from targeted ES cells by electroporating Cre. Two independently targeted ES clones were injected into blastocysts to generate syngenic C57 knock-in mice, obviating the necessity for extensive backcrossing. Results Generation of Ppt1-KI mice was confirmed by DNA sequencing, which showed the presence of c.451C>T mutation in the Ppt1 gene. These mice are viable and fertile, although they developed spasticity (a “clasping” phenotype) at a median age of 6 months. Autofluorescent storage materials accumulated throughout the brain regions and in visceral organs. Electron microscopic analysis of the brain and the spleen showed granular osmiophilic deposits. Increased neuronal apoptosis was particularly evident in cerebral cortex and abnormal histopathological and electroretinographic (ERG) analyses attested striking retinal degeneration. Progressive deterioration of motor coordination and behavioral parameters continued until eventual death. Interpretation Our findings show that Ppt1-KI mice reliably recapitulate INCL phenotype providing a platform for testing the efficacy of existing and novel nonsense suppressors in vivo. PMID:25574475

  7. Phenotypic similarities and differences in patients with a p.Met112Ile mutation in SOX10

    PubMed Central

    Pingault, Veronique; Pierre-Louis, Laurence; Chaoui, Asma; Verloes, Alain; Sarrazin, Elisabeth; Brandberg, Goran; Bondurand, Nadege; Uldall, Peter; Manouvrier-Hanu, Sylvie

    2014-01-01

    Waardenburg syndrome (WS) is characterized by an association of pigmentation abnormalities and sensorineural hearing loss. Four types, defined on clinical grounds, have been delineated, but this phenotypic classification correlates imperfectly with known molecular anomalies. SOX10 mutations have been found in patients with type II and type IV WS (i.e., with Hirschsprung disease), more complex syndromes, and partial forms of the disease. The phenotype induced by SOX10 mutations is highly variable and, except for the neurological forms of the disease, no genotype-phenotype correlation has been characterized to date. There is no mutation hotspot in SOX10 and most cases are sporadic, making it particularly difficult to correlate the phenotypic and genetic variability. This study reports on three independent families with SOX10 mutations predicted to result in the same missense mutation at the protein level (p.Met112Ile), offering a rare opportunity to improve our understanding of the mechanisms underlying phenotypic variability. The pigmentation defects of these patients are very similar, and the neurological symptoms showed a somewhat similar evolution over time, indicating a potential partial genotype-phenotype correlation. However, variability in gastrointestinal symptoms suggests that other genetic factors contribute to the expression of these phenotypes. No correlation between the rs2435357 polymorphism of RET and the expression of Hirschsprung disease was found. In addition, one of the patients has esophageal achalasia, which has rarely been described in WS. PMID:24845202

  8. The Relationship between the p.V37I Mutation in GJB2 and Hearing Phenotypes in Chinese Individuals.

    PubMed

    Huang, Shasha; Huang, Bangqing; Wang, Guojian; Yuan, Yongyi; Dai, Pu

    2015-01-01

    The most common cause of nonsyndromic autosomal recessive hearing loss is mutations in GJB2. The mutation spectrum and prevalence of mutations vary significantly among ethnic groups, and the relationship between p.V37I mutation in GJB2 and the hearing phenotype is controversial. Among the 3,864 patients in this study, 106 (2.74%) had a homozygous p.V37I variation or a compound p.V37I plus other GJB2 pathogenic mutation, a frequency that was significantly higher than that in the control group (600 individuals, 0%). The hearing loss phenotype ranged from mild to profound in all patients with the homozygous p.V37I variation or compound p.V37I plus other GJB2 pathogenic mutation. There was no difference in the distribution of the hearing level in the group with the homozygous p.V37I variation and the group with the compound p.V37I variation plus pathogenic mutation. Most patients (66.04%) with the V37I-homozygous variation or p.V37I plus other pathogenic mutation had a mild or moderate hearing level. This study found a definite relationship between p.V37I and deafness, and most patients who carried the pathogenic combination with p.V37I mutation had mild or moderate hearing loss. Therefore, otolaryngologists should consider that the milder phenotype might be caused by the GJB2 p.V37I mutation.

  9. Mosaicism for dominant collagen VI mutations as a cause for intra-familial phenotypic variability

    PubMed Central

    Donkervoort, Sandra; Hu, Ying; Stojkovic, Tanya; Voermans, Nicol; Foley, A. Reghan; Leach, Meganne E; Dastgir, Jahannaz; Bolduc, Veronique; Cullup, Thomas; de Becdelièvre, Alix; Yang, Lin; Su, Hai; Meilleur, Katherine; Schindler, Alice B.; Kamsteeg, Erik-Jan; Richard, Pascale; Butterfield, Russell; Winder, Thomas L.; Crawford, Thomas; Weiss, Robert B.; Muntoni, Francesco; Allamand, Valérie; Bönnemann, Carsten G.

    2015-01-01

    Collagen VI-related dystrophies and myopathies (COL6-RD) are a group of disorders that form a wide phenotypic spectrum, ranging from severe Ullrich congenital muscular dystrophy (UCMD), intermediate phenotypes, to the milder Bethlem myopathy (BM). Both inter- and intra-familial variable expressivity are commonly observed. We present clinical, immunohistochemical, and genetic data on four COL6-RD families with marked inter-generational phenotypic heterogeneity. This variable expression seemingly masquerades as anticipation is due to parental mosaicism for a dominant mutation, with subsequent full inheritance and penetrance of the mutation in the heterozygous offspring. We also present an additional 5th simplex patient identified as a mosaic carrier. Parental mosaicism was confirmed in the four families through quantitative analysis of the ratio of mutant versus wild-type allele (COL6A1, COL6A2 and COL6A3) in genomic DNA (gDNA) from various tissues; including blood, saliva, and dermal fibroblasts. Consistent with somatic mosaicism, parental samples had lower ratios of mutant versus wild-type allele compared to the fully heterozygote offspring. However, there was notable variability of the mutant allele levels between tissues tested, ranging from 16% (saliva) to 43% (fibroblasts) in one mosaic father. This is the first report demonstrating mosaicism as a cause of intra-familial/inter-generational variability of COL6-RD, and suggests that sporadic and parental mosaicism may be more common than previously suspected. PMID:25204870

  10. Activating mutations in RRAS underlie a phenotype within the RASopathy spectrum and contribute to leukaemogenesis

    PubMed Central

    Flex, Elisabetta; Jaiswal, Mamta; Pantaleoni, Francesca; Martinelli, Simone; Strullu, Marion; Fansa, Eyad K.; Caye, Aurélie; De Luca, Alessandro; Lepri, Francesca; Dvorsky, Radovan; Pannone, Luca; Paolacci, Stefano; Zhang, Si-Cai; Fodale, Valentina; Bocchinfuso, Gianfranco; Rossi, Cesare; Burkitt-Wright, Emma M.M.; Farrotti, Andrea; Stellacci, Emilia; Cecchetti, Serena; Ferese, Rosangela; Bottero, Lisabianca; Castro, Silvana; Fenneteau, Odile; Brethon, Benoît; Sanchez, Massimo; Roberts, Amy E.; Yntema, Helger G.; Van Der Burgt, Ineke; Cianci, Paola; Bondeson, Marie-Louise; Cristina Digilio, Maria; Zampino, Giuseppe; Kerr, Bronwyn; Aoki, Yoko; Loh, Mignon L.; Palleschi, Antonio; Di Schiavi, Elia; Carè, Alessandra; Selicorni, Angelo; Dallapiccola, Bruno; Cirstea, Ion C.; Stella, Lorenzo; Zenker, Martin; Gelb, Bruce D.; Cavé, Hélène; Ahmadian, Mohammad R.; Tartaglia, Marco

    2014-01-01

    RASopathies, a family of disorders characterized by cardiac defects, defective growth, facial dysmorphism, variable cognitive deficits and predisposition to certain malignancies, are caused by constitutional dysregulation of RAS signalling predominantly through the RAF/MEK/ERK (MAPK) cascade. We report on two germline mutations (p.Gly39dup and p.Val55Met) in RRAS, a gene encoding a small monomeric GTPase controlling cell adhesion, spreading and migration, underlying a rare (2 subjects among 504 individuals analysed) and variable phenotype with features partially overlapping Noonan syndrome, the most common RASopathy. We also identified somatic RRAS mutations (p.Gly39dup and p.Gln87Leu) in 2 of 110 cases of non-syndromic juvenile myelomonocytic leukaemia, a childhood myeloproliferative/myelodysplastic disease caused by upregulated RAS signalling, defining an atypical form of this haematological disorder rapidly progressing to acute myeloid leukaemia. Two of the three identified mutations affected known oncogenic hotspots of RAS genes and conferred variably enhanced RRAS function and stimulus-dependent MAPK activation. Expression of an RRAS mutant homolog in Caenorhabditis elegans enhanced RAS signalling and engendered protruding vulva, a phenotype previously linked to the RASopathy-causing SHOC2S2G mutant. Overall, these findings provide evidence of a functional link between RRAS and MAPK signalling and reveal an unpredicted role of enhanced RRAS function in human disease. PMID:24705357

  11. Neurobehavioral phenotype observed in KBG syndrome caused by ANKRD11 mutations.

    PubMed

    Lo-Castro, Adriana; Brancati, Francesco; Digilio, Maria Cristina; Garaci, Francesco Giuseppe; Bollero, Patrizio; Alfieri, Paolo; Curatolo, Paolo

    2013-01-01

    KBG syndrome is a rare disease characterized by typical facial dysmorphism, macrodontia of upper central incisors, skeletal abnormalities, and developmental delay. Recently, mutations in ANKRD11 gene have been identified in a subset of patients with KBG syndrome, while a contiguous gene deletion syndrome involving 16q24.3 region (including ANKRD11) was delineated in patients with facial dysmorphism, autism, intellectual disability, and brain abnormalities. Although numerous evidences point to a central causative role of ANKRD11 in the neurologic features of these patients, their neurocognitive and behavior phenotypes are still poorly characterized. Herein, we report the complete neurological and psychiatric features observed in two patients with KBG syndrome due to ANKRD11 mutations. Both patients show intellectual disabilities, severe impairment in communication skills, deficits in several aspects of executive functions and working memory and anxious traits. Their features are compared with those of previously reported patients with KBG syndrome aiding in the delineation of neurocognitive phenotype associated to ANKRD11 mutations.

  12. Activating mutations in RRAS underlie a phenotype within the RASopathy spectrum and contribute to leukaemogenesis.

    PubMed

    Flex, Elisabetta; Jaiswal, Mamta; Pantaleoni, Francesca; Martinelli, Simone; Strullu, Marion; Fansa, Eyad K; Caye, Aurélie; De Luca, Alessandro; Lepri, Francesca; Dvorsky, Radovan; Pannone, Luca; Paolacci, Stefano; Zhang, Si-Cai; Fodale, Valentina; Bocchinfuso, Gianfranco; Rossi, Cesare; Burkitt-Wright, Emma M M; Farrotti, Andrea; Stellacci, Emilia; Cecchetti, Serena; Ferese, Rosangela; Bottero, Lisabianca; Castro, Silvana; Fenneteau, Odile; Brethon, Benoît; Sanchez, Massimo; Roberts, Amy E; Yntema, Helger G; Van Der Burgt, Ineke; Cianci, Paola; Bondeson, Marie-Louise; Cristina Digilio, Maria; Zampino, Giuseppe; Kerr, Bronwyn; Aoki, Yoko; Loh, Mignon L; Palleschi, Antonio; Di Schiavi, Elia; Carè, Alessandra; Selicorni, Angelo; Dallapiccola, Bruno; Cirstea, Ion C; Stella, Lorenzo; Zenker, Martin; Gelb, Bruce D; Cavé, Hélène; Ahmadian, Mohammad R; Tartaglia, Marco

    2014-08-15

    RASopathies, a family of disorders characterized by cardiac defects, defective growth, facial dysmorphism, variable cognitive deficits and predisposition to certain malignancies, are caused by constitutional dysregulation of RAS signalling predominantly through the RAF/MEK/ERK (MAPK) cascade. We report on two germline mutations (p.Gly39dup and p.Val55Met) in RRAS, a gene encoding a small monomeric GTPase controlling cell adhesion, spreading and migration, underlying a rare (2 subjects among 504 individuals analysed) and variable phenotype with features partially overlapping Noonan syndrome, the most common RASopathy. We also identified somatic RRAS mutations (p.Gly39dup and p.Gln87Leu) in 2 of 110 cases of non-syndromic juvenile myelomonocytic leukaemia, a childhood myeloproliferative/myelodysplastic disease caused by upregulated RAS signalling, defining an atypical form of this haematological disorder rapidly progressing to acute myeloid leukaemia. Two of the three identified mutations affected known oncogenic hotspots of RAS genes and conferred variably enhanced RRAS function and stimulus-dependent MAPK activation. Expression of an RRAS mutant homolog in Caenorhabditis elegans enhanced RAS signalling and engendered protruding vulva, a phenotype previously linked to the RASopathy-causing SHOC2(S2G) mutant. Overall, these findings provide evidence of a functional link between RRAS and MAPK signalling and reveal an unpredicted role of enhanced RRAS function in human disease.

  13. Disintegrating the fly: A mutational perspective on phenotypic integration and covariation.

    PubMed

    Haber, Annat; Dworkin, Ian

    2017-01-01

    The structure of environmentally induced phenotypic covariation can influence the effective strength and magnitude of natural selection. Yet our understanding of the factors that contribute to and influence the evolutionary lability of such covariation is poor. Most studies have either examined environmental variation without accounting for covariation, or examined phenotypic and genetic covariation without distinguishing the environmental component. In this study, we examined the effect of mutational perturbations on different properties of environmental covariation, as well as mean shape. We use strains of Drosophila melanogaster bearing well-characterized mutations known to influence wing shape, as well as naturally derived strains, all reared under carefully controlled conditions and with the same genetic background. We find that mean shape changes more freely than the covariance structure, and that different properties of the covariance matrix change independently from each other. The perturbations affect matrix orientation more than they affect matrix eccentricity or total variance. Yet, mutational effects on matrix orientation do not cluster according to the developmental pathway that they target. These results suggest that it might be useful to consider a more general concept of "decanalization," involving all aspects of variation and covariation.

  14. Hereditary and Sporadic Papillary Renal Carcinomas with c-met Mutations Share a Distinct Morphological Phenotype

    PubMed Central

    Lubensky, Irina A.; Schmidt, Laura; Zhuang, Zhengping; Weirich, Gregor; Pack, Svetlana; Zambrano, Norman; Walther, McClellan M.; Choyke, Peter; Linehan, W. Marston; Zbar, Berton

    1999-01-01

    Germline mutations of c-met oncogene at 7q31 have been detected in patients with hereditary papillary renal cell carcinoma. In addition, c-met mutations were shown to play a role in 13% of patients with papillary renal cell carcinoma and no family history of renal tumors. The histopathology of papillary renal cell carcinoma with c-met mutations has not been previously described. We analyzed the histopathology of 103 bilateral archival papillary renal cell carcinomas and 4 metastases in 29 patients from 6 hereditary papillary renal cell carcinoma families with germline c-met mutations and 6 papillary renal cell carcinomas with c-met mutations from 5 patients with no family history of renal tumors. Twenty-five sporadic renal tumors with prominent papillary architecture and without somatic c-met mutations were evaluated for comparison. All papillary renal cell carcinomas with c-met mutations were 75 to 100% papillary/tubulopapillary in architecture and showed chromophil basophilic, papillary renal cell carcinoma type 1 histology. Fuhrman nuclear grade 1–2 was seen in tumors from 23 patients, and nuclear grade 3 was observed focally in 8 patients. Seventeen patients had multiple papillary adenomas and microscopic papillary lesions in the surrounding renal parenchyma. Clear cells with intracytoplasmic lipid and glycogen were focally present in tumors of 94% papillary renal cell carcinoma patients. Clear cells of papillary renal cell carcinoma had small basophilic nuclei, and clear cell areas lacked a fine vascular network characteristic of conventional (clear) cell renal cell carcinoma. We conclude that papillary renal cell carcinoma patients with c-met mutations develop multiple, bilateral, papillary macroscopic and microscopic renal lesions. Renal tumors with c-met genotype show a distinctive papillary renal cell carcinoma type 1 phenotype and are genetically and histologically different from renal tumors seen in other hereditary renal syndromes and most sporadic

  15. Mutation Update and Genotype–Phenotype Correlations of Novel and Previously Described Mutations in TPM2 and TPM3 Causing Congenital Myopathies

    PubMed Central

    Marttila, Minttu; Lehtokari, Vilma-Lotta; Marston, Steven; Nyman, Tuula A.; Barnerias, Christine; Beggs, Alan H.; Bertini, Enrico; Ceyhan-Birsoy, OÖzge; Cintas, Pascal; Gerard, Marion; Gilbert-Dussardier, Brigitte; Hogue, Jacob S.; Longman, Cheryl; Eymard, Bruno; Frydman, Moshe; Kang, Peter B.; Klinge, Lars; Kolski, Hanna; Lochmüller, Hans; Magy, Laurent; Manel, Véronique; Mayer, Michèle; Mercuri, Eugenio; North, Kathryn N.; Peudenier-Robert, Sylviane; Pihko, Helena; Probst, Frank J.; Reisin, Ricardo; Stewart, Willie; Taratuto, Ana Lia; de Visser, Marianne; Wilichowski, Ekkehard; Winer, John; Nowak, Kristen; Laing, Nigel G.; Winder, Tom L.; Monnier, Nicole; Clarke, Nigel F.; Pelin, Katarina; Grönholm, Mikaela; Wallgren-Pettersson, Carina

    2014-01-01

    Mutations affecting skeletal muscle isoforms of the tropomyosin genes may cause nemaline myopathy, cap myopathy, core-rod myopathy, congenital fiber-type disproportion, distal arthrogryposes, and Escobar syndrome. We correlate the clinical picture of these diseases with novel (19) and previously reported (31) mutations of the TPM2 and TPM3 genes. Included are altogether 93 families: 53 with TPM2 mutations and 40 with TPM3 mutations. Thirty distinct pathogenic variants of TPM2 and 20 of TPM3 have been published or listed in the Leiden Open Variant Database (http://www.dmd.nl/). Most are heterozygous changes associated with autosomal-dominant disease. Patients with TPM2 mutations tended to present with milder symptoms than those with TPM3 mutations, DA being present only in the TPM2 group. Previous studies have shown that five of the mutations in TPM2 and one in TPM3 cause increased Ca2+ sensitivity resulting in a hypercontractile molecular phenotype. Patients with hypercontractile phenotype more often had contractures of the limb joints (18/19) and jaw (6/19) than those with nonhypercontractile ones (2/22 and 1/22), whereas patients with the non-hypercontractile molecular phenotype more often (19/22) had axial contractures than the hypercontractile group (7/19). Our in silico predictions show that most mutations affect tropomyosin–actin association or tropomyosin head-to-tail binding. PMID:24692096

  16. Identification of constitutional WT1 mutations, in patients with isolated diffuse mesangial sclerosis, and analysis of genotype/phenotype correlations by use of a computerized mutation database.

    PubMed Central

    Jeanpierre, C; Denamur, E; Henry, I; Cabanis, M O; Luce, S; Cécille, A; Elion, J; Peuchmaur, M; Loirat, C; Niaudet, P; Gubler, M C; Junien, C

    1998-01-01

    Constitutional mutations of the WT1 gene, encoding a zinc-finger transcription factor involved in renal and gonadal development, are found in most patients with Denys-Drash syndrome (DDS), or diffuse mesangial sclerosis (DMS) associated with pseudohermaphroditism and/or Wilms tumor (WT). Most mutations in DDS patients lie in exon 8 or exon 9, encoding zinc finger 2 or zinc finger 3, respectively, with a hot spot (R394W) in exon 9. We analyzed a series of 24 patients, 10 with isolated DMS (IDMS), 10 with DDS, and 4 with urogenital abnormalities and/or WT. We report WT1 heterozygous mutations in 16 patients, 4 of whom presented with IDMS. One male and two female IDMS patients with WT1 mutations underwent normal puberty. Two mutations associated with IDMS are different from those described in DDS patients. No WT1 mutations were detected in the six other IDMS patients, suggesting genetic heterogeneity of this disease. We analyzed genotype/phenotype correlations, on the basis of the constitution of a WT1 mutation database of 84 germ-line mutations, to compare the distribution and type of mutations, according to the different symptoms. This demonstrated (1) the association between mutations in exons 8 and 9 and DMS; (2) among patients with DMS, a higher frequency of exon 8 mutations among 46, XY patients with female phenotype than among 46,XY patients with sexual ambiguity or male phenotype; and (3) statistically significant evidence that mutations in exons 8 and 9 preferentially affect amino acids with different functions. PMID:9529364

  17. Phenotypic population screen identifies a new mutation in bovine DGAT1 responsible for unsaturated milk fat

    PubMed Central

    Lehnert, Klaus; Ward, Hamish; Berry, Sarah D.; Ankersmit-Udy, Alex; Burrett, Alayna; Beattie, Elizabeth M.; Thomas, Natalie L.; Harris, Bevin; Ford, Christine A.; Browning, Sharon R.; Rawson, Pisana; Verkerk, Gwyneth A.; van der Does, Yvonne; Adams, Linda F.; Davis, Stephen R.; Jordan, T. William; MacGibbon, Alastair K. H.; Spelman, Richard J.; Snell, Russell G.

    2015-01-01

    Selective breeding has strongly reduced the genetic diversity in livestock species, and contemporary breeding practices exclude potentially beneficial rare genetic variation from the future gene pool. Here we test whether important traits arising by new mutations can be identified and rescued in highly selected populations. We screened milks from 2.5 million cows to identify an exceptional individual which produced milk with reduced saturated fat content, and improved unsaturated and omega-3 fatty acid concentrations. The milk traits were transmitted dominantly to her offspring, and genetic mapping and genome sequencing revealed a new mutation in a previously unknown splice enhancer of the DGAT1 gene. Homozygous carriers show features of human diarrheal disorders, and may be useful for the development of therapeutic strategies. Our study demonstrates that high-throughput phenotypic screening can uncover rich genetic diversity even in inbred populations, and introduces a novel strategy to develop novel milks with improved nutritional properties. PMID:25719731

  18. Phenotype Characterization and DSPP Mutational Analysis of Three Brazilian Dentinogenesis Imperfecta Type II Families

    PubMed Central

    Acevedo, A.C.; Santos, L.J.S.; Paula, L.M.; Dong, J.; MacDougall, M.

    2008-01-01

    The aim of this study was to perform phenotype analysis and dentin sialophosphoprotein (DSPP) mutational analysis on 3 Brazilian families diagnosed with dentinogenesis imperfecta type II (DGI-II) attending the Dental Anomalies Clinic in Brasilia, Brazil. Physical and oral examinations, as well as radiographic and histopathological analyses, were performed on 28 affected and unaffected individuals. Clinical, radiographic and histopathological analyses confirmed the diagnosis of DGI-II in 19 individuals. Pulp stones were observed in ground sections of several teeth in 2 families, suggesting that obliteration of pulp chambers and root canals results from the growth of these nodular structures. Mutational DSPP gene analysis of representative affected family members revealed 7 various non-disease-causing alterations in exons 1–4 within the dentin sialoprotein domain. Further longitudinal studies are necessary to elucidate the progression of pulpal obliteration in the DGI-II patients studied as well as the molecular basis of their disease. PMID:18797159

  19. Mutations Conferring a Noncytotoxic Phenotype on Chikungunya Virus Replicons Compromise Enzymatic Properties of Nonstructural Protein 2

    PubMed Central

    Utt, Age; Das, Pratyush Kumar; Varjak, Margus; Lulla, Valeria; Lulla, Aleksei

    2014-01-01

    ABSTRACT Chikungunya virus (CHIKV) (genus Alphavirus) has a positive-sense RNA genome. CHIKV nonstructural protein 2 (nsP2) proteolytically processes the viral nonstructural polyprotein, possesses nucleoside triphosphatase (NTPase), RNA triphosphatase, and RNA helicase activities, and induces cytopathic effects in vertebrate cells. Although alphaviral nsP2 mutations can result in a noncytotoxic phenotype, the effects of such mutations on nsP2 enzymatic activities are not well understood. In this study, we introduced a P718G (PG) mutation and selected for additional mutations in CHIKV nsP2 that resulted in a CHIKV replicon with a noncytotoxic phenotype in BHK-21 cells. Combinations of PG and either an E116K (EK) substitution or a GEEGS sequence insertion after residue T648 (5A) markedly reduced RNA synthesis; however, neither PG nor 5A prevented nsP2 nuclear translocation. Introducing PG into recombinant nsP2 inhibited proteolytic cleavage of nsP1/nsP2 and nsP3/nsP4 sites, reduced GTPase and RNA helicase activities, and abolished RNA stimulation of GTPase activity. 5A and EK modulated the effects of PG. However, only the RNA helicase activity of nsP2 was reduced by both of these mutations, suggesting that defects in this activity may be linked to a noncytotoxic phenotype. These results increase our understanding of the molecular basis for the cytotoxicity that accompanies alphaviral replication. Furthermore, adaptation of the CHIKV replicon containing both 5A and PG allowed the selection of a CHIKV replicon with adaptive mutations in nsP1 and nsP3 that enable persistence in human cell line. Such cell lines represent valuable experimental systems for discovering host factors and for screening inhibitors of CHIKV replication at lower biosafety levels. IMPORTANCE CHIKV is a medically important pathogen that causes febrile illness and can cause chronic arthritis. No approved vaccines or antivirals are available for CHIKV. The attenuation of CHIKV is critical to the

  20. Genitopatellar syndrome: expanding the phenotype and excluding mutations in LMX1B and TBX4.

    PubMed

    Abdul-Rahman, Omar A; La, Trang H; Kwan, Andrea; Schlaubitz, Silke; Barsh, Greg S; Enns, Gregory M; Hudgins, Louanne

    2006-07-15

    Genitopatellar syndrome is a newly described disorder characterized by absent/hypoplastic patellae, lower extremity contractures, urogenital anomalies, dysmorphic features, skeletal anomalies, and agenesis of the corpus callosum. More recently, cardiac anomalies and ectodermal dysplasia have been suggested as additional features of this syndrome. We report on two additional patients with genitopatellar syndrome and expand the spectrum of anomalies to include radio-ulnar synostosis. Since there exists significant overlap in the skeletal phenotype between genitopatellar syndrome and both the nail-patella and short patella syndromes, mutation screening of their causative genes, LMX1B and TBX4, was performed. Although there still does not appear to be an identifiable molecular etiology in genitopatellar syndrome, mutations in these two candidate genes have been excluded in our patients. Since both LMX1B and TBX4 are involved in a common molecular pathway, it is likely that the causative gene of genitopatellar syndrome functions within the same developmental process.

  1. Expansion of the TARP syndrome phenotype associated with de novo mutations and mosaicism.

    PubMed

    Johnston, Jennifer J; Sapp, Julie C; Curry, Cynthia; Horton, Margaret; Leon, Eyby; Cusmano-Ozog, Kristina; Dobyns, William B; Hudgins, Louanne; Zackai, Elaine; Biesecker, Leslie G

    2014-01-01

    The TARP syndrome (Talipes equinovarus, Atrial septal defect, Robin sequence, and Persistent left superior vena cava) is an X-linked disorder that was determined to be caused by mutations in RBM10 in two families, and confirmed in a subsequent case report. The first two original families were quite similar in phenotype, with uniform early lethality although a confirmatory case report showed survival into childhood. Here we report on five affecteds from three newly recognized families, including patients with atypical manifestations. None of the five patients had talipes and others also lacked cardinal TARP features of Robin sequence and atrial septal defect. All three families demonstrated de novo mutations, and one of the families had two recurrences, with demonstrable maternal mosaicism.

  2. Neuroimaging features in C9orf72 and TARDBP double mutation with FTD phenotype.

    PubMed

    Origone, Paola; Accardo, Jennifer; Verdiani, Simonetta; Lamp, Merit; Arnaldi, Dario; Bellone, Emilia; Picco, Agnese; Morbelli, Silvia; Mandich, Paola; Nobili, Flavio

    2015-01-01

    Increasing evidence has shown that morphological and functional neuroimaging may help to understand the pathophysiological mechanisms leading to behavioral disturbances in patients with genetic or sporadic frontotemporal dementia (FTD). The C9orf72 expansion was found in association with the N267S TARDBP mutation in two siblings with behavioral-variant FTD (bvFTD). In one of them with very mild dementia, MRI showed symmetric atrophy of temporal, inferolateral and orbital frontal cortex, while [18F]FDG-PET disclosed more extended hypometabolism in dorsolateral and inferolateral frontal cortex, anterior cingulate, and caudate nucleus. Hypometabolism in right lateral and orbital frontal cortex was confirmed also in comparison with a group of sporadic bvFTD patients. These findings appear as the neuroimaging hallmark of double C9orf72 and TARDBP gene mutation with a bvFTD phenotype.

  3. Cystic fibrosis mice carrying the missense mutation G551D replicate human genotype-phenotype correlations.

    PubMed Central

    Delaney, S J; Alton, E W; Smith, S N; Lunn, D P; Farley, R; Lovelock, P K; Thomson, S A; Hume, D A; Lamb, D; Porteous, D J; Dorin, J R; Wainwright, B J

    1996-01-01

    We have generated a mouse carrying the human G551D mutation in the cystic fibrosis transmembrane conductance regulator gene (CFTR) by a one-step gene targeting procedure. These mutant mice show cystic fibrosis pathology but have a reduced risk of fatal intestinal blockage compared with 'null' mutants, in keeping with the reduced incidence of meconium ileus in G551D patients. The G551D mutant mice show greatly reduced CFTR-related chloride transport, displaying activity intermediate between that of cftr(mlUNC) replacement ('null') and cftr(mlHGU) insertional (residual activity) mutants and equivalent to approximately 4% of wild-type CFTR activity. The long-term survival of these animals should provide an excellent model with which to study cystic fibrosis, and they illustrate the value of mouse models carrying relevant mutations for examining genotype-phenotype correlations. Images PMID:8605891

  4. Phenotypic spectrum of the Tubulin-related Disorders and Functional Implications of Disease-causing Mutations

    PubMed Central

    Tischfield, Max A.; Cederquist, Gustav Y.; Gupta, Mohan L.; Engle, Elizabeth C.

    2011-01-01

    A spectrum of neurological disorders characterized by abnormal neuronal migration, differentiation, and axon guidance and maintenance have recently been attributed to missense mutations in the genes that encode α– and β-tubulin isotypes TUBA1A, TUBA8, TUBB2B, and TUBB3, all of which putatively co-assemble into neuronal microtubules. The resulting nervous system malformations can include different types of cortical malformations, defects in commissural fiber tracts, and degeneration of motor and sensory axons. Many clinical phenotypes and brain malformations are shared among the various mutations regardless of structural location and/or isotype, while others segregate with distinct amino acids or functional domains within tubulin. Collectively, these disorders provide novel paradigms for understanding the biological functions of microtubules and their core components in normal health and disease. PMID:21292473

  5. Colorectal Carcinomas With CpG Island Methylator Phenotype 1 Frequently Contain Mutations in Chromatin Regulators

    PubMed Central

    Tahara, Tomomitsu; Yamamoto, Eiichiro; Madireddi, Priyanka; Suzuki, Hiromu; Maruyama, Reo; Chung, Woonbok; Garriga, Judith; Jelinek, Jaroslav; Yamano, Hiro-o; Sugai, Tamotsu; Kondo, Yutaka; Toyota, Minoru; Issa, Jean-Pierre J.; Estécio, Marcos R. H.

    2014-01-01

    BACKGROUND & AIMS Subgroups of colorectal carcinomas (CRCs) characterized by DNA methylation anomalies are termed CpG island methylator phenotype (CIMP)1, CIMP2, or CIMP-negative. The pathogenesis of CIMP1 colorectal carcinomas, and their effects on patients’ prognoses and responses to treatment, differ from those of other CRCs. We sought to identify genetic somatic alterations associated with CIMP1 CRCs. METHODS We examined genomic DNA samples from 100 primary CRCs, 10 adenomas, and adjacent normal-appearing mucosae from patients undergoing surgery or colonoscopy at 3 tertiary medical centers. We performed exome sequencing of 16 colorectal tumors and their adjacent normal tissues. Extensive comparison with known somatic alterations in CRCs allowed segregation of CIMP1-exclusive alterations. The prevalence of mutations in selected genes was determined from an independent cohort. RESULTS We found that genes that regulate chromatin were mutated in CIMP1 CRCs; the highest rates of mutation were observed in CHD7 and CHD8, which encode members of the chromodomain helicase/adenosine triphosphate—dependent chromatin remodeling family. Somaticmutations in these 2 genes were detected in 5 of 9 CIMP1 CRCs. A prevalence screen showed that nonsilencing mutations in CHD7 and CHD8 occurred significantly more frequently in CIMP1 tumors (18 of 42 [43%]) than in CIMP2 (3 of 34 [9%]; P < .01) or CIMP-negative tumors (2 of 34 [6%]; P < .001). CIMP1 markers had increased binding by CHD7, compared with all genes. Genes altered in patients with CHARGE syndrome (congenital malformations involving the central nervous system, eye, ear, nose, and mediastinal organs) who had CHD7 mutations were also altered in CRCs with mutations in CHD7. CONCLUSIONS Aberrations in chromatin remodeling could contribute to the development of CIMP1 CRCs. A better understanding of the biological determinants of CRCs can be achieved when these tumors are categorized according to their epigenetic status. PMID

  6. Prediction of phenotypes of missense mutations in human proteins from biological assemblies.

    PubMed

    Wei, Qiong; Xu, Qifang; Dunbrack, Roland L

    2013-02-01

    Single nucleotide polymorphisms (SNPs) are the most frequent variation in the human genome. Nonsynonymous SNPs that lead to missense mutations can be neutral or deleterious, and several computational methods have been presented that predict the phenotype of human missense mutations. These methods use sequence-based and structure-based features in various combinations, relying on different statistical distributions of these features for deleterious and neutral mutations. One structure-based feature that has not been studied significantly is the accessible surface area within biologically relevant oligomeric assemblies. These assemblies are different from the crystallographic asymmetric unit for more than half of X-ray crystal structures. We find that mutations in the core of proteins or in the interfaces in biological assemblies are significantly more likely to be disease-associated than those on the surface of the biological assemblies. For structures with more than one protein in the biological assembly (whether the same sequence or different), we find the accessible surface area from biological assemblies provides a statistically significant improvement in prediction over the accessible surface area of monomers from protein crystal structures (P = 6e-5). When adding this information to sequence-based features such as the difference between wildtype and mutant position-specific profile scores, the improvement from biological assemblies is statistically significant but much smaller (P = 0.018). Combining this information with sequence-based features in a support vector machine leads to 82% accuracy on a balanced dataset of 50% disease-associated mutations from SwissVar and 50% neutral mutations from human/primate sequence differences in orthologous proteins.

  7. A de-novo STXBP1 gene mutation in a patient showing the Rett syndrome phenotype.

    PubMed

    Romaniello, Romina; Saettini, Francesco; Panzeri, Elena; Arrigoni, Filippo; Bassi, Maria T; Borgatti, Renato

    2015-03-25

    This study reports on a 9-year-old girl who developed West syndrome and showed clinical features fulfilling the main revised diagnostic criteria for typical Rett syndrome (hand washing, severe cognitive impairment with absence of language, ataxic gait, progressive scoliosis and autistic features). Mutation analyses for methyl-CpG-binding protein 2 (MECP2), cyclin-dependent kinase-like 5 (CDKL5/STK9), ARX and Forkhead box G1 (FOXG1) genes were carried out, with negative results. A known de-novo c.1217G>A missense mutation in exon 14 leading to the substitution of a conserved residue, p.R406H in domain3b of the syntaxin-binding protein 1 (STXBP1) gene, was detected. The STXBP1 gene encodes the syntaxin-binding protein 1, a neuron-specific protein involved in synaptic vesicle release at both glutaminergic and GABAergic synapses. This function is also affected by MECP2 gene mutations, which are known to lead to a decrease in glutamate and GABA receptors' density. It is possible to speculate that the impairment in synaptic plasticity represents the pathogenic link between MECP2 and STXBP1 gene mutations. On reviewing the clinical features of the reported patients with the same mutation in the STXBP1 gene, it has been observed that poor eye contact, tremour, dyskinesia, head/hand stereotypies and both cognitive and motor progressive deterioration are common symptoms, although never considered as indicative of a Rett syndrome phenotype. In conclusion, the case described here suggests a relationship between the Rett syndrome and the STXBP1 gene not described so far, making the search for STXBP1 gene mutations advisable in patients with Rett syndrome and early onset of epilepsy.

  8. Pleiotropic effect of a novel mutation in GCNT2 causing congenital cataract and a rare adult i blood group phenotype

    PubMed Central

    Cheong, Sek-Shir; Hull, Sarah; Jones, Benjamin; Chana, Ravinder; Thornton, Nicole; Plagnol, Vincent; Moore, Anthony T; Hardcastle, Alison J

    2017-01-01

    Mutations in GCNT2 have been associated with the rare adult i blood group phenotype with or without congenital cataract. We report a novel homozygous frameshift mutation c.1163_1166delATCA, p.(Asn388Argfs*20) as the cause of congenital cataract in two affected siblings. Blood group typing confirmed that both affected males have the rare adult i phenotype, supporting the hypothesis that the partial association of I/i phenotype and congenital cataract is due to the differential expression of GCNT2 isoforms. PMID:28224043

  9. Different attenuated phenotypes of GM2 gangliosidosis variant B in Japanese patients with HEXA mutations at codon 499, and five novel mutations responsible for infantile acute form.

    PubMed

    Tanaka, Akemi; Hoang, Lan Thi Ngcok; Nishi, Yasuaki; Maniwa, Satoshi; Oka, Makio; Yamano, Tsunekazu

    2003-01-01

    Eight mutations of the alpha subunit of beta-hexosaminidase A gene ( HEXA) were identified in eight patients with GM2 gangliosidosis variant B. They were five missense mutations, two splice-site mutations, and one two-base deletion. Five of them, R252L (CGT-->CTT), N295S (AAT-->AAC), W420C (TGG-->TGT), IVS 13, +2A-->C, and del 265-266AC (exon 2), were novel mutations responsible for infantile acute form of GM2 gangliosidosis. Two missense mutations, R499H and R499C, were found in one allele of two patients with attenuated phenotypes. The patient with R499C showed a late infantile form, and the other patient with R499H showed a juvenile form. These two mutations have been reported previously in the patients of other ethnic groups, and they have been known to cause attenuated phenotypes. The milder phenotypes of GM2 gangliosidosis variant B, different from the infantile acute form, have not been reported so far in Japan, and this is the first report of Japanese patients with attenuated phenotypes and their molecular analysis.

  10. XPD Helicase Structures And Activities: Insights Into the Cancer And Aging Phenotypes From XPD Mutations

    SciTech Connect

    Fan, L.; Fuss, J.O.; Cheng, Q.J.; Arvai, A.S.; Hammel, M.; Roberts, V.A.; Cooper, P.K.; Tainer, J.A.

    2009-05-18

    Mutations in XPD helicase, required for nucleotide excision repair (NER) as part of the transcription/repair complex TFIIH, cause three distinct phenotypes: cancer-prone xeroderma pigmentosum (XP), or aging disorders Cockayne syndrome (CS), and trichothiodystrophy (TTD). To clarify molecular differences underlying these diseases, we determined crystal structures of the XPD catalytic core from Sulfolobus acidocaldarius and measured mutant enzyme activities. Substrate-binding grooves separate adjacent Rad51/RecA-like helicase domains (HD1, HD2) and an arch formed by 4FeS and Arch domains. XP mutations map along the HD1 ATP-binding edge and HD2 DNA-binding channel and impair helicase activity essential for NER. XP/CS mutations both impair helicase activity and likely affect HD2 functional movement. TTD mutants lose or retain helicase activity but map to sites in all four domains expected to cause framework defects impacting TFIIH integrity. These results provide a foundation for understanding disease consequences of mutations in XPD and related 4Fe-4S helicases including FancJ.

  11. Further defining the phenotypic spectrum of B4GALT7 mutations.

    PubMed

    Salter, Claire G; Davies, Justin H; Moon, Rebecca J; Fairhurst, Joanna; Bunyan, David; Foulds, Nicola

    2016-06-01

    Proteoglycans are components of the extracellular matrix with diverse biological functions. Defects in proteoglycan synthesis have been linked to several human diseases with common features of short stature, hypermobility, joint dislocations, and skeletal dysplasia. B4GALT7 encodes galactosyltransferase-I that catalyzes the addition of a galactose moiety to a xylosyl group in the tetrasaccharide linker of proteoglycans. Mutations in this gene have been associated with the rare progeroid form of Ehlers Danlos syndrome and in addition more recently found to underlie Larsen of Reunion Island syndrome. Nine individuals have been reported with a diagnosis of the progeroid form of Ehlers Danlos syndrome, four of whom have had molecular characterization showing homozygous or compound heterozygous mutations in B4GALT7. We report two newly described patients with compound heterozygous mutations in B4GALT7, and show that the six individuals with confirmed mutations do not have the progeroid features described in the original five patients with a clinical diagnosis of the progeroid form of Ehlers Danlos syndrome. We suggest that galactosyltransferase-I deficiency does not cause the progeroid form of Ehlers Danlos syndrome, but instead results in a clinically recognizable syndrome comprising short stature, joint hypermobility, radioulnar synostosis, and severe hypermetropia. This group of syndromic patients are on a phenotypic spectrum with individuals who have Larsen of Reunion Island syndrome, although the key features of osteopenia, fractures and hypermetropia have not been reported in patients from Reunion Island. © 2016 Wiley Periodicals, Inc.

  12. Phenotype of the fibroblast growth factor receptor 2 Ser351Cys mutation: Pfeiffer syndrome type III.

    PubMed

    Gripp, K W; Stolle, C A; McDonald-McGinn, D M; Markowitz, R I; Bartlett, S P; Katowitz, J A; Muenke, M; Zackai, E H

    1998-07-24

    We present a patient with pansynostosis, hydrocephalus, seizures, extreme proptosis with luxation of the eyes out of the lids, apnea and airway obstruction, intestinal non-rotation, and severe developmental delay. His skeletal abnormalities include bilateral elbow ankylosis, radial head dislocation, and unilateral broad and deviated first toe. The phenotype of this patient is consistent with that previously reported in Pfeiffer syndrome type III, but is unusual for the lack of broad thumbs. Our patient most closely resembles the case described by Kerr et al. [1996: Am J Med Genet 66:138-143] as Pfeiffer syndrome type III with normal thumbs. Mutations in the genes for fibroblast growth factor receptors (FGFR) 1 and 2 have previously been seen in patients with Pfeiffer syndrome type I. The mutation identified in our patient, Ser351Cys in FGFR2, represents the first reported cause of Pfeiffer syndrome type III. An identical mutation was described once previously by Pulleyn et al., in a patient whose brief clinical description included cloverleaf skull, significant developmental delay, and normal hands and feet [Eur. J. Hum. Genet. 4: 283-291, 1996]. In our patient, previously performed single-strand conformation polymorphism analysis failed to detect a band shift; the mutation was identified only after independent sequence analysis.

  13. XPD Helicase Structures and Activities: Insights into the Cancer and Aging Phenotypes from XPD Mutations

    SciTech Connect

    Tainer, John; Fan, Li; Fuss, Jill O.; Cheng, Quen J.; Arvai, Andrew S.; Hammel, Michal; Roberts, Victoria A.; Cooper, Priscilla K.; Tainer, John A.

    2008-06-02

    Mutations in XPD helicase, required for nucleotide excision repair (NER) as part of the transcription/repair complex TFIIH, cause three distinct phenotypes: cancer-prone xeroderma pigmentosum (XP), or aging disorders Cockayne syndrome (CS), and trichothiodystrophy (TTD). To clarify molecular differences underlying these diseases, we determined crystal structures of the XPD catalytic core from Sulfolobus acidocaldarius and measured mutant enzyme activities. Substrate-binding grooves separate adjacent Rad51/RecA-like helicase domains (HD1, HD2) and an arch formed by 4FeS and Arch domains. XP mutations map along the HD1 ATP-binding edge and HD2 DNA-binding channel and impair helicase activity essential for NER. XP/CS mutations both impair helicase activity and likely affect HD2 functional movement. TTD mutants lose or retain helicase activity but map to sites in all four domains expected to cause framework defects impacting TFIIH integrity. These results provide a foundation for understanding disease consequences of mutations in XPD and related 4Fe-4S helicases including FancJ.

  14. Different phenotypes in vivo are associated with ATPase motif mutations in Schizosaccharomyces pombe minichromosome maintenance proteins.

    PubMed Central

    Gómez, Eliana B; Catlett, Michael G; Forsburg, Susan L

    2002-01-01

    The six conserved MCM proteins are essential for normal DNA replication. They share a central core of homology that contains sequences related to DNA-dependent and AAA(+) ATPases. It has been suggested that the MCMs form a replicative helicase because a hexameric subcomplex formed by MCM4, -6, and -7 proteins has in vitro DNA helicase activity. To test whether ATPase and helicase activities are required for MCM protein function in vivo, we mutated conserved residues in the Walker A and Walker B motifs of MCM4, -6, and -7 and determined that equivalent mutations in these three proteins have different in vivo effects in fission yeast. Some mutations reported to abolish the in vitro helicase activity of the mouse MCM4/6/7 subcomplex do not affect the in vivo function of fission yeast MCM complex. Mutations of consensus CDK sites in Mcm4p and Mcm7p also have no phenotypic consequences. Co-immunoprecipitation analyses and in situ chromatin-binding experiments were used to study the ability of the mutant Mcm4ps to associate with the other MCMs, localize to the nucleus, and bind to chromatin. We conclude that the role of ATP binding and hydrolysis is different for different MCM subunits. PMID:11973289

  15. Late-onset spastic ataxia phenotype in a patient with a homozygous DDHD2 mutation

    PubMed Central

    Doi, Hiroshi; Ushiyama, Masao; Baba, Takashi; Tani, Katsuko; Shiina, Masaaki; Ogata, Kazuhiro; Miyatake, Satoko; Fukuda-Yuzawa, Yoko; Tsuji, Shoji; Nakashima, Mitsuko; Tsurusaki, Yoshinori; Miyake, Noriko; Saitsu, Hirotomo; Ikeda, Shu-ichi; Tanaka, Fumiaki; Matsumoto, Naomichi; Yoshida, Kunihiro

    2014-01-01

    Autosomal recessive cerebellar ataxias and autosomal recessive hereditary spastic paraplegias (ARHSPs) are clinically and genetically heterogeneous neurological disorders. Herein we describe Japanese siblings with a midlife-onset, slowly progressive type of cerebellar ataxia and spastic paraplegia, without intellectual disability. Using whole exome sequencing, we identified a homozygous missense mutation in DDHD2, whose mutations were recently identified as the cause of early-onset ARHSP with intellectual disability. Brain MRI of the patient showed a thin corpus callosum. Cerebral proton magnetic resonance spectroscopy revealed an abnormal lipid peak in the basal ganglia, which has been reported as the hallmark of DDHD2-related ARHSP (SPG 54). The mutation caused a marked reduction of phospholipase A1 activity, supporting that this mutation is the cause of SPG54. Our cases indicate that the possibility of SPG54 should also be considered when patients show a combination of adult-onset spastic ataxia and a thin corpus callosum. Magnetic resonance spectroscopy may be helpful in the differential diagnosis of patients with spastic ataxia phenotype. PMID:25417924

  16. Genotype–Phenotype Correlations in Ornithine Transcarbamylase Deficiency: A Mutation Update

    PubMed Central

    Caldovic, Ljubica; Abdikarim, Iman; Narain, Sahas; Tuchman, Mendel; Morizono, Hiroki

    2015-01-01

    Ornithine transcarbamylase (OTC) deficiency is an X-linked trait that accounts for nearly half of all inherited disorders of the urea cycle. OTC is one of the enzymes common to both the urea cycle and the bacterial arginine biosynthesis pathway; however, the role of OTC has changed over evolution. For animals with a urea cycle, defects in OTC can trigger hyperammonemic episodes that can lead to brain damage and death. This is the fifth mutation update for human OTC with previous updates reported in 1993, 1995, 2002, and 2006. In the 2006 update, 341 mutations were reported. This current update contains 417 disease-causing mutations, and also is the first report of this series to incorporate information about natural variation of the OTC gene in the general population through examination of publically available genomic data and examination of phenotype/genotype correlations from patients participating in the Urea Cycle Disorders Consortium Longitudinal Study and the first to evaluate the suitability of systematic computational approaches to predict severity of disease associated with different types of OTC mutations. PMID:26059767

  17. Genotype-Phenotype Correlations in Ornithine Transcarbamylase Deficiency: A Mutation Update.

    PubMed

    Caldovic, Ljubica; Abdikarim, Iman; Narain, Sahas; Tuchman, Mendel; Morizono, Hiroki

    2015-05-20

    Ornithine transcarbamylase (OTC) deficiency is an X-linked trait that accounts for nearly half of all inherited disorders of the urea cycle. OTC is one of the enzymes common to both the urea cycle and the bacterial arginine biosynthesis pathway; however, the role of OTC has changed over evolution. For animals with a urea cycle, defects in OTC can trigger hyperammonemic episodes that can lead to brain damage and death. This is the fifth mutation update for human OTC with previous updates reported in 1993, 1995, 2002, and 2006. In the 2006 update, 341 mutations were reported. This current update contains 417 disease-causing mutations, and also is the first report of this series to incorporate information about natural variation of the OTC gene in the general population through examination of publicly available genomic data and examination of phenotype/genotype correlations from patients participating in the Urea Cycle Disorders Consortium Longitudinal Study and the first to evaluate the suitability of systematic computational approaches to predict severity of disease associated with different types of OTC mutations.

  18. Novel phenotype associated with a mutation in the KCNA1(Kv1.1) gene

    PubMed Central

    D'Adamo, Maria C.; Gallenmüller, Constanze; Servettini, Ilenio; Hartl, Elisabeth; Tucker, Stephen J.; Arning, Larissa; Biskup, Saskia; Grottesi, Alessandro; Guglielmi, Luca; Imbrici, Paola; Bernasconi, Pia; Di Giovanni, Giuseppe; Franciolini, Fabio; Catacuzzeno, Luigi; Pessia, Mauro; Klopstock, Thomas

    2015-01-01

    Episodic ataxia type 1 (EA1) is an autosomal dominant K+ channelopathy which manifests with short attacks of cerebellar ataxia and dysarthria, and may also show interictal myokymia. Episodes can be triggered by emotional or physical stress, startle response, sudden postural change or fever. Here we describe a 31-year-old man displaying markedly atypical symptoms, including long-lasting attacks of jerking muscle contractions associated with hyperthermia, severe migraine, and a relatively short-sleep phenotype. A single nucleotide change in KCNA1 (c.555C>G) was identified that changes a highly conserved residue (p.C185W) in the first transmembrane segment of the voltage-gated K+ channel Kv1.1. The patient is heterozygous and the mutation was inherited from his asymptomatic mother. Next generation sequencing revealed no variations in the CACNA1A, CACNB4, KCNC3, KCNJ10, PRRT2 or SCN8A genes of either the patient or mother, except for a benign variant in SLC1A3. Functional analysis of the p.C185W mutation in KCNA1 demonstrated a deleterious dominant-negative phenotype where the remaining current displayed slower activation kinetics, subtle changes in voltage-dependence and faster recovery from slow inactivation. Structural modeling also predicts the C185W mutation to be functionally deleterious. This description of novel clinical features, associated with a Kv1.1 mutation highlights a possibly unrecognized relationship between K+ channel dysfunction, hyperthermia and migraine in EA1, and suggests that thorough assessments for these symptoms should be carefully considered for all patients affected by EA1. PMID:25642194

  19. Simultaneous Expression of ABCA4 and GPR143 Mutations: A Complex Phenotypic Manifestation

    PubMed Central

    Lee, Winston; Schuerch, Kaspar; Xie, Yajing; Zernant, Jana; Tsang, Stephen H.; Sparrow, Janet R.; Allikmets, Rando

    2016-01-01

    Purpose To describe the complex, overlapping phenotype expressed in a two generation family harboring pathogenic mutations in the ABCA4 and GPR143 genes. Methods Clinical evaluation of a two generation family included quantitative autofluorescence imaging (qAF, 488-nm excitation) using a modified confocal scanning laser ophthalmoscope equipped with an internal fluorescent reference to account for varying laser power detector sensitivity, spectral-domain optical coherence tomography, and full-field ERG testing. Complete sequencing of the ABCA4 and GPR143 genes was carried out in each individual. Results Affected individuals presented with bull's eye lesions and qAF levels above the 95% confidence interval for healthy eyes; full-field ERG revealed no generalized rod dysfunction but mild implicit time delays in cone responses. Complete sequencing of the ABCA4 gene revealed two disease-causing mutations, p.L541P and p.G1961E; and mutational phase was confirmed in each unaffected parent. Further examination in the affected patients revealed a peripheral “mud-splattered” pattern of hypopigmented RPE after which sequencing of GPR143 revealed a novel missense variant, p.Y157C. The GPR143 variant segregated from the father who did not exhibit any indications of retinal disease with the exception of an abnormal near-infrared autofluorescence (NIR-AF) signal distribution in the macula. Conclusions An individual carrying both ABCA4 and GPR143 disease-causing mutations can express a complex, overlapping phenotype associated with both Stargardt disease and X-linked ocular albinism (OA1). The absence of OA1-related disease changes (with the exception of NIR-AF changes associated with melanin distribution) in the father may be indicative of mild expressivity or variable gene penetrance. PMID:27367509

  20. MUTATIONS IN TTC37 CAUSE TRICHOHEPATOENTERIC SYNDROME (PHENOTYPIC DIARRHOEA OF INFANCY)

    PubMed Central

    Hartley, Jane Louise; Zachos, Nicholas C.; Dawood, Ban; Donowitz, Mark; Forman, Julia; Pollitt, Rodney J; Morgan, Neil V; Tee, Louise; Gissen, Paul; Kahr, Walter H.A.; Knisely, A.S.; Watson, Steve; Chitayat, David; Booth, IW; Protheroe, Sue; Murphy, Stephen; de Vries, Esther; Kelly, Deirdre A; Maher, Eamonn R

    2010-01-01

    Background Trichohepatoenteric syndrome (THES) is an autosomal recessive disorder characterised by life-threatening diarrhoea in infancy, immunodeficiency, liver disease, trichorrhexis nodosa, facial dysmorphism, hypopigmentation and cardiac defects. We attempted to characterise the phenotype and elucidate the molecular basis of THES. Methods Twelve patients with classical THES from 11 families had detailed phenotyping. Autozygosity mapping was undertaken in 8 patients from consanguineous families using 250k single nucleotide polymorphism (SNP) arrays and linked regions evaluated using microsatellite markers. Linkage was confirmed to one region from which candidate genes were analysed. The effect of mutations on protein production and/or localisation in hepatocytes and intestinal epithelial cells from affected patients was characterised by immunohistochemistry. Results Previously unrecognised platelet abnormalities (reduced platelet α-granules, unusual stimulated alpha granule content release, abnormal lipid inclusions, abnormal platelet canalicular system and reduced number of microtubules) were identified. The THES locus was mapped to 5q14.3 – 5q21.2. Sequencing of candidate genes demonstrated mutations in TTC37, which encodes the uncharacterised tetratricopeptide repeat protein, thespin. Bioinformatic analysis suggested thespin to be involved in protein-protein interactions or chaperone. Preliminary studies of enterocyte brush-border ion transporter proteins (NHE2, NHE3, Aquaporin 7, Na/I symporter and H / K ATPase) showed reduced expression or mislocalisation in all THES patients with different profiles for each. In contrast the basolateral localisation of Na/K ATPase was not altered. Conclusion THES is caused by mutations in TTC37. TTC37 mutations have a multisystem effect which may be due to abnormal stability and / or intracellular localisation of TTC37 target proteins. PMID:20176027

  1. Ophthalmological phenotype associated with homozygous null mutation in the NEUROD1 gene

    PubMed Central

    Orosz, Orsolya; Czeglédi, Miklós; Kántor, Irén; Balogh, István; Vajas, Attila; Takács, Lili; Berta, András

    2015-01-01

    Purpose NEUROD1 is a tissue-specific basic helix loop helix (bHLH) protein involved in the development and maintenance of the endocrine pancreas and neuronal elements. Loss of NEUROD1 causes ataxia, cerebellar hypoplasia, sensorineural deafness, and severe retinal dystrophy in mice. Heterozygous loss-of-function mutations in NEUROD1 have previously been described as a cause of maturity-onset diabetes of the young (MODY) and late-onset diabetes. To date, homozygous loss-of-function NEUROD1 mutations have only been detected in two patients. Both mutations caused permanent neonatal diabetes and severe neurologic defects, including visual impairment. However, a detailed ophthalmological phenotype of this novel syndrome has not yet been reported. Our aim was to characterize the ophthalmological phenotype associated with the previously reported homozygous c.427_428CT mutation in the NEUROD1 gene. Methods The female patient was investigated on multiple occasions between 2009 (age 14) and 2014 (age 19), including visual acuity testing, automated perimetry, funduscopy, anterior-segment imaging, optical coherence tomography of the posterior pole, standard full-field electroretinography, and fundus-autofluorescence imaging. Results The patient had nyctalopia, blurry vision, and visual field constriction from early childhood. Her best corrected visual acuity ranged between 20/25 and 15/25 during the investigation period. Perimetry showed concentric constriction of the visual field, sparing only the central 30 degrees in both eyes. The anterior segment did not show any morphological changes. Optical coherence tomography revealed total absence of the photoreceptor layer of the retina outside the fovea, where a discoid remnant of cone photoreceptors could be detected. Neither setting of the standard full-field electroretinography could detect any electrical response from the retina. Color fundus photos presented peripheral chorioretinal atrophy and central RPE mottling. A

  2. Diverse Phenotypic Expression of Cardiomyopathies in a Family with TNNI3 p.Arg145Trp Mutation

    PubMed Central

    Hwang, Ji-won; Jang, Mi-Ae; Jang, Shin Yi; Seo, Soo Hyun; Seong, Moon-Woo; Park, Sung Sup; Ki, Chang-Seok

    2017-01-01

    Genetic diagnosis of cardiomyopathies is challenging, due to the marked genetic and allelic heterogeneity and the lack of knowledge of the mutations that lead to clinical phenotypes. Here, we present the case of a large family, in which a single TNNI3 mutation caused variable phenotypic expression, ranging from restrictive cardiomyopathy (RCMP) to hypertrophic cardiomyopathy (HCMP) to near-normal phenotype. The proband was a 57-year-old female with HCMP. Examining the family history revealed that her elder sister had expired due to severe RCMP. Using a next-generation sequencing-based gene panel to analyze the proband, we identified a known TNNI3 gene mutation, c.433C>T, which is predicted to cause an amino acid substitution (p.Arg145Trp) in the highly conserved inhibitory region of the cardiac troponin I protein. Sanger sequencing confirmed that six relatives with RCMP or near-normal phenotypes also carried this mutation. To our knowledge, this is the first genetically confirmed family with diverse phenotypic expression of cardiomyopathies in Korea. Our findings demonstrate familial implications, where a single mutation in a sarcomere protein can cause diverse phenotypic expression of cardiomyopathies. PMID:28382084

  3. Further insight into the phenotype associated with a mutation in the ORC6 gene, causing Meier-Gorlin syndrome 3.

    PubMed

    Shalev, Stavit Allon; Khayat, Morad; Etty, Daniel-Spiegl; Elpeleg, Orly

    2015-03-01

    Mutations in genes encoding the origin recognition complex subunits cause Meier-Gorlin syndrome. The disease manifests a triad of short stature, small ears, and small and/or absent patellae with variable expressivity. We report on the identification of a homozygous deleterious mutation in the ORC6 gene in previously described fetuses at the severe end of the Meier-Gorlin spectrum. The phenotype included severe intrauterine growth retardation, dislocation of knees, gracile bones, clubfeet, and small mandible and chest. To date, the clinical presentation of ORC6-associated Meier-Gorlin syndrome has been mild compared to other the phenotype associated with other loci. The present report expands the clinical phenotype associated with ORC6 mutations to include severely abnormal embryological development suggesting a possible genotype-phenotype correlation.

  4. Impact of JAK2V617F Mutational Status on Phenotypic Features in Essential Thrombocythemia and Primary Myelofibrosis

    PubMed Central

    Yönal, İpek; Dağlar-Aday, Aynur; Akadam-Teker, Başak; Yılmaz, Ceylan; Nalçacı, Meliha; Yavuz, Akif Selim; Sargın, Fatma Deniz

    2016-01-01

    Objective: The JAK2V617F mutation is present in the majority of patients with essential thrombocythemia (ET) and primary myelofibrosis (PMF). The impact of this mutation on disease phenotype in ET and PMF is still a matter of discussion. This study aims to determine whether there are differences in clinical presentation and disease outcome between ET and PMF patients with and without the JAK2V617F mutation. Materials and Methods: In this single-center study, a total of 184 consecutive Philadelphia-negative chronic myeloproliferative neoplasms, 107 cases of ET and 77 cases of PMF, were genotyped for JAK2V617F mutation using the JAK2 Ipsogen MutaScreen assay, which involves allele-specific polymerase chain reaction. Results: ET patients positive for JAK2V617F mutation had higher hemoglobin (Hb) and hematocrit (Hct) levels, lower platelet counts, and more prevalent splenomegaly at diagnosis compared to patients negative for the JAK2V617F mutation, but rates of major thrombotic events, arterial thrombosis, and venous thrombosis were comparable between the groups. At presentation, PMF patients with JAK2V617F mutation had significantly higher Hb and Hct levels and leukocyte counts than patients without the mutation. Similar to the findings of ET patients, thromboembolic rates were similar in PMF patients with and without theJAK2V617F mutation. For ET and PMF patients, no difference was observed in rates of death with respect to JAK2V617F mutational status. Moreover, leukemic transformation rate was not different in our PMF patients with and without JAK2V617F mutation. Conclusion: We conclude that JAK2V617F-mutated ET patients express a polycythemia vera-like phenotype and JAK2V617F mutation in PMF patients is associated with a more pronounced myeloproliferative phenotype. PMID:25913509

  5. De novo heterozygous mutations in SMC3 cause a range of Cornelia de Lange syndrome-overlapping phenotypes.

    PubMed

    Gil-Rodríguez, María Concepción; Deardorff, Matthew A; Ansari, Morad; Tan, Christopher A; Parenti, Ilaria; Baquero-Montoya, Carolina; Ousager, Lilian B; Puisac, Beatriz; Hernández-Marcos, María; Teresa-Rodrigo, María Esperanza; Marcos-Alcalde, Iñigo; Wesselink, Jan-Jaap; Lusa-Bernal, Silvia; Bijlsma, Emilia K; Braunholz, Diana; Bueno-Martinez, Inés; Clark, Dinah; Cooper, Nicola S; Curry, Cynthia J; Fisher, Richard; Fryer, Alan; Ganesh, Jaya; Gervasini, Cristina; Gillessen-Kaesbach, Gabriele; Guo, Yiran; Hakonarson, Hakon; Hopkin, Robert J; Kaur, Maninder; Keating, Brendan J; Kibaek, María; Kinning, Esther; Kleefstra, Tjitske; Kline, Antonie D; Kuchinskaya, Ekaterina; Larizza, Lidia; Li, Yun R; Liu, Xuanzhu; Mariani, Milena; Picker, Jonathan D; Pié, Ángeles; Pozojevic, Jelena; Queralt, Ethel; Richer, Julie; Roeder, Elizabeth; Sinha, Anubha; Scott, Richard H; So, Joyce; Wusik, Katherine A; Wilson, Louise; Zhang, Jianguo; Gómez-Puertas, Paulino; Casale, César H; Ström, Lena; Selicorni, Angelo; Ramos, Feliciano J; Jackson, Laird G; Krantz, Ian D; Das, Soma; Hennekam, Raoul C M; Kaiser, Frank J; FitzPatrick, David R; Pié, Juan

    2015-04-01

    Cornelia de Lange syndrome (CdLS) is characterized by facial dysmorphism, growth failure, intellectual disability, limb malformations, and multiple organ involvement. Mutations in five genes, encoding subunits of the cohesin complex (SMC1A, SMC3, RAD21) and its regulators (NIPBL, HDAC8), account for at least 70% of patients with CdLS or CdLS-like phenotypes. To date, only the clinical features from a single CdLS patient with SMC3 mutation has been published. Here, we report the efforts of an international research and clinical collaboration to provide clinical comparison of 16 patients with CdLS-like features caused by mutations in SMC3. Modeling of the mutation effects on protein structure suggests a dominant-negative effect on the multimeric cohesin complex. When compared with typical CdLS, many SMC3-associated phenotypes are also characterized by postnatal microcephaly but with a less distinctive craniofacial appearance, a milder prenatal growth retardation that worsens in childhood, few congenital heart defects, and an absence of limb deficiencies. While most mutations are unique, two unrelated affected individuals shared the same mutation but presented with different phenotypes. This work confirms that de novo SMC3 mutations account for ∼ 1%-2% of CdLS-like phenotypes.

  6. UV fingerprints predominate in the PTCH mutation spectra of basal cell carcinomas independent of clinical phenotype.

    PubMed

    Heitzer, Ellen; Lassacher, Anita; Quehenberger, Franz; Kerl, Helmut; Wolf, Peter

    2007-12-01

    Basal cell carcinoma (BCC) shows a wide interpatient variation in lesion accrual. To determine whether certain tumorigenic fingerprints and potentially predisposing patched (PTCH) tumor suppressor single-nucleotide polymorphisms (SNPs) are distributed differently among sporadic BCC patients, we compared the PTCH mutation spectra in early-onset BCC (first lesion at age < 35 years), regular BCC (first lesion at age > or = 35 years and < 10 lesions), and multiple BCC (> or = 10 lesions). The PTCH gene was mutated in 29 of 60 cases (48%). Most of the PTCH mutations bore the UV fingerprint (i.e., C --> T or tandem CC --> TT transitions at dipyrimidine sites). However, neither the proportion nor the spectra of exonic PTCH mutations differed significantly among the three groups. A large number of SNPs (IVS10+99C/T, IVS11-51G/C, 1665T/C, 1686C/T, IVS15+9G/C, IVS16-80G/C, IVS17+21G/A, and 3944C/T or its combinations) were also detected, but again their incidence did not differ significantly among the groups. Interestingly, expression of the IVS16-80G/C and the IVS17+21G/A genotype did not achieve the Hardy-Weinberg equilibrium in patients with regular and/or early-onset BCC. These data suggest that a (UV-) mutated PTCH gene is important for sporadic BCC formation independent of clinical phenotype and that the IVS16-80G/C and/or IVS17+21G/A SNP site might be important for tumorigenesis in certain BCC patients.

  7. Suppression of pleiotropic phenotypes of a Burkholderia multivorans fur mutant by oxyR mutation.

    PubMed

    Kimura, Akane; Yuhara, Satoshi; Ohtsubo, Yoshiyuki; Nagata, Yuji; Tsuda, Masataka

    2012-05-01

    Fur (ferric uptake regulator) is an iron-responsive transcriptional regulator in many bacterial species, and the fur mutant of Burkholderia multivorans ATCC 17616 exhibits pleiotropic phenotypes, such as an inability to efficiently use several carbon sources, as well as high sensitivity to hydrogen peroxide (H(2)O(2)), paraquat (a superoxide-producing compound) and nitric oxide (NO). To gain more insight into the pleiotropic role of the Fur protein of ATCC 17616, spontaneous suppressor mutants of the ATCC 17616 fur mutant that restored tolerance to NO were isolated and characterized in this study. The microarray-based comparative genomic analysis and subsequent sequencing analysis indicated that such suppressor mutants had a 2 bp deletion in the oxyR gene, whose orthologues encode H(2)O(2)-responsive transcriptional regulators in other bacterial species. The suppressor mutants and the reconstructed fur-oxyR double-deletion mutant showed indistinguishable phenotypes in that they were all (i) more resistant than the fur mutant to H(2)O(2), superoxide, NO and streptonigrin (an iron-activated antibiotic) and (ii) able to use carbon sources that cannot efficiently support the growth of the fur mutant. These results clearly indicate that the oxyR mutation suppressed the pleiotropic effect of the B. multivorans fur mutant. The fur-oxyR double mutants were found to overexpress the KatG (catalase/peroxidase) and AhpC1 and AhpD (alkyl hydroperoxide reductase subunits C and D) proteins, and their enzymic activities to remove reactive oxygen and nitrogen species were suggested to be responsible for the suppression of phenotypes caused by the fur mutation.

  8. Two mutations within a feline mucopolysaccharidosis type VI colony cause three different clinical phenotypes.

    PubMed Central

    Crawley, A C; Yogalingam, G; Muller, V J; Hopwood, J J

    1998-01-01

    Mucopolysaccharidosis type VI (MPS VI) is a lysosomal storage disease caused by a deficiency of N-acetylgalactosamine-4-sulfatase (4S). A feline MPS VI model used to demonstrate efficacy of enzyme replacement therapy is due to the homozygous presence of an L476P mutation in 4-sulfatase. An additional mutation, D520N, inherited independently from L476P and recently identified in the same family of cats, has resulted in three clinical phenotypes. L476P homozygotes exhibit dwarfism and facial dysmorphia due to epiphyseal dysplasia, abnormally low leukocyte 4S/betahexosaminidase ratios, dermatan sulfaturia, lysosomal inclusions in most tissues including chondrocytes, corneal clouding, degenerative joint disease, and abnormal leukocyte inclusions. Similarly, D520N/D520N and L476P/D520N cats have abnormally low leukocyte 4S/betahexosaminidase ratios, mild dermatan sulfaturia, lysosomal inclusions in some chondrocytes, and abnormal leukocyte inclusions. However, both have normal growth and appearance. In addition, L476P/D520N cats have a high incidence of degenerative joint disease. We conclude that L476P/D520N cats have a very mild MPS VI phenotype not previously described in MPS VI humans. The study of L476P/D520N and D520N/ D520N genotypes will improve understanding of genotype to phenotype correlations and the pathogenesis of skeletal dysplasia and joint disease in MPS VI, and will assist in development of therapies to prevent lysosomal storage in chondrocytes. PMID:9421472

  9. Specific point mutations in Lactobacillus casei ATCC 27139 cause a phenotype switch from Lac- to Lac+.

    PubMed

    Tsai, Yu-Kuo; Chen, Hung-Wen; Lo, Ta-Chun; Lin, Thy-Hou

    2009-03-01

    Lactose metabolism is a changeable phenotype in strains of Lactobacillus casei. In this study, we found that L. casei ATCC 27139 was unable to utilize lactose. However, when exposed to lactose as the sole carbon source, spontaneous Lac(+) clones could be obtained. A gene cluster (lacTEGF-galKETRM) involved in the metabolism of lactose and galactose in L. casei ATCC 27139 (Lac(-)) and its Lac(+) revertant (designated strain R1) was sequenced and characterized. We found that only one nucleotide, located in the lacTEGF promoter (lacTp), of the two lac-gal gene clusters was different. The protein sequence identity between the lac-gal gene cluster and those reported previously for some L. casei (Lac(+)) strains was high; namely, 96-100 % identity was found and no premature stop codon was identified. A single point mutation located within the lacTp promoter region was also detected for each of the 41 other independently isolated Lac(+) revertants of L. casei ATCC 27139. The revertants could be divided into six classes based on the positions of the point mutations detected. Primer extension experiments conducted on transcription from lacTp revealed that the lacTp promoter of these six classes of Lac(+) revertants was functional, while that of L. casei ATCC 27139 was not. Northern blotting experiments further confirmed that the lacTEGF operon of strain R1 was induced by lactose but suppressed by glucose, whereas no blotting signal was ever detected for L. casei ATCC 27139. These results suggest that a single point mutation in the lacTp promoter was able to restore the transcription of a fully functional lacTEGF operon and cause a phenotype switch from Lac(-) to Lac(+) for L. casei ATCC 27139.

  10. X-linked MCT8 gene mutations: characterization of the pediatric neurologic phenotype.

    PubMed

    Holden, Kenton R; Zuñiga, Oscar F; May, Melanie M; Su, Humberto; Molinero, Marco R; Rogers, R Curtis; Schwartz, Charles E

    2005-10-01

    We report a family with X-linked mental retardation that has a novel mutation in the monocarboxylate transporter 8 (MCT8) gene associated with a characteristic neurodevelopmental phenotype with early childhood hypotonia that progresses to spasticity and global developmental delays. Affected patients experience moderate to severe psychomotor delays and congenital hypotonia, develop a myopathic facies, have diminished muscle bulk and generalized muscle weakness, develop progressive spasticity and movement disorders, and have limited speech but alert, affable personalities. Acquired microcephaly and abnormal myelination on brain magnetic resonance imaging can be present. Normal monocarboxylate transporter 8 gene functioning appears to be necessary for normal thyroid-associated metabolism in neurons. Abnormal thyroid function tests appear to be a consistent finding in the absence of typical signs of thyroid dysfunction. Although the phenotype appears to be consistent, and although the neurotoxic effects of abnormal central and peripheral neuromuscular system thyroid metabolism might be partly or wholly responsible for the neurologic phenotype reported, the exact mechanism remains unclear.

  11. CYP24A1 loss of function: Clinical phenotype of monoallelic and biallelic mutations.

    PubMed

    Carpenter, Thomas O

    2017-01-16

    CYP24A1, encoding the vitamin D-24-hydroxylase, is of major clinical and physiologic importance, serving to regulate the catabolism of 1,25-(OH)2D, the physiologically active vitamin D metabolite. In addition to facilitating catabolism of 1,25-(OH)2D, CYP24A1 also enhances the turnover and elimination of 25-OHD, the abundant precursor metabolite and storage form of the vitamin. CYP24A1 can be stimulated hormonally by 1,25-(OH)2D and by FGF23, whereas CYP27B1, encoding the vitamin D-1α-hydroxylase, is stimulated hormonally by parathyroid hormone (PTH) and downregulated by FGF23. Thus CYP24A1 and CYP27B1, together, provide for alternate and regulated fates of 25-OHD, and control the availability of the active metabolite, 1,25-(OH)2D, depending upon physiologic needs. These two enzymes, are therefore central to the homeostatic control of vitamin D metabolism, and as a result affect calcium metabolism in critical ways. Disruption of CYP24A1 in mice results in elevated circulating 1,25-(OH)2D, substantiating the importance of the enzyme in the maintenance of vitamin D metabolism. The consequential skeletal phenotype in these mice further demonstrates the biologic sequelae of the disruption of the vitamin D pathway, and illustrates a specific developmental pathology mediated largely by oversupply of 1,25-(OH)2D. More recent evidence has identified loss of function mutations in CYP24A1 in association with hypercalcemia, hypercalciuria and nephrolithiasis in humans. Initial reports described certain variant mutations in CYP24A1 as an unrecognized cause of "Idiopathic Infantile Hypercalcemia," and more recently older children and adults have been identified with a similar phenotype. Over 25 likely disease-causing variants are described. Homozygous and compound heterozygote mutations account for the overwhelming majority of cases, however the heterozygous loss-of-function mutations of CYP24A1 do not appear to consistently result in symptomatic hypercalcemia. Considerations

  12. Parkinson disease phenotype in Ashkenazi Jews with and without LRRK2 G2019S mutations.

    PubMed

    Alcalay, Roy N; Mirelman, Anat; Saunders-Pullman, Rachel; Tang, Ming-X; Mejia Santana, Helen; Raymond, Deborah; Roos, Ernest; Orbe-Reilly, Martha; Gurevich, Tanya; Bar Shira, Anat; Gana Weisz, Mali; Yasinovsky, Kira; Zalis, Maayan; Thaler, Avner; Deik, Andres; Barrett, Matthew James; Cabassa, Jose; Groves, Mark; Hunt, Ann L; Lubarr, Naomi; San Luciano, Marta; Miravite, Joan; Palmese, Christina; Sachdev, Rivka; Sarva, Harini; Severt, Lawrence; Shanker, Vicki; Swan, Matthew Carrington; Soto-Valencia, Jeannie; Johannes, Brooke; Ortega, Robert; Fahn, Stanley; Cote, Lucien; Waters, Cheryl; Mazzoni, Pietro; Ford, Blair; Louis, Elan; Levy, Oren; Rosado, Llency; Ruiz, Diana; Dorovski, Tsvyatko; Pauciulo, Michael; Nichols, William; Orr-Urtreger, Avi; Ozelius, Laurie; Clark, Lorraine; Giladi, Nir; Bressman, Susan; Marder, Karen S

    2013-12-01

    The phenotype of Parkinson's disease (PD) in patients with and without leucine-rich repeat kinase 2 (LRRK2) G2019S mutations reportedly is similar; however, large, uniformly evaluated series are lacking. The objective of this study was to characterize the clinical phenotype of Ashkenazi Jewish (AJ) PD carriers of the LRRK2 G2019S mutation. We studied 553 AJ PD patients, including 65 patients who were previously reported, from three sites (two in New York and one in Tel-Aviv). Glucocerebrosidase (GBA) mutation carriers were excluded. Evaluations included the Montreal Cognitive Assessment (MoCA), the Unified Parkinson's Disease Rating Scale (UPDRS), the Geriatric Depression Scale (GDS) and the Non-Motor Symptoms (NMS) questionnaire. Regression models were constructed to test the association between clinical and demographic features and LRRK2 status (outcome) in 488 newly recruited participants. LRRK2 G2019S carriers (n = 97) and non-carriers (n = 391) were similar in age and age at onset of PD. Carriers had longer disease duration (8.6 years vs. 6.1 years; P < 0.001), were more likely to be women (51.5% vs. 37.9%; P = 0.015), and more often reported first symptoms in the lower extremities (40.0% vs. 19.2%; P < 0.001). In logistic models that were adjusted for age, disease duration, sex, education, and site, carriers were more likely to have lower extremity onset (P < 0.001), postural instability and gait difficulty (PIGD) (P = 0.043), and a persistent levodopa response for >5 years (P = 0.042). Performance on the UPDRS, MoCA, GDS, and NMS did not differ by mutation status. PD in AJ LRRK2 G2019S mutation carriers is similar to idiopathic PD but is characterized by more frequent lower extremity involvement at onset and PIGD without the associated cognitive impairment.

  13. Natural and laboratory mutations in kuzbanian are associated with zinc stress phenotypes in Drosophila melanogaster

    PubMed Central

    Le Manh, Hung; Guio, Lain; Merenciano, Miriam; Rovira, Quirze; Barrón, Maite G.; González, Josefa

    2017-01-01

    Organisms must cope with altered environmental conditions such as high concentrations of heavy metals. Stress response to heavy metals is mediated by the metal-responsive transcription factor 1 (MTF-1), which is conserved from Drosophila to humans. MTF-1 binds to metal response elements (MREs) and changes the expression of target genes. kuzbanian (kuz), a metalloendopeptidase that activates the evolutionary conserved Notch signaling pathway, has been identified as an MTF-1 target gene. We have previously identified a putatively adaptive transposable element in the Drosophila melanogaster genome, named FBti0019170, inserted in a kuz intron. In this work, we investigated whether a laboratory mutant stock overexpressing kuz is associated with zinc stress phenotypes. We found that both embryos and adult flies overexpressing kuz are more tolerant to zinc compared with wild-type flies. On the other hand, we found that the effect of FBti0019170 on zinc stress tolerance depends on developmental stage and genetic background. Moreover, in the majority of the genetic backgrounds analyzed, FBti0019170 has a deleterious effect in unpolluted environments in pre-adult stages. These results highlight the complexity of natural mutations and suggest that besides laboratory mutations, natural mutations should be studied in order to accurately characterize gene function and evolution. PMID:28218276

  14. Reversible severe combined immunodeficiency phenotype secondary to a mutation of the proton-coupled folate transporter

    PubMed Central

    Borzutzky, Arturo; Crompton, Brian; Bergmann, Anke K.; Giliani, Silvia; Baxi, Sachin; Martin, Madelena; Neufeld, Ellis J.; Notarangelo, Luigi D.

    2009-01-01

    Hereditary folate malabsorption is a rare inborn error of metabolism due to mutations in the proton-coupled folate transporter (PCFT). Clinical presentation of PCFT deficiency may mimic severe combined immune deficiency (SCID). We report a 4-month-old female who presented with failure to thrive, normocytic anemia, Pneumocystis jirovecii pneumonia and systemic cytomegalovirus infection. Immunological evaluation revealed hypogammaglobulinemia, absent antibody responses, and lack of mitogen-induced lymphocyte proliferative responses. However, the absolute number and distribution of lymphocyte subsets, including naïve T cells and recent thymic emigrants, were normal, arguing against primary SCID. Serum and cerebrospinal fluid folate levels were undetectable. A homozygous 1082-1G>A mutation of the PCFT gene was found, resulting in skipping of exon 3. Parenteral folinic acid repletion resulted in normalization of anemia, humoral and cellular immunity, and full clinical recovery. PCFT mutations should be considered in infants with SCID-like phenotype, as the immunodeficiency is reversible with parenteral folinic acid repletion. PMID:19740703

  15. Gene therapy for retinitis pigmentosa caused by MFRP mutations: human phenotype and preliminary proof of concept.

    PubMed

    Dinculescu, Astra; Estreicher, Jackie; Zenteno, Juan C; Aleman, Tomas S; Schwartz, Sharon B; Huang, Wei Chieh; Roman, Alejandro J; Sumaroka, Alexander; Li, Qiuhong; Deng, Wen-Tao; Min, Seok-Hong; Chiodo, Vince A; Neeley, Andy; Liu, Xuan; Shu, Xinhua; Matias-Florentino, Margarita; Buentello-Volante, Beatriz; Boye, Sanford L; Cideciyan, Artur V; Hauswirth, William W; Jacobson, Samuel G

    2012-04-01

    Autosomal recessive retinitis pigmentosa (RP), a heterogeneous group of degenerations of the retina, can be due to mutations in the MFRP (membrane-type frizzled-related protein) gene. A patient with RP with MFRP mutations, one of which is novel and the first splice site mutation reported, was characterized by noninvasive retinal and visual studies. The phenotype, albeit complex, suggested that this retinal degeneration may be a candidate for gene-based therapy. Proof-of-concept studies were performed in the rd6 Mfrp mutant mouse model. The fast-acting tyrosine-capsid mutant AAV8 (Y733F) vector containing the small chicken β-actin promoter driving the wild-type mouse Mfrp gene was used. Subretinal vector delivery on postnatal day 14 prevented retinal degeneration. Treatment rescued rod and cone photoreceptors, as assessed by electroretinography and retinal histology at 2 months of age. This AAV-mediated gene delivery also resulted in robust MFRP expression predominantly in its normal location within the retinal pigment epithelium apical membrane and its microvilli. The clinical features of MFRP-RP and our preliminary data indicating a response to gene therapy in the rd6 mouse suggest that this form of RP is a potential target for gene-based therapy.

  16. Impact of a mutator phenotype on motility and cell adherence in Salmonella Heidelberg.

    PubMed

    Le Bars, Hervé; Le Gall-David, Sandrine; Renoux, Virginie Madeleine; Bonnaure-Mallet, Martine; Jolivet-Gougeon, Anne; Bousarghin, Latifa

    2012-09-14

    In this study, we investigated adherence and motility of the hypermutator Salmonella enterica Heidelberg B182 bovine strain related to a 12bp deletion in mutS. This mutator phenotype was associated with increased adherence to epithelial cells and with high expression of fimA as shown by real-time RT-PCR. Motility studies showed that fliC were up-regulated in the B182 strain, while fljA and fljB were down-regulated. In order to determine if mutated mutS is implicated in this genes expression, isogenic strains, derived from a WT strain, containing the 12bp deletion in mutS (Δ12bpmutS) or an inactivated mutS (ΔmutS) were generated. Δ12bpmutS and ΔmutS strains showed a spontaneous mutation rate similar to the environmental strain B182, but exhibited lower adherence capacity and fimA expression. In contrast to the fimbriae genes, in Δ12bpmutS, fliC expression was up-regulated, but fljA and fljB expression were decreased, as in the B182 strain. Only fljB expression was increased in ΔmutS mutants. Taken together, our data suggest that mutS alteration does not influence fimbriae expression but can impact flagella genes.

  17. Gene Therapy for Retinitis Pigmentosa Caused by MFRP Mutations: Human Phenotype and Preliminary Proof of Concept

    PubMed Central

    Dinculescu, Astra; Estreicher, Jackie; Zenteno, Juan C.; Aleman, Tomas S.; Schwartz, Sharon B.; Huang, Wei Chieh; Roman, Alejandro J.; Sumaroka, Alexander; Li, Qiuhong; Deng, Wen-Tao; Min, Seok-Hong; Chiodo, Vince A.; Neeley, Andy; Liu, Xuan; Shu, Xinhua; Matias-Florentino, Margarita; Buentello-Volante, Beatriz; Boye, Sanford L.; Cideciyan, Artur V.

    2011-01-01

    Abstract Autosomal recessive retinitis pigmentosa (RP), a heterogeneous group of degenerations of the retina, can be due to mutations in the MFRP (membrane-type frizzled-related protein) gene. A patient with RP with MFRP mutations, one of which is novel and the first splice site mutation reported, was characterized by noninvasive retinal and visual studies. The phenotype, albeit complex, suggested that this retinal degeneration may be a candidate for gene-based therapy. Proof-of-concept studies were performed in the rd6 Mfrp mutant mouse model. The fast-acting tyrosine-capsid mutant AAV8 (Y733F) vector containing the small chicken β-actin promoter driving the wild-type mouse Mfrp gene was used. Subretinal vector delivery on postnatal day 14 prevented retinal degeneration. Treatment rescued rod and cone photoreceptors, as assessed by electroretinography and retinal histology at 2 months of age. This AAV-mediated gene delivery also resulted in robust MFRP expression predominantly in its normal location within the retinal pigment epithelium apical membrane and its microvilli. The clinical features of MFRP-RP and our preliminary data indicating a response to gene therapy in the rd6 mouse suggest that this form of RP is a potential target for gene-based therapy. PMID:22142163

  18. Clinical Auditory Phenotypes Associated with GATA3 Gene Mutations in Familial Hypoparathyroidism-deafness-renal Dysplasia Syndrome

    PubMed Central

    Wang, Li; Lin, Qiong-Fen; Wang, Hong-Yang; Guan, Jing; Lan, Lan; Xie, Lin-Yi; Yu, Lan; Yang, Ju; Zhao, Cui; Liang, Jin-Long; Zhou, Han-Lin; Yang, Huan-Ming; Xiong, Wen-Ping; Zhang, Qiu-Jing; Wang, Da-Yong; Wang, Qiu-Ju

    2017-01-01

    Background: Hypoparathyroidism-deafness-renal dysplasia (HDR) syndrome is an autosomal dominant disorder primarily caused by haploinsufficiency of GATA binding protein 3 (GATA3) gene mutations, and hearing loss is the most frequent phenotypic feature. This study aimed at identifying the causative gene mutation for a three-generation Chinese family with HDR syndrome and analyzing auditory phenotypes in all familial HDR syndrome cases. Methods: Three affected family members underwent otologic examinations, biochemistry tests, and other clinical evaluations. Targeted genes capture combining next-generation sequencing was performed within the family. Sanger sequencing was used to confirm the causative mutation. The auditory phenotypes of all reported familial HDR syndrome cases analyzed were provided. Results: In Chinese family 7121, a heterozygous nonsense mutation c.826C>T (p.R276*) was identified in GATA3. All the three affected members suffered from sensorineural deafness and hypocalcemia; however, renal dysplasia only appeared in the youngest patient. Furthermore, an overview of thirty HDR syndrome families with corresponding GATA3 mutations revealed that hearing impairment occurred earlier in the younger generation in at least nine familial cases (30%) and two thirds of them were found to carry premature stop mutations. Conclusions: This study highlights the phenotypic heterogeneity of HDR and points to a possible genetic anticipation in patients with HDR, which needs to be further investigated. PMID:28303854

  19. Null mutations at the p66 and bradykinin 2 receptor loci induce divergent phenotypes in the diabetic kidney

    PubMed Central

    Vashistha, Himanshu; Singhal, Pravin C.; Malhotra, Ashwani; Husain, Mohammad; Mathieson, Peter; Saleem, Moin A.; Kuriakose, Cyril; Seshan, Surya; Wilk, Anna; DelValle, Luis; Peruzzi, Francesca; Giorgio, Marco; Pelicci, Pier Giuseppe; Smithies, Oliver; Kim, Hyung-Suk; Kakoki, Masao; Reiss, Krzysztof

    2012-01-01

    Candidate genes have been identified that confer increased risk for diabetic glomerulosclerosis (DG). Mice heterozygous for the Akita (Ins2+/C96Y) diabetogenic mutation with a second mutation introduced at the bradykinin 2 receptor (B2R−/−) locus express a disease phenotype that approximates human DG. Src homology 2 domain transforming protein 1 (p66) controls mitochondrial metabolism and cellular responses to oxidative stress, aging, and apoptosis. We generated p66-null Akita mice to test whether inactivating mutations at the p66 locus will rescue kidneys of Akita mice from disease-causing mutations at the Ins2 and B2R loci. Here we show null mutations at the p66 and B2R loci interact with the Akita (Ins2+/C96Y) mutation, independently and in combination, inducing divergent phenotypes in the kidney. The B2R−/− mutation induces detrimental phenotypes, as judged by increased systemic and renal levels of oxidative stress, histology, and urine albumin excretion, whereas the p66-null mutation confers a powerful protection phenotype. To elucidate the mechanism(s) of the protection phenotype, we turned to our in vitro system. Experiments with cultured podocytes revealed previously unrecognized cross talk between p66 and the redox-sensitive transcription factor p53 that controls hyperglycemia-induced ROS metabolism, transcription of p53 target genes (angiotensinogen, angiotensin II type-1 receptor, and bax), angiotensin II generation, and apoptosis. RNA-interference targeting p66 inhibits all of the above. Finally, protein levels of p53 target genes were upregulated in kidneys of Akita mice but unchanged in p66-null Akita mice. Taken together, p66 is a potential molecular target for therapeutic intervention in DG. PMID:23019230

  20. The Tyr-265-to-Cys mutator mutant of DNA polymerase β induces a mutator phenotype in mouse LN12 cells

    PubMed Central

    Clairmont, Caroline A.; Narayanan, Latha; Sun, Ka-Wai; Glazer, Peter M.; Sweasy, Joann B.

    1999-01-01

    DNA polymerase β functions in both base excision repair and meiosis. Errors committed by polymerase β during these processes could result in mutations. Using a complementation system, in which rat DNA polymerase β substitutes for DNA polymerase I of Escherichia coli, we previously isolated a DNA polymerase β mutant in which Tyr-265 was altered to Cys (Y265C). The Y265C mutant is dominant to wild-type DNA polymerase β and possesses an intrinsic mutator activity. We now have expressed the wild-type DNA polymerase and the Y265C mutator mutant in mouse LN12 cells, which have endogenous DNA polymerase β activity. We demonstrate that expression of the Y265C mutator mutant in the LN12 cells results in an 8-fold increase in the spontaneous mutation frequency of λcII mutants compared with expression of the wild-type protein. Expression of Y265C results in at least a 40-fold increase in the frequency of deletions of three bases or more and a 7-fold increase in point mutations. Our results suggest that the mutations we observe in vivo result directly from the action of the mutator polymerase. To our knowledge, this is the first demonstration of a mutator phenotype resulting from expression of a DNA polymerase mutator mutant in mammalian cells. This work raises the possibility that variant polymerases may act in a dominant fashion in human cells, leading to genetic instability and carcinogenesis. PMID:10449735

  1. Mutation Spectrum in the Large GTPase Dynamin 2, and Genotype–Phenotype Correlation in Autosomal Dominant Centronuclear Myopathy

    PubMed Central

    Böhm, Johann; Biancalana, Valérie; DeChene, Elizabeth T.; Bitoun, Marc; Pierson, Christopher R.; Schaefer, Elise; Karasoy, Hatice; Dempsey, Melissa A.; Klein, Fabrice; Dondaine, Nicolas; Kretz, Christine; Haumesser, Nicolas; Poirson, Claire; Toussaint, Anne; Greenleaf, Rebecca S.; Barger, Melissa A.; Mahoney, Lane J.; Kang, Peter B.; Zanoteli, Edmar; Vissing, John; Witting, Nanna; Echaniz-Laguna, Andoni; Wallgren-Pettersson, Carina; Dowling, James; Merlini, Luciano; Oldfors, Anders; Ousager, Lilian Bomme; Melki, Judith; Krause, Amanda; Jern, Christina; Oliveira, Acary S. B.; Petit, Florence; Jacquette, Aurélia; Chaussenot, Annabelle; Mowat, David; Leheup, Bruno; Cristofano, Michele; Aldea, Juan José Poza; Michel, Fabrice; Furby, Alain; Llona, Jose E. Barcena; Van Coster, Rudy; Bertini, Enrico; Urtizberea, Jon Andoni; Drouin-Garraud, Valérie; Béroud, Christophe; Prudhon, Bernard; Bedford, Melanie; Mathews, Katherine; Erby, Lori A. H.; Smith, Stephen A.; Roggenbuck, Jennifer; Crowe, Carol A.; Spitale, Allison Brennan; Johal, Sheila C.; Amato, Anthony A.; Demmer, Laurie A.; Jonas, Jessica; Darras, Basil T.; Bird, Thomas D.; Laurino, Mercy; Welt, Selman I.; Trotter, Cynthia; Guicheney, Pascale; Das, Soma; Mandel, Jean-Louis; Beggs, Alan H.; Laporte, Jocelyn

    2012-01-01

    Centronuclear myopathy (CNM) is a genetically heterogeneous disorder associated with general skeletal muscle weakness, type I fiber predominance and atrophy, and abnormally centralized nuclei. Autosomal dominant CNM is due to mutations in the large GTPase dynamin 2 (DNM2), a mechanochemical enzyme regulating cytoskeleton and membrane trafficking in cells. To date, 40 families with CNM-related DNM2 mutations have been described, and here we report 60 additional families encompassing a broad genotypic and phenotypic spectrum. In total, 18 different mutations are reported in 100 families and our cohort harbors nine known and four new mutations, including the first splice-site mutation. Genotype–phenotype correlation hypotheses are drawn from the published and new data, and allow an efficient screening strategy for molecular diagnosis. In addition to CNM, dissimilar DNM2 mutations are associated with Charcot–Marie–Tooth (CMT) peripheral neuropathy (CMTD1B and CMT2M), suggesting a tissue-specific impact of the mutations. In this study, we discuss the possible clinical overlap of CNM and CMT, and the biological significance of the respective mutations based on the known functions of dynamin 2 and its protein structure. Defects in membrane trafficking due to DNM2 mutations potentially represent a common pathological mechanism in CNM and CMT. PMID:22396310

  2. A novel mutation in NDUFB11 unveils a new clinical phenotype associated with lactic acidosis and sideroblastic anemia.

    PubMed

    Torraco, A; Bianchi, M; Verrigni, D; Gelmetti, V; Riley, L; Niceta, M; Martinelli, D; Montanari, A; Guo, Y; Rizza, T; Diodato, D; Di Nottia, M; Lucarelli, B; Sorrentino, F; Piemonte, F; Francisci, S; Tartaglia, M; Valente, E M; Dionisi-Vici, C; Christodoulou, J; Bertini, E; Carrozzo, R

    2017-03-01

    NDUFB11, a component of mitochondrial complex I, is a relatively small integral membrane protein, belonging to the "supernumerary" group of subunits, but proved to be absolutely essential for the assembly of an active complex I. Mutations in the X-linked nuclear-encoded NDUFB11 gene have recently been discovered in association with two distinct phenotypes, i.e. microphthalmia with linear skin defects and histiocytoid cardiomyopathy. We report on a male with complex I deficiency, caused by a de novo mutation in NDUFB11 and displaying early-onset sideroblastic anemia as the unique feature. This is the third report that describes a mutation in NDUFB11, but all are associated with a different phenotype. Our results further expand the molecular spectrum and associated clinical phenotype of NDUFB11 defects.

  3. Genotype-phenotype relationship in patients with mutations in thyroid hormone transporter MCT8.

    PubMed

    Jansen, Jurgen; Friesema, Edith C H; Kester, Monique H A; Schwartz, Charles E; Visser, Theo J

    2008-05-01

    Loss-of-function mutations in thyroid hormone transporter monocarboxylate transporter 8 (MCT8) lead to severe X-linked psychomotor retardation and elevated serum T(3) levels. Most patients, for example those with mutations V235M, S448X, insI189, or delF230, cannot stand, walk, or speak. Patients with mutations L434W, L568P, and S194F, however, walk independently and/or develop some dysarthric speech. To study the relationship between mutation and phenotype, we transfected JEG3 and COS1 cells with wild-type or mutant MCT8. Expression and function of the transporter were studied by analyzing T(3) and T(4) uptake, T(3) metabolism (by cotransfected type 3 deiodinase), Western blotting, affinity labeling with N-bromoacetyl-T(3), immunocytochemistry, and quantitative RT-PCR. Wild-type MCT8 increased T(3) uptake and metabolism about 5-fold compared with empty vector controls. Mutants V235M, S448X, insI189, and delF230 did not significantly increase transport. However, S194F, L568P, and L434W showed about 20, 23, and 37% of wild-type activity. RT-PCR did not show significant differences in mRNA expression between wild-type and mutant MCT8. Immunocytochemistry detected the nonfunctional mutants V235M, insI189, and delF230 mostly in the cytoplasm, whereas mutants with residual function were expressed at the plasma membrane. Mutants S194F and L434W showed high protein expression but low affinity for N-bromoacetyl-T(3); L568P was detected in low amounts but showed relatively high affinity. Mutations in MCT8 cause loss of function through reduced protein expression, impaired trafficking to the plasma membrane, or reduced substrate affinity. Mutants L434W, L568P, and S194F showed significant residual transport capacity, which may underlie the more advanced psychomotor development observed in patients with these mutations.

  4. Variable phenotypes in a family with mitochondrial encephalomyopathy harboring a 3291T > C mutation in mitochondrial DNA.

    PubMed

    Sunami, Yoko; Sugaya, Keizo; Chihara, Norio; Goto, Yu-ichi; Matsubara, Shiro

    2011-10-01

    We present a Japanese family suffering from mitochondrial encephalomyopathy associated with a T-to-C transition at mitochondrial DNA (mtDNA) nucleotide position 3291. Clinical manifestations of the patients include cerebellar ataxia with myopathy, recurrent headache, and myoclonus and epilepsy. The phenotypic variation among the affected members of a single family and the mutational analysis showing maternal inheritance in a heteroplasmic fashion are consistent with well-recognized phenomena associated with many pathogenic point mutations of mtDNA tRNA genes. The 3291 mutation is a rare mtDNA mutation whose clinical presentation had only been reported in three sporadic cases. This is the first report of a family segregating the 3291 mutation with multigenerational matrilinear recurrence of mitochondrial encephalopathy. Our findings provide conclusive evidence for the pathogenicity of the 3291T > C mutation in mtDNA and its characteristic clinical heterogeneity.

  5. Gastrointestinal stromal tumors with KIT exon 9 mutations: Update on genotype-phenotype correlation and validation of a high-resolution melting assay for mutational testing.

    PubMed

    Künstlinger, Helen; Huss, Sebastian; Merkelbach-Bruse, Sabine; Binot, Elke; Kleine, Michaela Angelika; Loeser, Heike; Mittler, Jens; Hartmann, Wolfgang; Hohenberger, Peter; Reichardt, Peter; Büttner, Reinhard; Wardelmann, Eva; Schildhaus, Hans-Ulrich

    2013-11-01

    KIT exon 9 mutations in gastrointestinal stromal tumors (GISTs) are highly relevant and have direct therapeutic implications. In this context, we established and validated a fast and sensitive high-resolution melting assay. Analyzing 126 primary and 18 metastatic KIT exon 9-mutated cases from our registry, we demonstrate that the mutational spectrum of exon 9 is broader than previously thought and describe 3 novel mutations. Including these cases and the common p.A502_Y503dup mutation, we provide a comprehensive list of all known KIT exon 9 mutations according to the Human Genome Variation Society nomenclature. Two of the newly described mutations were associated with an aggressive phenotype and tumor progression while being treated with 400 mg imatinib, indicating that also GIST with rare exon 9 mutations could be treated with increased imatinib dosage. On the basis of >1500 GISTs from our registry, we have determined the frequency of KIT exon 9 mutations to be 9.2% among all GISTs and 22.5% among small-bowel cases. We describe for the first time that nearly 20% of exon 9-mutated GIST occur in the stomach or rectum. Furthermore, we provide first evidence that exon 9-mutated GISTs metastasize significantly more often to the peritoneum than to the liver. Performing extensive statistical analyses on data from our registry and from the literature, we demonstrate that KIT exon 9 mutations are neither associated with intermediate-risk/high-risk status nor overrepresented among metastatic lesions. Thus, we conclude that exon 9 mutations per se do not have prognostic relevance.

  6. Genetic and phenotypic dissection of 1q43q44 microdeletion syndrome and neurodevelopmental phenotypes associated with mutations in ZBTB18 and HNRNPU.

    PubMed

    Depienne, Christel; Nava, Caroline; Keren, Boris; Heide, Solveig; Rastetter, Agnès; Passemard, Sandrine; Chantot-Bastaraud, Sandra; Moutard, Marie-Laure; Agrawal, Pankaj B; VanNoy, Grace; Stoler, Joan M; Amor, David J; Billette de Villemeur, Thierry; Doummar, Diane; Alby, Caroline; Cormier-Daire, Valérie; Garel, Catherine; Marzin, Pauline; Scheidecker, Sophie; de Saint-Martin, Anne; Hirsch, Edouard; Korff, Christian; Bottani, Armand; Faivre, Laurence; Verloes, Alain; Orzechowski, Christine; Burglen, Lydie; Leheup, Bruno; Roume, Joelle; Andrieux, Joris; Sheth, Frenny; Datar, Chaitanya; Parker, Michael J; Pasquier, Laurent; Odent, Sylvie; Naudion, Sophie; Delrue, Marie-Ange; Le Caignec, Cédric; Vincent, Marie; Isidor, Bertrand; Renaldo, Florence; Stewart, Fiona; Toutain, Annick; Koehler, Udo; Häckl, Birgit; von Stülpnagel, Celina; Kluger, Gerhard; Møller, Rikke S; Pal, Deb; Jonson, Tord; Soller, Maria; Verbeek, Nienke E; van Haelst, Mieke M; de Kovel, Carolien; Koeleman, Bobby; Monroe, Glen; van Haaften, Gijs; Attié-Bitach, Tania; Boutaud, Lucile; Héron, Delphine; Mignot, Cyril

    2017-04-01

    Subtelomeric 1q43q44 microdeletions cause a syndrome associating intellectual disability, microcephaly, seizures and anomalies of the corpus callosum. Despite several previous studies assessing genotype-phenotype correlations, the contribution of genes located in this region to the specific features of this syndrome remains uncertain. Among those, three genes, AKT3, HNRNPU and ZBTB18 are highly expressed in the brain and point mutations in these genes have been recently identified in children with neurodevelopmental phenotypes. In this study, we report the clinical and molecular data from 17 patients with 1q43q44 microdeletions, four with ZBTB18 mutations and seven with HNRNPU mutations, and review additional data from 37 previously published patients with 1q43q44 microdeletions. We compare clinical data of patients with 1q43q44 microdeletions with those of patients with point mutations in HNRNPU and ZBTB18 to assess the contribution of each gene as well as the possibility of epistasis between genes. Our study demonstrates that AKT3 haploinsufficiency is the main driver for microcephaly, whereas HNRNPU alteration mostly drives epilepsy and determines the degree of intellectual disability. ZBTB18 deletions or mutations are associated with variable corpus callosum anomalies with an incomplete penetrance. ZBTB18 may also contribute to microcephaly and HNRNPU to thin corpus callosum, but with a lower penetrance. Co-deletion of contiguous genes has additive effects. Our results confirm and refine the complex genotype-phenotype correlations existing in the 1qter microdeletion syndrome and define more precisely the neurodevelopmental phenotypes associated with genetic alterations of AKT3, ZBTB18 and HNRNPU in humans.

  7. Deep intronic mis-splicing mutation in JAK3 gene underlies T-B+NK- severe combined immunodeficiency phenotype.

    PubMed

    Stepensky, Polina; Keller, Baerbel; Shamriz, Oded; NaserEddin, Adeeb; Rumman, Nisreen; Weintraub, Michael; Warnatz, Klaus; Elpeleg, Orly; Barak, Yaacov

    2016-02-01

    Severe combined immune deficiency (SCID) is a group of genetically heterogeneous diseases caused by an early block in T cell differentiation and present with life threatening infections, often within the first year of life. Janus kinase (JAK)3 gene mutations have been found to cause autosomal recessive T-B+ SCID phenotype. In this study we describe three patients with a novel deep intronic mis-splicing mutation in JAK3 as a cause of T-B+NK- SCID highlighting the need for careful evaluation of intronic regulatory elements of known genes associated with clearly defined clinical phenotypes. We present the cases and discuss the current literature.

  8. Heterozygous Germline Mutations in the CBL Tumor-Suppressor Gene Cause a Noonan Syndrome-like Phenotype

    PubMed Central

    Martinelli, Simone; De Luca, Alessandro; Stellacci, Emilia; Rossi, Cesare; Checquolo, Saula; Lepri, Francesca; Caputo, Viviana; Silvano, Marianna; Buscherini, Francesco; Consoli, Federica; Ferrara, Grazia; Digilio, Maria C.; Cavaliere, Maria L.; van Hagen, Johanna M.; Zampino, Giuseppe; van der Burgt, Ineke; Ferrero, Giovanni B.; Mazzanti, Laura; Screpanti, Isabella; Yntema, Helger G.; Nillesen, Willy M.; Savarirayan, Ravi; Zenker, Martin; Dallapiccola, Bruno; Gelb, Bruce D.; Tartaglia, Marco

    2010-01-01

    RAS signaling plays a key role in controlling appropriate cell responses to extracellular stimuli and participates in early and late developmental processes. Although enhanced flow through this pathway has been established as a major contributor to oncogenesis, recent discoveries have revealed that aberrant RAS activation causes a group of clinically related developmental disorders characterized by facial dysmorphism, a wide spectrum of cardiac disease, reduced growth, variable cognitive deficits, ectodermal and musculoskeletal anomalies, and increased risk for certain malignancies. Here, we report that heterozygous germline mutations in CBL, a tumor-suppressor gene that is mutated in myeloid malignancies and encodes a multivalent adaptor protein with E3 ubiquitin ligase activity, can underlie a phenotype with clinical features fitting or partially overlapping Noonan syndrome (NS), the most common condition of this disease family. Independent CBL mutations were identified in two sporadic cases and two families from among 365 unrelated subjects who had NS or suggestive features and were negative for mutations in previously identified disease genes. Phenotypic heterogeneity and variable expressivity were documented. Mutations were missense changes altering evolutionarily conserved residues located in the RING finger domain or the linker connecting this domain to the N-terminal tyrosine kinase binding domain, a known mutational hot spot in myeloid malignancies. Mutations were shown to affect CBL-mediated receptor ubiquitylation and dysregulate signal flow through RAS. These findings document that germline mutations in CBL alter development to cause a clinically variable condition that resembles NS and that possibly predisposes to malignancies. PMID:20619386

  9. Delineation of the Marfan phenotype associated with mutations in exons 23-32 of the FBN1 gene

    SciTech Connect

    Putnam, E.A.; Cho, M.; Milewicz, D.M.

    1996-03-29

    Marfan syndrome is a dominantly inherited connective tissue disorder with a wide range of phenotypic severity. The condition is the result of mutations in FBN1, a large gene composed of 65 exons encoding the fibrillin-1 protein. While mutations causing classic manifestations of Marfan syndrome have been identified throughout the FBN1 gene, the six previously characterized mutations resulting in the severe, perinatal lethal form of Marfan syndrome have clustered in exons 24-32 of the gene. We screened 8 patients with either neonatal Marfan syndrome or severe cardiovascular complications of Marfan syndrome for mutations in this region of the gene. Using intron-based exon-specific primers, we amplified exons 23-32 from genomic DNAs, screened these fragments by single-stranded conformational polymorphism analysis, and sequenced indicated exons. This analysis documented mutations in exons 25-27 of the FBN1 mutations in 6 of these patients. These results, taken together with previously published FBN1 mutations in this region, further define the phenotype associated with mutations in exons 24-32 of the FBN1 gene, information important for the development of possible diagnostic tests and genetic counseling. 49 refs., 4 figs., 2 tabs.

  10. Grey, a novel mutation in the murine Lyst gene, causes the beige phenotype by skipping of exon 25.

    PubMed

    Runkel, Fabian; Büssow, Heinrich; Seburn, Kevin L; Cox, Gregory A; Ward, Diane McVey; Kaplan, Jerry; Franz, Thomas

    2006-03-01

    The murine beige mutant phenotype and the human Chediak-Higashi syndrome are caused by mutations in the murine Lyst (lysosomal trafficking regulator) gene and the human CHS gene, respectively. In this report we have analyzed a novel murine mutant Lyst allele, called Lyst(bg-grey), that had been found in an ENU mutation screen and named grey because of the grey coat color of affected mice. The phenotype caused by the Lyst(bg-grey) mutation was inherited in a recessive fashion. Melanosomes of melanocytes associated with hair follicles and the choroid layer of the eye, as well as melanosomes in the neural tube-derived pigment epithelium of the retina, were larger and irregularly shaped in homozygous mutants compared with those of wild-type controls. Secretory vesicles in dermal mast cells of the mutant skin were enlarged as well. Test crosses with beige homozygous mutant mice (Lyst(bg)) showed that double heterozygotes (Lyst(bg)/Lyst(bg-grey)) were phenotypically indistinguishable from either homozygous parent, demonstrating that the ENU mutation was an allele of the murine Lyst gene. RT-PCR analyses revealed the skipping of exon 25 in Lyst(bg-grey) mutants, which is predicted to cause a missense D2399E mutation and the loss of the following 77 amino acids encoded by exon 25 but leave the C-terminal end of the protein intact. Analysis of the genomic Lyst locus around exon 25 showed that the splice donor at the end of exon 25 showed a T-to-C transition point mutation. Western blot analysis suggests that the Lyst(bg-grey) mutation causes instability of the LYST protein. Because the phenotype of Lyst(bg) and Lyst(bg-grey) mutants is indistinguishable, at least with respect to melanosomes and secretory granules in mast cells, the Lyst(bg-grey) mutation defines a critical region for the stability of the murine LYST protein.

  11. Hypo- and Hypermorphic FOXC1 Mutations in Dominant Glaucoma: Transactivation and Phenotypic Variability

    PubMed Central

    Medina-Trillo, Cristina; Sánchez-Sánchez, Francisco; Aroca-Aguilar, José-Daniel; Ferre-Fernández, Jesús-José; Morales, Laura; Méndez-Hernández, Carmen-Dora; Blanco-Kelly, Fiona; Ayuso, Carmen; García-Feijoo, Julián; Escribano, Julio

    2015-01-01

    Dominant glaucoma, a heterogeneous, infrequent and irreversible optic neuropathy, is often associated with elevated intraocular pressure and early-onset. The role of FOXC1 in this type of glaucoma was investigated in twelve Spanish probands via nucleotide variation screening of its proximal promoter and unique exon. Functional evaluations of the identified variants included analyses of the transcriptional activity, protein stability, DNA binding ability and subcellular localization. Four different mutations that were identified in four probands (33.3%) were associated with remarkable phenotypic variability and were functionally classified as either hypermorphic (p.Y47X, p.Q106X and p.G447_G448insDG) or hypomorphic (p.I126S) alleles. To the best of our knowledge, three of the variants are novel (p.Y47X, p.I126S and p.G447_G448insDG) and, in addition, hypermorphic FOXC1 mutations are reported herein for the first time. The presence of an intact N-terminal activation domain in the truncated proteins p.Y47X and p.Q106X may underlie their associated transactivation hyperactivity by a gain-of-function mechanism involving dysregulated protein-protein interactions. Similarly, altered molecular interactions may also lead to increased p.G447_G448insDG activity. In contrast, the partial loss-of-function associated with p.I126S was due to impaired protein stability, DNA binding, protein phosphorylation and subcellular distribution. These results support that moderate and variable FOXC1 transactivation changes are associated with moderate goniodysgenesis, dominant glaucoma and remarkable phenotypic variability. PMID:25786029

  12. Hypo- and hypermorphic FOXC1 mutations in dominant glaucoma: transactivation and phenotypic variability.

    PubMed

    Medina-Trillo, Cristina; Sánchez-Sánchez, Francisco; Aroca-Aguilar, José-Daniel; Ferre-Fernández, Jesús-José; Morales, Laura; Méndez-Hernández, Carmen-Dora; Blanco-Kelly, Fiona; Ayuso, Carmen; García-Feijoo, Julián; Escribano, Julio

    2015-01-01

    Dominant glaucoma, a heterogeneous, infrequent and irreversible optic neuropathy, is often associated with elevated intraocular pressure and early-onset. The role of FOXC1 in this type of glaucoma was investigated in twelve Spanish probands via nucleotide variation screening of its proximal promoter and unique exon. Functional evaluations of the identified variants included analyses of the transcriptional activity, protein stability, DNA binding ability and subcellular localization. Four different mutations that were identified in four probands (33.3%) were associated with remarkable phenotypic variability and were functionally classified as either hypermorphic (p.Y47X, p.Q106X and p.G447_G448insDG) or hypomorphic (p.I126S) alleles. To the best of our knowledge, three of the variants are novel (p.Y47X, p.I126S and p.G447_G448insDG) and, in addition, hypermorphic FOXC1 mutations are reported herein for the first time. The presence of an intact N-terminal activation domain in the truncated proteins p.Y47X and p.Q106X may underlie their associated transactivation hyperactivity by a gain-of-function mechanism involving dysregulated protein-protein interactions. Similarly, altered molecular interactions may also lead to increased p.G447_G448insDG activity. In contrast, the partial loss-of-function associated with p.I126S was due to impaired protein stability, DNA binding, protein phosphorylation and subcellular distribution. These results support that moderate and variable FOXC1 transactivation changes are associated with moderate goniodysgenesis, dominant glaucoma and remarkable phenotypic variability.

  13. Severe and mild phenotypes in Pfeiffer syndrome with splice acceptor mutations in exon IIIc of FGFR2.

    PubMed

    Teebi, Ahmad S; Kennedy, Shelley; Chun, Kathy; Ray, Peter N

    2002-01-01

    Pfeiffer syndrome is clinically and genetically heterogeneous. Three clinical subtypes have been delineated based on the severity of acrocephalysyndactyly and associated manifestations. Severe cases are usually sporadic and caused by a number of different mutations in exons IIIa and IIIc of the fibroblast growth factor receptor 2 (FGFR2) gene. Mild cases are either sporadic or familial and are caused by mutations in FGFR2 or FGFR1, respectively. We report on two individuals with different novel de novo mutations in FGFR2. The first is a 17-year-old male who has a severe phenotype, within the spectrum of subtype 1 including severe ocular proptosis, elbow ankylosis, visceral anomalies, and normal intelligence. This patient was found to have a novel complex mutation at the 3' acceptor site of exon IIIc of FGFR2, denoted as C952-3 del10insACC. The other patient, a 2-year-old female, has a mild phenotype, typical of the classic subtype 1 including brachycephaly with coronal synostosis and hypertelorism. She was also found to have a mutation at the 3' acceptor site (the same splice site) of exon IIIc of FGFR2, a point mutation designated as 952-1G-->A. Speculation on the molecular mechanisms that cause severe and mild phenotypes is presented in relation to these two cases.

  14. Hereditary Angioedema Due to C1 Inhibitor Deficiency in Serbia: Two Novel Mutations and Evidence of Genotype-Phenotype Association

    PubMed Central

    Andrejević, Slađana; Korošec, Peter; Šilar, Mira; Košnik, Mitja; Mijanović, Radovan; Bonači-Nikolić, Branka; Rijavec, Matija

    2015-01-01

    Hereditary angioedema due to C1 inhibitor deficiency (C1-INH-HAE) is a rare autosomal dominant disease characterized by recurrent life-threatening oedemas and/or abdominal pain and caused by mutations affecting the C1 inhibitor gene, SERPING1. We sought to investigate the spectrum of SERPING1 mutations in Serbia and the possible genotype-phenotype association. C1-INH-HAE was diagnosed on the basis of clinical and laboratory criteria in 40 patients from 27 families; four were asymptomatic. Mutational analysis of the SERPING1 gene was performed by sequencing and multiplex ligation-dependent probe amplification. Disease-causing mutations in SERPING1 were identified in all patients. In C1-INH-HAE type I, we identified 19 different mutations, including 6 missense mutations, 6 nonsense mutations, 2 small deletions, 1 small insertion, 2 splicing defects and 2 large deletions. Two of the mutations (c.300C>T and c.1184_1185insTA) are reported here for the first time. All C1-INH-HAE type II patients from three families harboured the same substitution (c.1396C>T). Based on the type of mutation identified in the SERPING1 gene, patients were divided into two groups: group 1 (nonsense, frameshift, large deletions/insertions, splicing defect, and mutations at Arg444) or group 2 (missense, excluding mutations at Arg444). Significant differences were found in the clinical severity score (P = 0.005), prevalence of laryngeal (P = 0.040) and facial (P = 0.013) oedema, and long-term prophylaxis (P = 0.023) between the groups with different types of mutations. Because our population consisted of related subjects, differences in the severity score between mutation groups were further confirmed using the generalized estimating equation (P = 0.038). Our study identified 20 different disease-causing mutations, including two novel mutations, in all C1-INH-HAE patients, highlighting the heterogeneity of mutations in the SERPING1 gene. Furthermore, it appears that mutations with a clear effect

  15. Mutator Phenotype and DNA Double-Strand Break Repair in BLM Helicase-Deficient Human Cells

    PubMed Central

    Suzuki, Tetsuya; Yasui, Manabu

    2016-01-01

    Bloom syndrome (BS), an autosomal recessive disorder of the BLM gene, predisposes sufferers to various cancers. To investigate the mutator phenotype and genetic consequences of DNA double-strand breaks (DSBs) in BS cells, we developed BLM helicase-deficient human cells by disrupting the BLM gene. Cells with a loss of heterozygosity (LOH) due to homologous recombination (HR) or nonhomologous end joining (NHEJ) can be restored with or without site-directed DSB induction. BLM cells exhibited a high frequency of spontaneous interallelic HR with crossover, but noncrossover events with long-tract gene conversions also occurred. Despite the highly interallelic HR events, BLM cells predominantly produced hemizygous LOH by spontaneous deletion. These phenotypes manifested during repair of DSBs. Both NHEJ and HR appropriately repaired DSBs in BLM cells, resulting in hemizygous and homozygous LOHs, respectively. However, the magnitude of the LOH was exacerbated in BLM cells, as evidenced by large deletions and long-tract gene conversions with crossover. BLM helicase suppresses the elongation of branch migration and crossover of double Holliday junctions (HJs) during HR repair, and a deficiency in this enzyme causes collapse, abnormal elongation, and/or preferable resolution to crossover of double HJs, resulting in a large-scale LOH. This mechanism underlies the predisposition for cancer in BS. PMID:27601585

  16. Identification of a novel ZNF469 mutation in a large family with Ehlers-Danlos phenotype.

    PubMed

    Al-Owain, Mohammed; Al-Dosari, Mohammed S; Sunker, Asma; Shuaib, Taghreed; Alkuraya, Fowzan S

    2012-12-15

    Brittle cornea syndrome (BCS) is a genetically heterogeneous disorder characterized by extreme corneal fragility and thinning, which may lead to spontaneous or trauma-induced corneal rupture. BCS-1 and BCS-2 are caused by recessive mutations in ZNF469 and PRDM5, respectively. Both genes play a role in the regulatory pathway of corneal development and maintenance. We report a consanguineous family with five patients affected with the cardinal ocular features of BCS and significant musculoskeletal findings primarily in the form of joint hypermobility and severe kyphoscoliosis. The patients had thin velvety skin, hallux valgus, variable sensorineural hearing loss and arachnodactyly. Interestingly, one of the patients additionally had phenylketonuria and showed a milder ophthalmological and musculoskeletal phenotype than his affected siblings. The urinary pyridinoline and deoxypyridinoline concentrations and their ratios were mildly elevated indicating increased bone-collagen turnover. A novel homozygous 14 bp duplication in exon 2 of ZNF469 (c.8817_8830dup) was uncovered by direct sequencing. This family highlights the phenotypic overlap between BCS and Ehlers-Danlos syndrome.

  17. Abetalipoproteinemia in an infant with severe clinical phenotype and a novel mutation.

    PubMed

    Uslu, Nuray; Gürakan, Figen; Yüce, Aysel; Demir, Hülya; Tarugi, Patrizia

    2010-01-01

    Abetalipoproteinemia (ABL) is a rare autosomal disorder characterized by extremely low levels of plasma lipids and apolipoprotein B (apoB) with a variable phenotype. Mutations in the MTP gene encoding the microsomal triglyceride transfer protein (MTP) cause the disease. A five-month-old boy, born from consanguineous parents, with chronic diarrhea and severe malnutrition had extremely low plasma lipids and apoB levels suggesting the diagnosis of ABL. He was not responsive to treatment with low-fat diet and fat-soluble vitamins and died at 13 months of age with severe malnutrition. Analysis of the MTP gene showed that he was homozygous for a two nucleotide deletion in exon 4 (c.398-399delAA) expected to cause a frameshift in the mRNA leading to a premature termination codon. The normolipidemic proband's parents were found to be heterozygous for the mutation. This observation underscores that in some cases, ABL can be extremely severe from early post-natal life and poorly responsive to treatment.

  18. 'North Sea' progressive myoclonus epilepsy: phenotype of subjects with GOSR2 mutation.

    PubMed

    Boissé Lomax, Lysa; Bayly, Marta A; Hjalgrim, Helle; Møller, Rikke S; Vlaar, Annemarie M; Aaberg, Kari M; Marquardt, Iris; Gandolfo, Luke C; Willemsen, Michèl; Kamsteeg, Erik-Jan; O'Sullivan, John D; Korenke, G Christoph; Bloem, Bastiaan R; de Coo, Irenaeus F; Verhagen, Judith M A; Said, Ines; Prescott, Trine; Stray-Pedersen, Asbjørg; Rasmussen, Magnhild; Vears, Danya F; Lehesjoki, Anna-Elina; Corbett, Mark A; Bahlo, Melanie; Gecz, Jozef; Dibbens, Leanne M; Berkovic, Samuel F

    2013-04-01

    We previously identified a homozygous mutation in the Golgi SNAP receptor complex 2 gene (GOSR2) in six patients with progressive myoclonus epilepsy. To define the syndrome better we analysed the clinical and electrophysiological phenotype in 12 patients with GOSR2 mutations, including six new unrelated subjects. Clinical presentation was remarkably similar with early onset ataxia (average 2 years of age), followed by myoclonic seizures at the average age of 6.5 years. Patients developed multiple seizure types, including generalized tonic clonic seizures, absence seizures and drop attacks. All patients developed scoliosis by adolescence, making this an important diagnostic clue. Additional skeletal deformities were present, including pes cavus in four patients and syndactyly in two patients. All patients had elevated serum creatine kinase levels (median 734 IU) in the context of normal muscle biopsies. Electroencephalography revealed pronounced generalized spike and wave discharges with a posterior predominance and photosensitivity in all patients, with focal EEG features seen in seven patients. The disease course showed a relentless decline; patients uniformly became wheelchair bound (mean age 13 years) and four had died during their third or early fourth decade. All 12 cases had the same variant (c.430G>T, G144W) and haplotype analyses confirmed a founder effect. The cases all came from countries bounding the North Sea, extending to the coastal region of Northern Norway. 'North Sea' progressive myoclonus epilepsy has a homogeneous clinical presentation and relentless disease course allowing ready identification from the other progressive myoclonus epilepsies.

  19. Phenotypic characterization of spontaneously mutated rats showing lethal dwarfism and epilepsy.

    PubMed

    Suzuki, Hiroetsu; Takenaka, Motoo; Suzuki, Katsushi

    2007-08-01

    We have characterized the phenotype of spontaneously mutated rats, found during experimental inbreeding in a closed colony of Wistar Imamichi rats. Mutant rats showed severe dwarfism, short lifespan (early postnatal lethality), and high incidence of epileptic seizures. Mutant rats showed growth retardation after 3 d of age, and at 21 d their weight was about 56% that of normal rats. Most mutant rats died without reaching maturity, and 95% of the mutant rats had an ataxic gait. About 34% of the dwarf rats experienced epileptic seizures, most of which started as 'wild running' convulsions, progressing to generalized tonic-clonic convulsions. At age 28 d, the relative weight of the testes was significantly lower, and the relative weight of the brain was significantly higher, in mutant than in normal rats. Histologically, increased apoptotic germ cells, lack of spermatocytes, and immature Leydig cells were found in the mutant testes, and extracellular vacuoles of various sizes were present in the hippocampus and amygdala of the mutant brain. Mutant rats had significantly increased concentrations of plasma urea nitrogen, creatinine, and inorganic phosphate, as well as decreased concentrations of plasma growth hormone. Hereditary analysis showed that the defects were inherited as a single recessive trait. We have named the hypothetically mutated gene as lde (lethal dwarfism with epilepsy).

  20. A novel mutation at the JK locus causing Jk null phenotype in a Chinese family.

    PubMed

    Meng, Yan; Zhou, Xueyan; Li, Yang; Zhao, Dan; Liang, Shuyuan; Zhao, Xuejian; Yang, Baoxue

    2005-12-01

    Urea transporters are a group of proteins that facilitate urea movement across biological membranes. Kidd blood group (Jk antigen) and urea transporter of human erythrocytes are carried by the same protein UT-B. To investigate the molecular basis of the Jk null phenotype in the Chinese population, blood samples from Chinese individuals were screened using the 2 mol/L urea solution hemolysis test. Urea and water permeability of erythrocytes membrane was measured by stopped-flow light scattering. Genomic DNA was extracted from lymphocytes. UT-B gene of JKnnu's family was analyzed using genomic PCR by primers designed to cover sequences of all exons and exon-intron boundaries in human UT-B gene. One Jk null subject was found from twenty thousand screened Chinese individuals, and it was confirmed that this individual did not express the erythrocyte urea transporter. Genomic sequence analysis of the Jk null individual showed that there were two point mutations, G-->C, which is novel, and G-->A, at the 3'-acceptor splice site (AG) of intron 5 of UT-B gene. Exon 6 is spliced out in the UT-B transcript due to either of these mutations. Water permeability in Jk null erythrocytes (Pf, -0.00037 cm/s) was significantly lower than that in normal erythrocytes (Pf, -0.00062 cm/s) after HgCl2 incubation, providing evidence for UT-B facilitated water transport in human erythrocytes.

  1. Diamond-Blackfan anemia: genotype-phenotype correlations in Italian patients with RPL5 and RPL11 mutations

    PubMed Central

    Quarello, Paola; Garelli, Emanuela; Carando, Adriana; Brusco, Alfredo; Calabrese, Roberto; Dufour, Carlo; Longoni, Daniela; Misuraca, Aldo; Vinti, Luciana; Aspesi, Anna; Biondini, Laura; Loreni, Fabrizio; Dianzani, Irma; Ramenghi, Ugo

    2010-01-01

    Background Diamond-Blackfan anemia is a rare, pure red blood cell aplasia of childhood due to an intrinsic defect in erythropoietic progenitors. About 40% of patients display various malformations. Anemia is corrected by steroid treatment in more than 50% of cases; non-responders need chronic transfusions or stem cell transplantation. Defects in the RPS19 gene, encoding the ribosomal protein S19, are the main known cause of Diamond-Blackfan anemia and account for more than 25% of cases. Mutations in RPS24, RPS17, and RPL35A described in a minority of patients show that Diamond-Blackfan anemia is a disorder of ribosome biogenesis. Two new genes (RPL5, RPL11), encoding for ribosomal proteins of the large subunit, have been reported to be involved in a considerable percentage of patients. Design and Methods In this genotype-phenotype analysis we screened the coding sequence and intron-exon boundaries of RPS14, RPS16, RPS24, RPL5, RPL11, and RPL35A in 92 Italian patients with Diamond-Blackfan anemia who were negative for RPS19 mutations. Results About 20% of the patients screened had mutations in RPL5 or RPL11, and only 1.6% in RPS24. All but three mutations that we report here are new mutations. No mutations were found in RPS14, RPS16, or RPL35A. Remarkably, we observed a higher percentage of somatic malformations in patients with RPL5 and RPL11 mutations. A close association was evident between RPL5 mutations and craniofacial malformations, and between hand malformations and RPL11 mutations. Conclusions Mutations in four ribosomal proteins account for around 50% of all cases of Diamond-Blackfan anemia in Italian patients. Genotype-phenotype data suggest that mutation screening should begin with RPL5 and RPL11 in patients with Diamond-Blackfan anemia with malformations. PMID:19773262

  2. The Phenotype of the Musculocontractural Type of Ehlers-Danlos Syndrome due to CHST14 Mutations

    PubMed Central

    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 biallelic 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 hadmildly 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

  3. The chemical chaperone phenylbutyrate rescues MCT8 mutations associated with milder phenotypes in patients with AHDS.

    PubMed

    Braun, Doreen; Schweizer, Ulrich

    2016-12-15

    Mutations in the thyroid hormone transporter MCT8 prevent appropriate entry of thyroid hormones into brain cells during development and cause severe mental retardation in affected patients. Current treatment options are thyromimetic compounds that enter the brain independent of MCT8. Some MCT8 deficient patients (e.g. those carrying MCT8(delF501)) are not as severely affected than most others. We have shown that MCT8(delF501) protein has decreased protein stability, but significant residual function once it reaches the plasma membrane. We were able to rescue protein expression and function of MCT8(delF501) in a MDCK1 cell model by application of the chemical chaperone sodium phenylbutyrate (NaPB), a drug that has been used to treat patients with cystic fibrosis and urea cycle defects over extended periods of time. Here we extend our previous study and report on the NaPB dependent rescue of a series of other pathogenic MCT8 mutants that are associated with milder patient phenotypes. We show that NaPB can functionally rescue expression and activities of Ser194Phe, Ser290Phe, Leu434Trp, Arg445Cys, Leu492Pro, and Leu568Pro mutations in MCT8 in a dose-dependent manner. The soy isoflavone genistein, a dietary supplement, which was effective in MCT8(delF501), was also effective in increasing expression and transport of these MCT8 mutants, but the effect size differed among mutants. Kinetic analyses revealed that Michaelis constants of the mutants towards the primary substrate T3 were not much different from the wild type value suggesting that these mutants are not impaired in their interaction with substrate, but rather destabilized by the mutation and degraded.

  4. 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.

  5. Arylamine N-acetyltransferase (NAT2) mutations and their allelic linkage in unrelated caucasian individuals: Correlation with phenotypic activity

    SciTech Connect

    Cascorbi, I.; Drakoulis, N.; Brockmoeller, J.

    1995-09-01

    The polymorphic arylamine N-acetyltransferase (NAT2; EC2.3.1.5) is supposed to be a susceptibility factor for several drug side effects and certain malignancies. A group of 844 unrelated German subjects was genotyped for their acetylation type, and 563 of them were also phenotyped. Seven mutations of the NAT2 gene were evaluated by allele-specific PCR (mutation 341C to T) and PCR-RFLP for mutations at nt positions 191, 282, 481, 590, 803, and 857. From the mutation pattern eight different alleles, including the wild type coding for rapid acetylation and seven alleles coding for slow phenotype, were determined. Four hundred ninety-seven subjects had a genotype of slow acetylation (58.9%; 95% confidence limits 55.5%-62.2%). Phenotypic acetylation capacity was expressed as the ratio of 5-acetylamino-6-formylamino-3-methyluracil and 1-methylxanthine in urine after caffeine intake. Some 6.7% of the cases deviated in genotype and phenotype, but sequencing DNA of these probands revealed no new mutations. Furthermore, linkage pattern of the mutations was always confirmed, as tested in 533 subjects. In vivo acetylation capacity of homozygous wild-type subjects (NAT2{sup *}4/{sup *}4) was significantly higher than in heterozygous genotypes (P = .001). All mutant alleles showed low in vivo acetylation capacities, including the previously not-yet-defined alleles {sup *}5A, {sup *}5C, and {sup *}13. Moreover, distinct slow genotypes differed significantly among each other, as reflected in lower acetylation capacity of {sup *}6A, {sup *}7B, and {sup *}13 alleles than the group of {sup *}5 alleles. The study demonstrated differential phenotypic activity of various NAT2 genes and gives a solid basis for clinical and molecular-epidemiological investigations. 34 refs., 4 figs., 7 tabs.

  6. Screening of RB1 gene mutations in Chinese patients with retinoblastoma and preliminary exploration of genotype–phenotype correlations

    PubMed Central

    He, Ming-yan; An, Yu; Qian, Xiao-wen; Li, Gang; Qian, Jiang

    2014-01-01

    Purpose Retinoblastoma (RB) sets the paradigm for hereditary cancer syndromes, for which medical care can change depending on the results of genetic testing. In this study, we screened constitutional mutations in the RB1 gene via a method combining DNA sequencing and multiplex ligation-dependent probe amplification (MLPA), and performed a preliminary exploration of genotype–phenotype correlations. Methods The peripheral blood of 85 retinoblastoma probands, including 39 bilateral and 46 unilateral, was collected, and genomic DNA was extracted. DNA sequencing was conducted first. MLPA analysis was applied for patients with bilateral RB with negative sequencing results and unilateral probands whose age at diagnosis was less than 1 year old. Results Thirty-four distinct mutations were identified in 40 (47.1%) of the 85 probands (36 bilateral and four unilateral), of which 20% (8/40) was identified by MLPA. The total detection rate in bilateral cases was 92.3% (36/39). Of the total mutations identified, 77.5% (31/40) probands with a mean age of 10.7 months at diagnosis had null mutations, and 22.5% (9/40) with a mean age of 13.5 months at diagnosis had in-frame mutations. Of the 31 probands with null mutations, bilateral RB accounted for 96.8% (30/31). Of the nine probands with in-frame mutations, 66.7% had bilateral RB. There were seven new mutations of RB1 identified in this report, including six null mutations and one missense mutation. Clinical staging of the tumor did not show obvious differences between patients with null mutations and in-frame mutations. Conclusions Our results confirm that the type of mutation is related to age of onset and the laterality, but not staging of the retinoblastoma tumor. MLPA is a reliable method for detecting gross deletion or duplication of the RB1 gene. The combination of sequencing and MLPA improves the clinical diagnosis of RB. PMID:24791139

  7. Identification of a frameshift mutation responsible for the silent phenotype of human serum cholinesterase, Gly 117 (GGT----GGAG).

    PubMed Central

    Nogueira, C P; McGuire, M C; Graeser, C; Bartels, C F; Arpagaus, M; Van der Spek, A F; Lightstone, H; Lockridge, O; La Du, B N

    1990-01-01

    A frameshift mutation that causes a silent phenotype for human serum cholinesterase was identified in the DNA of seven individuals of two unrelated families. The mutation, identified using the polymerase chain reaction, causes a shift in the reading frame from Gly 117, where GGT (Gly)----GGAG (Gly+ 1 base) to a new stop codon created at position 129. This alteration is upstream of the active site (Ser 198), and, if any protein were made, it would represent only 22% of the mature enzyme found in normal serum. Results of analysis of the enzymatic activities in serum agreed with the genotypes inferred from the nucleotide sequence. Rocket immunoelectrophoresis using alpha-naphthyl acetate to detect enzymatic activity showed an absence of cross-reactive material, as expected. One additional individual with a silent phenotype did not show the same frameshift mutation. This was not unexpected, since there must be considerable molecular heterogeneity involved in causes for the silent cholinesterase phenotype. This is the first report of a molecular mechanism underlying the silent phenotype for serum cholinesterase. The analytical approach used was similar to the one we recently employed to identify the mutation that causes the atypical cholinesterase variant. Images Figure 3 Figure 5 Figure 6 PMID:2339692

  8. CDH23 Mutation and Phenotype Heterogeneity: A Profile of 107 Diverse Families with Usher Syndrome and Nonsyndromic Deafness

    PubMed Central

    Astuto, L. M.; Bork, J. M.; Weston, M. D.; Askew, J. W.; Fields, R. R.; Orten, D. J.; Ohliger, S. J.; Riazuddin, S.; Morell, R. J.; Khan, S.; Riazuddin, S.; Kremer, H.; van Hauwe, P.; Moller, C. G.; Cremers, C. W. R. J.; Ayuso, C.; Heckenlively, J. R.; Rohrschneider, K.; Spandau, U.; Greenberg, J.; Ramesar, R.; Reardon, W.; Bitoun, P.; Millan, J.; Legge, R.; Friedman, T. B.; Kimberling, W. J.

    2002-01-01

    Usher syndrome type I is characterized by congenital hearing loss, retinitis pigmentosa (RP), and variable vestibular areflexia. Usher syndrome type ID, one of seven Usher syndrome type I genetic localizations, have been mapped to a chromosomal interval that overlaps with a nonsyndromic-deafness localization, DFNB12. Mutations in CDH23, a gene that encodes a putative cell-adhesion protein with multiple cadherin-like domains, are responsible for both Usher syndrome and DFNB12 nonsyndromic deafness. Specific CDH23 mutational defects have been identified that differentiate these two phenotypes. Only missense mutations of CDH23 have been observed in families with nonsyndromic deafness, whereas nonsense, frameshift, splice-site, and missense mutations have been identified in families with Usher syndrome. In the present study, a panel of 69 probands with Usher syndrome and 38 probands with recessive nonsyndromic deafness were screened for the presence of mutations in the entire coding region of CDH23, by heteroduplex, single-strand conformation polymorphism, and direct sequence analyses. A total of 36 different CDH23 mutations were detected in 45 families; 33 of these mutations were novel, including 18 missense, 3 nonsense, 5 splicing defects, 5 microdeletions, and 2 insertions. A total of seven mutations were common to more than one family. Numerous exonic and intronic polymorphisms also were detected. Results of ophthalmologic examinations of the patients with nonsyndromic deafness have found asymptomatic RP–like manifestations, indicating that missense mutations may have a subtle effect in the retina. Furthermore, patients with mutations in CDH23 display a wide range of hearing loss and RP phenotypes, differing in severity, age at onset, type, and the presence or absence of vestibular areflexia. PMID:12075507

  9. Mismatch repair genes of Streptococcus pneumoniae: HexA confers a mutator phenotype in Escherichia coli by negative complementation.

    PubMed

    Prudhomme, M; Méjean, V; Martin, B; Claverys, J P

    1991-11-01

    DNA repair systems able to correct base pair mismatches within newly replicated DNA or within heteroduplex molecules produced during recombination are widespread among living organisms. Evidence that such generalized mismatch repair systems evolved from a common ancestor is particularly strong for two of them, the Hex system of the gram-positive Streptococcus pneumoniae and the Mut system of the gram-negative Escherichia coli and Salmonella typhimurium. The homology existing between HexA and MutS and between HexB and MutL prompted us to investigate the effect of expressing hex genes in E. coli. Complementation of mutS or mutL mutations, which confer a mutator phenotype, was assayed by introducing on a multicopy plasmid the hexA and hexB genes, under the control of an inducible promoter, either individually or together in E. coli strains. No decrease in mutation rate was conferred by either hexA or hexB gene expression. However, a negative complementation effect was observed in wild-type E. coli cells: expression of hexA resulted in a typical Mut- mutator phenotype. hexB gene expression did not increase the mutation rate either individually or in conjunction with hexA. Since expression of hexA did not affect the mutation rate in mutS mutant cells and the hexA-induced mutator effect was recA independent, it is concluded that this effect results from inhibition of the Mut system. We suggest that HexA, like its homolog MutS, binds to mismatches resulting from replication errors, but in doing so it protects them from repair by the Mut system. In agreement with this hypothesis, an increase in mutS gene copy number abolished the hexA-induced mutator phenotype. HexA protein could prevent repair either by being unable to interact with Mut proteins or by producing nonfunctional repair complexes.

  10. A chondrodysplasia family produced by mutations in the diastrophic dysplasia sulfate transporter gene: Genotype/phenotype correlations

    SciTech Connect

    Superti-Furga, A.; Steinmann, B.; Gitzelmann, R.; Rossi, A.

    1996-05-03

    Achondrogenesis type 1B (ACG-1B), atelosteogenesis type 2 (AO-2), and diastrophic dysplasia (DTD) are recessively inherited chondrodysplasia of decreasing severity caused by mutations in the diastrophic dysplasia sulfate transporter (DTDST) gene on chromosome 5. In these conditions, sulfate transport across the cell membrane is impaired which results in insufficient sulfation of cartilage proteoglycans and thus in an abnormally low sulfate content of cartilage. The severity of the phenotype correlates well with the predicted effect of the underlying DTDST mutations: homozygosity or compound heterozygosity for stop codons or transmembrane domain substitutions mostly result in achondrogenesis type 1B, while other structural or regulatory mutations usually result in one of the less severe phenotypes. The chondrodysplasia arising at the DTDST locus constitute a bone dysplasia family with recessive inheritance. 28 refs., 2 tabs.

  11. Clinical Relevance and Molecular Phenotypes in Gastric Cancer, of TP53 Mutations and Gene Expressions, in Combination With Other Gene Mutations

    PubMed Central

    Park, Sungjin; Lee, Jinhyuk; Kim, Yon Hui; Park, Jaheun; Shin, Jung-Woog; Nam, Seungyoon

    2016-01-01

    While altered TP53 is the most frequent mutation in gastric cancer (GC), its association with molecular or clinical phenotypes (e.g., overall survival, disease-free survival) remains little known. To that end, we can use genome-wide approaches to identify altered genes significantly related to mutated TP53. Here, we identified significant differences in clinical outcomes, as well as in molecular phenotypes, across specific GC tumor subpopulations, when combining TP53 with other signaling networks, including WNT and its related genes NRXN1, CTNNB1, SLITRK5, NCOR2, RYR1, GPR112, MLL3, MTUS2, and MYH6. Moreover, specific GC subpopulations indicated by dual mutation of NRXN1 and TP53 suggest different drug responses, according to the Connectivity Map, a pharmacological drug-gene association tool. Overall, TP53 mutation status in GC is significantly relevant to clinical or molecular categories. Thus, our approach can potentially provide a patient stratification strategy by dissecting previously unknown multiple TP53-mutated patient groups. PMID:27708434

  12. Interaction between mutations in the suppressor of Hairy wing and modifier of mdg4 genes of Drosophila melanogaster affecting the phenotype of gypsy-induced mutations

    SciTech Connect

    Georgiev, P.; Kozycina, M.

    1996-02-01

    The suppressor of Hairy-wing [su(Hw)] protein mediates the mutagenic effect of the gypsy retrotransposon by repressing the function of transcriptional enhancers located distally from the promoter with respect to the position of the su(Hw)-binding region. Mutations in a second gene, modifier of mdg4, also affect the gypsy-induced phenotype. Two major effects of the mod(mdg4){sup lu1} mutation can be distinguished: the interference with insulation by the su(Hw)-binding region and direct inhibition of gene expression that is not dependent on the su(Hw)-binding region position. The mod(mdg4){sup lu1} mutation partially suppresses ct{sup 6}, sc{sup D1} and Hw{sup 1} mutations, possibly by interfering with the insulation effect of the su(Hw)-binding region. An example of the second effect of mod(mdg4){sup lu1} is a complete inactivation of yellow expression in combination with the y{sup 2} allele. Phenotypic analyses of flies with combinations of mdg(mdg4){sup lu1} and different su(Hw) mutations, or with constructions carrying deletions of the acidic domains of the su(Hw) protein, suggest that the carboxy-terminal acidic domain is important for direct inhibition of yellow transcription in bristles, while the amino-terminal acidic domain is more essential for insulation. 31 refs., 1 fig., 6 tabs.

  13. ATM gene mutations result in both recessive and dominant expression phenotypes of genes and microRNAs.

    PubMed

    Smirnov, Denis A; Cheung, Vivian G

    2008-08-01

    The defining characteristic of recessive disorders is the absence of disease in heterozygous carriers of the mutant alleles. However, it has been recognized that recessive carriers may differ from noncarriers in some phenotypes. Here, we studied ataxia telangiectasia (AT), a classical recessive disorder caused by mutations in the ataxia telangiectasia mutated (ATM) gene. We compared the gene and microRNA expression phenotypes of noncarriers, AT carriers who have one copy of the ATM mutations, and AT patients with two copies of ATM mutations. We found that some phenotypes are more similar between noncarriers and AT carriers compared to AT patients, as expected for a recessive disorder. However, for some expression phenotypes, AT carriers are more similar to the patients than to the noncarriers. Analysis of one of these expression phenotypes, TNFSF4 level, allowed us to uncover a regulatory pathway where ATM regulates TNFSF4 expression through MIRN125B (also known as miR-125b or miR125b) [corrected] In AT carriers and AT patients, this pathway is disrupted. As a result, the level of MIRN125B is lower and the level of its target gene, TNFSF4, is higher than in noncarriers. A decreased level of MIRN125B is associated with breast cancer, and an elevated level of TNFSF4 is associated with atherosclerosis. Thus, our findings provide a mechanistic suggestion for the increased risk of breast cancer and heart disease in AT carriers. By integrating molecular and computational analyses of gene and microRNA expression, we show the complex consequences of a human gene mutation.

  14. HSP90 Stabilizes Auxin-Responsive Phenotypes by Masking a Mutation in the Auxin Receptor TIR1.

    PubMed

    Watanabe, Etsuko; Mano, Shoji; Nomoto, Mika; Tada, Yasuomi; Hara-Nishimura, Ikuko; Nishimura, Mikio; Yamada, Kenji

    2016-11-01

    Heat shock protein 90 (HSP90) is a molecular chaperone that is required for the function of various substrate proteins, also known as client proteins. It is proposed that HSP90 buffers or hides phenotypic variations in animals and plants by masking mutations in some of its client proteins. However, none of the client proteins with cryptic mutations has been identified to date. Here, we identify the first client protein example by which HSP90 buffers a mutation: the auxin receptor transport inhibitor response 1 (TIR1). TIR1 interacts with HSP90 in the nucleus. An HSP90-specific inhibitor abolished the nuclear localization of TIR1 and the auxin-induced degradation of a TIR1-substrate, indicating that TIR1 is an HSP90 client protein. Plants with a null mutation in the TIR1 gene had a defect in auxin response, whereas plants with a point mutation in the TIR1 gene responded to auxin treatment in young seedlings, but a cryptic defect in its auxin response was exposed with HSP90 inhibitor treatment. These results demonstrate that HSP90 masks a point mutation in the auxin receptor TIR1 and thereby buffers auxin-responsive phenotypes.

  15. Mice with missense and nonsense NF1 mutations display divergent phenotypes compared with human neurofibromatosis type I

    PubMed Central

    Li, Kairong; Turner, Ashley N.; Chen, Min; Brosius, Stephanie N.; Schoeb, Trenton R.; Messiaen, Ludwine M.; Bedwell, David M.; Zinn, Kurt R.; Anastasaki, Corina; Gutmann, David H.; Korf, Bruce R.

    2016-01-01

    ABSTRACT Neurofibromatosis type 1 (NF1) is a common genetic disorder characterized by the occurrence of nerve sheath tumors and considerable clinical heterogeneity. Some translational studies have been limited by the lack of animal models available for assessing patient-specific mutations. In order to test therapeutic approaches that might restore function to the mutated gene or gene product, we developed mice harboring NF1 patient-specific mutations including a nonsense mutation (c.2041C>T; p.Arg681*) and a missense mutation (c.2542G>C; p.Gly848Arg). The latter is associated with the development of multiple plexiform neurofibromas along spinal nerve roots. We demonstrate that the human nonsense NF1Arg681* and missense NF1Gly848Arg mutations have different effects on neurofibromin expression in the mouse and each recapitulates unique aspects of the NF1 phenotype, depending upon the genetic context when assessed in the homozygous state or when paired with a conditional knockout allele. Whereas the missense Nf1Gly848Arg mutation fails to produce an overt phenotype in the mouse, animals homozygous for the nonsense Nf1Arg681* mutation are not viable. Mice with one Nf1Arg681* allele in combination with a conditional floxed Nf1 allele and the DhhCre transgene (Nf14F/Arg681*; DhhCre) display disorganized nonmyelinating axons and neurofibromas along the spinal column, which leads to compression of the spinal cord and paralysis. This model will be valuable for preclinical testing of novel nonsense suppression therapies using drugs to target in-frame point mutations that create premature termination codons in individuals with NF1. PMID:27482814

  16. Mice with missense and nonsense NF1 mutations display divergent phenotypes compared with human neurofibromatosis type I.

    PubMed

    Li, Kairong; Turner, Ashley N; Chen, Min; Brosius, Stephanie N; Schoeb, Trenton R; Messiaen, Ludwine M; Bedwell, David M; Zinn, Kurt R; Anastasaki, Corina; Gutmann, David H; Korf, Bruce R; Kesterson, Robert A

    2016-07-01

    Neurofibromatosis type 1 (NF1) is a common genetic disorder characterized by the occurrence of nerve sheath tumors and considerable clinical heterogeneity. Some translational studies have been limited by the lack of animal models available for assessing patient-specific mutations. In order to test therapeutic approaches that might restore function to the mutated gene or gene product, we developed mice harboring NF1 patient-specific mutations including a nonsense mutation (c.2041C>T; p.Arg681*) and a missense mutation (c.2542G>C; p.Gly848Arg). The latter is associated with the development of multiple plexiform neurofibromas along spinal nerve roots. We demonstrate that the human nonsense NF1(Arg681*) and missense NF1(Gly848Arg) mutations have different effects on neurofibromin expression in the mouse and each recapitulates unique aspects of the NF1 phenotype, depending upon the genetic context when assessed in the homozygous state or when paired with a conditional knockout allele. Whereas the missense Nf1(Gly848Arg) mutation fails to produce an overt phenotype in the mouse, animals homozygous for the nonsense Nf1(Arg681*) mutation are not viable. Mice with one Nf1(Arg681*) allele in combination with a conditional floxed Nf1 allele and the DhhCre transgene (Nf1(4F/Arg681*); DhhCre) display disorganized nonmyelinating axons and neurofibromas along the spinal column, which leads to compression of the spinal cord and paralysis. This model will be valuable for preclinical testing of novel nonsense suppression therapies using drugs to target in-frame point mutations that create premature termination codons in individuals with NF1.

  17. Polymorphisms, Chromosomal Rearrangements, and Mutator Phenotype Development during Experimental Evolution of Lactobacillus rhamnosus GG

    PubMed Central

    Douillard, François P.; Ribbera, Angela; Xiao, Kun; Ritari, Jarmo; Rasinkangas, Pia; Paulin, Lars; Palva, Airi; Hao, Yanling

    2016-01-01

    ABSTRACT Lactobacillus rhamnosus GG is a lactic acid bacterium widely marketed by the food industry. Its genomic analysis led to the identification of a gene cluster encoding mucus-binding SpaCBA pili, which is located in a genomic island enriched in insertion sequence (IS) elements. In the present study, we analyzed by genome-wide resequencing the genomic integrity of L. rhamnosus GG in four distinct evolutionary experiments conducted for approximately 1,000 generations under conditions of no stress or salt, bile, and repetitive-shearing stress. Under both stress-free and salt-induced stress conditions, the GG population (excluding the mutator lineage in the stress-free series [see below]) accumulated only a few single nucleotide polymorphisms (SNPs) and no frequent chromosomal rearrangements. In contrast, in the presence of bile salts or repetitive shearing stress, some IS elements were found to be activated, resulting in the deletion of large chromosomal segments that include the spaCBA-srtC1 pilus gene cluster. Remarkably, a high number of SNPs were found in three strains obtained after 900 generations of stress-free growth. Detailed analysis showed that these three strains derived from a founder mutant with an altered DNA polymerase subunit that resulted in a mutator phenotype. The present work confirms the stability of the pilus production phenotype in L. rhamnosus GG under stress-free conditions, highlights the possible evolutionary scenarios that may occur when this probiotic strain is extensively cultured, and identifies external factors that affect the chromosomal integrity of GG. The results provide mechanistic insights into the stability of GG in regard to its extensive use in probiotic and other functional food products. IMPORTANCE Lactobacillus rhamnosus GG is a widely marketed probiotic strain that has been used in numerous clinical studies to assess its health-promoting properties. Hence, the stability of the probiotic functions of L. rhamnosus GG

  18. Phenotype-genotype correlations in mouse models of amelogenesis imperfecta caused by Amelx and Enam mutations.

    PubMed

    Coxon, Thomas Liam; Brook, Alan Henry; Barron, Martin John; Smith, Richard Nigel

    2012-01-01

    Mutations in human and in mouse orthologous genes Amelx and Enam result in a diverse range of enamel defects. In this study we aimed to investigate the phenotype-genotype correlation between the mutants and the wild-type controls in mouse models of amelogenesis imperfecta using novel measurement approaches. Ten hemi-mandibles and incisors were dissected from each group of Amelx(WT), Amelx(X/Y64H), Amelx(Y/Y64H), Amelx(Y64H/Y64H), and Enam(WT), Enam(Rgsc395) heterozygous and Enam(Rgsc395) homozygous mice. Their macro-morphology, colour and micro-topography were assessed using bespoke 2D and 3D image analysis systems and customized colour and whiteness algorithms. The novel methods identified significant differences (p ≤ 0.05) between the Amelx groups for mandible and incisor size and enamel colour and between the Enam groups for incisor size and enamel colour. The Amelx(WT) mice had the largest mandibles and incisors, followed in descending order of size by the Amelx(X/Y64H), Amelx(Y/Y64H) and Amelx(Y64H/Y64H) mice. Within the Enam groups the Enam(WT) incisors were largest and the Enam(Rgsc395) heterozygous mice were smallest. The effect on tooth morphology was also reflected by the severity of the enamel defects in the colour and whiteness assessment. Amelogenin affected mandible morphology and incisor enamel formation, while enamelin only affected incisors, supporting the multifunctional role of amelogenin. The enamelin mutation was associated with earlier forming enamel defects. The study supported the critical involvement of amelogenin and enamelin in enamel mineralization.

  19. Compound Mutations Cause Increased Cardiac Events in Children with Long QT Syndrome: Can the Sequence Homology-Based Tools be Applied for Prediction of Phenotypic Severity?

    PubMed

    Izumi, Gaku; Hayama, Emiko; Yamazawa, Hirokuni; Inai, Kei; Shimada, Mitsuyo; Furutani, Michiko; Nishizawa, Tsutomu; Furutani, Yoshiyuki; Matsuoka, Rumiko; Nakanishi, Toshio

    2016-06-01

    Long QT syndrome (LQTS) can cause syncope, ventricular fibrillation, and death. Recently, several disease-causing mutations in ion channel genes have been identified, and compound mutations have also been detected. It is unclear whether children who are carriers of compound mutations exhibit a more severe phenotype than those with single mutations. Although predicting phenotypic severity is clinically important, the availability of prediction tools for LQTS is unknown. To determine whether the severity of the LQTS phenotype can be predicted by the presence of compound mutations in children is needed. We detected 97 single mutations (Group S) and 13 compound mutations (Group C) between 1998 and 2012, age at diagnosis ranging 0-19 years old (median age is 9.0) and 18.0 years of follow-up period. The phenotypes and Kaplan-Meier event-free rates of the two groups were compared for cardiac events. This study investigated phenotypic severity in relation to the location of mutations in the protein sequence, which was analyzed using two sequence homology-based tools. In results, compound mutations in children were associated with a high incidence of syncope within the first decade (Group S: 32 % vs. Group C: 61 %), requiring an ICD in the second decade (Group S: 3 % vs. Group C: 56 %). Mortality in these patients was high within 5 years of birth (23 %). Phenotypic prediction tools correctly predicted the phenotypic severity in both Groups S and C, especially by using their coupling method. The coupling prediction method is useful in the initial evaluation of phenotypes both with single and compound mutations of LQTS patients. However, it should be noted that the compound mutation makes more severe phenotype.

  20. What is influencing the phenotype of the common homozygous polymerase-γ mutation p.Ala467Thr?

    PubMed Central

    Neeve, Vivienne C. M.; Samuels, David C.; Bindoff, Laurence A.; van den Bosch, Bianca; Van Goethem, Gert; Smeets, Hubert; Lombès, Anne; Jardel, Claude; Hirano, Michio; DiMauro, Salvatore; De Vries, Maaike; Smeitink, Jan; Smits, Bart W.; de Coo, Ireneus F. M.; Saft, Carsten; Klopstock, Thomas; Keiling, Bianca-Cortina; Czermin, Birgit; Abicht, Angela; Lochmüller, Hanns; Hudson, Gavin; Gorman, Grainne G.; Turnbull, Doug M.; Taylor, Robert W.; Holinski-Feder, Elke; Chinnery, Patrick F.

    2012-01-01

    Polymerase-γ (POLG) is a major human disease gene and may account for up to 25% of all mitochondrial diseases in the UK and in Italy. To date, >150 different pathogenic mutations have been described in POLG. Some mutations behave as both dominant and recessive alleles, but an autosomal recessive inheritance pattern is much more common. The most frequently detected pathogenic POLG mutation in the Caucasian population is c.1399G>A leading to a p.Ala467Thr missense mutation in the linker domain of the protein. Although many patients are homozygous for this mutation, clinical presentation is highly variable, ranging from childhood-onset Alpers-Huttenlocher syndrome to adult-onset sensory ataxic neuropathy dysarthria and ophthalmoparesis. The reasons for this are not clear, but familial clustering of phenotypes suggests that modifying factors may influence the clinical manifestation. In this study, we collected clinical, histological and biochemical data from 68 patients carrying the homozygous p.Ala467Thr mutation from eight diagnostic centres in Europe and the USA. We performed DNA analysis in 44 of these patients to search for a genetic modifier within POLG and flanking regions potentially involved in the regulation of gene expression, and extended our analysis to other genes affecting mitochondrial DNA maintenance (POLG2, PEO1 and ANT1). The clinical presentation included almost the entire phenotypic spectrum of all known POLG mutations. Interestingly, the clinical presentation was similar in siblings, implying a genetic basis for the phenotypic variability amongst homozygotes. However, the p.Ala467Thr allele was present on a shared haplotype in each affected individual, and there was no correlation between the clinical presentation and genetic variants in any of the analysed nuclear genes. Patients with mitochondrial DNA haplogroup U developed epilepsy significantly less frequently than patients with any other mitochondrial DNA haplotype. Epilepsy was reported

  1. What is influencing the phenotype of the common homozygous polymerase-γ mutation p.Ala467Thr?

    PubMed

    Neeve, Vivienne C M; Samuels, David C; Bindoff, Laurence A; van den Bosch, Bianca; Van Goethem, Gert; Smeets, Hubert; Lombès, Anne; Jardel, Claude; Hirano, Michio; Dimauro, Salvatore; De Vries, Maaike; Smeitink, Jan; Smits, Bart W; de Coo, Ireneus F M; Saft, Carsten; Klopstock, Thomas; Keiling, Bianca-Cortina; Czermin, Birgit; Abicht, Angela; Lochmüller, Hanns; Hudson, Gavin; Gorman, Grainne G; Turnbull, Doug M; Taylor, Robert W; Holinski-Feder, Elke; Chinnery, Patrick F; Horvath, Rita

    2012-12-01

    Polymerase-γ (POLG) is a major human disease gene and may account for up to 25% of all mitochondrial diseases in the UK and in Italy. To date, >150 different pathogenic mutations have been described in POLG. Some mutations behave as both dominant and recessive alleles, but an autosomal recessive inheritance pattern is much more common. The most frequently detected pathogenic POLG mutation in the Caucasian population is c.1399G>A leading to a p.Ala467Thr missense mutation in the linker domain of the protein. Although many patients are homozygous for this mutation, clinical presentation is highly variable, ranging from childhood-onset Alpers-Huttenlocher syndrome to adult-onset sensory ataxic neuropathy dysarthria and ophthalmoparesis. The reasons for this are not clear, but familial clustering of phenotypes suggests that modifying factors may influence the clinical manifestation. In this study, we collected clinical, histological and biochemical data from 68 patients carrying the homozygous p.Ala467Thr mutation from eight diagnostic centres in Europe and the USA. We performed DNA analysis in 44 of these patients to search for a genetic modifier within POLG and flanking regions potentially involved in the regulation of gene expression, and extended our analysis to other genes affecting mitochondrial DNA maintenance (POLG2, PEO1 and ANT1). The clinical presentation included almost the entire phenotypic spectrum of all known POLG mutations. Interestingly, the clinical presentation was similar in siblings, implying a genetic basis for the phenotypic variability amongst homozygotes. However, the p.Ala467Thr allele was present on a shared haplotype in each affected individual, and there was no correlation between the clinical presentation and genetic variants in any of the analysed nuclear genes. Patients with mitochondrial DNA haplogroup U developed epilepsy significantly less frequently than patients with any other mitochondrial DNA haplotype. Epilepsy was reported

  2. Germline mutations and genotype-phenotype associations in head and neck paraganglioma patients with negative family history in China.

    PubMed

    Zhu, W D; Wang, Z Y; Chai, Y C; Wang, X W; Chen, D Y; Wu, H

    2015-09-01

    The aim of this study was to assess the frequency of germline mutations and to explore genotype-phenotype associations in Chinese head and neck paraganglioma (HNPGL) patients without family history. Twenty-six Chinese patients with a diagnosis of HNPGL(14 male and 12 female, respectively)were recruited, who were followed up from 2000 to 2012. Genomic DNA was obtained from resected tumor tissues and peripheral blood samples. Seven genes, Succinate dehydrogenase complex A,B,C,D (SDHA, SDHB, SDHC, SDHD), succinate dehydrogenase complex assembly factor 2 (SDHAF2), TMEM127 (transmembrane protein 127) and VHL (Von Hippel-Lindau), were screened by direct sequencing and multiplex ligation-dependent probe amplification (MLPA) was performed to search for potential large deletions or duplications of SDHB, SDHC, SDHD, SDHAF1 and SDHAF2. The total frequency of germline mutations was 30.8% (8/26), including 5 cases with missense mutation p.Met1Ile in SDHD, 1 case with missense mutation p.Tyr216Cys in SDHB, and 1 case with a novel truncation mutation p.Gln44Ter in SDHAF2. MLPA showed one patient with malignant HNPGL had heterozygous deletions of exon1, 2, 3, 7 and 8 in SDHB. Mutations in SDHD were the leading cause of HNPGL in this study. Mutation carriers were younger than non-mutation carriers (p < 0.01) and more likely to suffer from multiple tumors (p = 0.048), especially with mutations in SDHD. The presence of mutation was associated with the development of larger tumors (p = 0.021). This study confirmed that the missense mutation p.Met1Ile at the start codon in SDHD was a hotspot in chinese patients with HNPGLs. We recommend genetic analysis in patients below 45 years, especially SDHD gene.

  3. Molecular immunity to mycobacteria: knowledge from the mutation and phenotype spectrum analysis of Mendelian susceptibility to mycobacterial diseases

    PubMed Central

    Qu, Hui-Qi; Fisher-Hoch, Susan P.; McCormick, Joseph B.

    2011-01-01

    Summary Understanding molecular immunity against mycobacterial infection is critical for the development of effective strategies to control tuberculosis (TB), which is a major health issue in the developing world. Host immunogenetic studies represent an indispensable approach to understand the molecular mechanisms against mycobacterial infection. A superb paradigm is the identification of rare mutations causing Mendelian susceptibility to mycobacterial diseases (MSMD). Mutations in the interferon-gamma (IFN-γ) receptor genes are highly specific (although not exclusive) for mycobacterial infection. Only dominant negative mutations of STAT1 have specific susceptibility to mycobacterial infection. Mutations in the interleukin-12 (IL-12) signaling genes have phenotypes with non-specificity. Current studies highlight a complex molecular network in antimycobacterial immunity, centered on IFN-γ signaling. PMID:21330176

  4. Impaired mechanical response of an EDMD mutation leads to motility phenotypes that are repaired by loss of prenylation.

    PubMed

    Zuela, Noam; Zwerger, Monika; Levin, Tal; Medalia, Ohad; Gruenbaum, Yosef

    2016-05-01

    There are roughly 14 distinct heritable autosomal dominant diseases associated with mutations in lamins A/C, including Emery-Dreifuss muscular dystrophy (EDMD). The mechanical model proposes that the lamin mutations change the mechanical properties of muscle nuclei, leading to cell death and tissue deterioration. Here, we developed an experimental protocol that analyzes the effect of disease-linked lamin mutations on the response of nuclei to mechanical strain in living Caenorhabditis elegans We found that the EDMD mutation L535P disrupts the nuclear mechanical response specifically in muscle nuclei. Inhibiting lamin prenylation rescued the mechanical response of the EDMD nuclei, reversed the muscle phenotypes and led to normal motility. The LINC complex and emerin were also required to regulate the mechanical response of C. elegans nuclei. This study provides evidence to support the mechanical model and offers a potential future therapeutic approach towards curing EDMD.

  5. Novel mutations in the PRX and the MTMR2 genes are responsible for unusual Charcot-Marie-Tooth disease phenotypes.

    PubMed

    Nouioua, Sonia; Hamadouche, Tarik; Funalot, Benoit; Bernard, Rafaëlle; Bellatache, Nora; Bouderba, Radia; Grid, Djamel; Assami, Salima; Benhassine, Traki; Levy, Nicolas; Vallat, Jean-Michel; Tazir, Meriem

    2011-08-01

    Autosomal recessive Charcot-Marie-Tooth diseases, relatively common in Algeria due to high prevalence of consanguineous marriages, are clinically and genetically heterogeneous. We report on two consanguineous families with demyelinating autosomal recessive Charcot-Marie-Tooth disease (CMT4) associated with novel homozygous mutations in the MTMR2 gene, c.331dupA (p.Arg111LysfsX24) and PRX gene, c.1090C>T (p.Arg364X) respectively, and peculiar clinical phenotypes. The three patients with MTMR2 mutations (CMT4B1 family) had a typical phenotype of severe early onset motor and sensory neuropathy with typical focally folded myelin on nerve biopsy. Associated clinical features included vocal cord paresis, prominent chest deformities and claw hands. Contrasting with the classical presentation of CMT4F (early-onset Dejerine-Sottas phenotype), the four patients with PRX mutations (CMT4F family) had essentially a late age of onset and a protracted and relatively benign evolution, although they presented marked spine deformities. These observations broaden the spectrum of clinical phenotypes associated with these two CMT4 forms.

  6. Phenotypic characterization of the Komeda miniature rat Ishikawa, an animal model of dwarfism caused by a mutation in Prkg2.

    PubMed

    Tsuchida, Atsuko; Yokoi, Norihide; Namae, Misako; Fuse, Masanori; Masuyama, Taku; Sasaki, Masashi; Kawazu, Shoji; Komeda, Kajuro

    2008-12-01

    The Komeda miniature rat Ishikawa (KMI) is a spontaneous animal model of dwarfism caused by a mutation in Prkg2, which encodes cGMP-dependent protein kinase type II (cGKII). This strain has been maintained as a segregating inbred strain for the mutated allele mri. In this study, we characterized the phenotype of the KMI strain, particularly growth traits, craniofacial measurements, and organ weights. The homozygous mutant (mri/mri) animals were approximately 70% to 80% of the size of normal, heterozygous (mri/+) animals in regard to body length, weight, and naso-occipital length of the calvarium, and the retroperitoneal fat of mri/mri rats was reduced greatly. In addition, among progeny of the (BNxKMI-mri/mri)F1xKMI-mri/mri backcross, animals with the KMI phenotype (mri/mri) were easily distinguished from those showing the wild-type phenotype (mri/+) by using growth traits such as body length and weight. Genetic analysis revealed that all of the backcrossed progeny exhibiting the KMI phenotype were homozygous for the KMI allele in the 1.2-cM region between D14Rat5 and D14Rat80 on chromosome 14, suggesting strongly that mri acts in a completely recessive manner. The KMI strain is the first and only rat model with a confirmed mutation in Prkg2 and is a valuable model for studying dwarfism and longitudinal growth traits in humans and for functional studies of cGKII.

  7. A new family with an SLC9A6 mutation expanding the phenotypic spectrum of Christianson syndrome.

    PubMed

    Masurel-Paulet, Alice; Piton, Amélie; Chancenotte, Sophie; Redin, Claire; Thauvin-Robinet, Christel; Henrenger, Yvan; Minot, Delphine; Creppy, Audrey; Ruffier-Bourdet, Marie; Thevenon, Julien; Kuentz, Paul; Lehalle, Daphné; Curie, Aurore; Blanchard, Gaelle; Ghosn, Ezzat; Bonnet, Marlene; Archimbaud-Devilliers, Mélanie; Huet, Frédéric; Perret, Odile; Philip, Nicole; Mandel, Jean-Louis; Faivre, Laurence

    2016-08-01

    Using targeted next generation sequencing, we have identified a splicing mutation (c.526-9_526-5del) in the SLC9A6 gene in a 9-year-old boy with mild intellectual disability (ID), microcephaly, and social interaction disabilities. This intronic microdeletion leads to the skipping of exon 3 and to an in-frame deletion of 26 amino acids in the TM4 domain. It segregates with cognitive impairment or learning difficulties in other members of the family. Mutations in SLC9A6 have been reported in X-linked Christianson syndrome associating severe to profound intellectual deficiency and an Angelman-like phenotype with microcephaly, absent speech, ataxia with progressive cerebellar atrophy, ophthalmoplegia, epilepsy, and neurological regression. The proband and his maternal uncle both have an attenuated phenotype with mild ID, attention deficit disorder, speech difficulties, and mild asymptomatic cerebellar atrophy. The proband also have microcephaly. The mutation cosegregated with learning disabilities and speech difficulties in the female carriers (mother and three sisters of the proband). Detailed neuropsychological, speech, and occupational therapy investigations in the female carriers revealed impaired oral and written language acquisition, with dissociation between verbal and performance IQ. An abnormal phenotype, ranging from learning disability with predominant speech difficulties to mild intellectual deficiency, has been described previously in a large proportion of female carriers. Besides broadening the clinical spectrum of SLC9A6 gene mutations, we present an example of a monogenic origin of mild learning disability. © 2016 Wiley Periodicals, Inc.

  8. A Unique Mutation in a MYB Gene Cosegregates with the Nectarine Phenotype in Peach

    PubMed Central

    Dondini, Luca; Pacheco, Igor; Dettori, Maria Teresa; Gazza, Laura; Scalabrin, Simone; Strozzi, Francesco; Tartarini, Stefano; Bassi, Daniele; Verde, Ignazio; Rossini, Laura

    2014-01-01

    Nectarines play a key role in peach industry; the fuzzless skin has implications for consumer acceptance. The peach/nectarine (G/g) trait was described as monogenic and previously mapped on chromosome 5. Here, the position of the G locus was delimited within a 1.1 cM interval (635 kb) based on linkage analysis of an F2 progeny from the cross ‘Contender’ (C, peach) x ‘Ambra’ (A, nectarine). Careful inspection of the genes annotated in the corresponding genomic sequence (Peach v1.0), coupled with variant discovery, led to the identification of MYB gene PpeMYB25 as a candidate for trichome formation on fruit skin. Analysis of genomic re-sequencing data from five peach/nectarine accessions pointed to the insertion of a LTR retroelement in exon 3 of the PpeMYB25 gene as the cause of the recessive glabrous phenotype. A functional marker (indelG) developed on the LTR insertion cosegregated with the trait in the CxA F2 progeny and was validated on a broad panel of genotypes, including all known putative donors of the nectarine trait. This marker was shown to efficiently discriminate between peach and nectarine plants, indicating that a unique mutational event gave rise to the nectarine trait and providing a useful diagnostic tool for early seedling selection in peach breeding programs. PMID:24595269

  9. Mutations in collagen 18A1 and their relevance to the human phenotype.

    PubMed

    Passos-Bueno, Maria Rita; Suzuki, Oscar T; Armelin-Correa, Lucia M; Sertié, Andréa L; Errera, Flavia I V; Bagatini, Kelly; Kok, Fernando; Leite, Katia R M

    2006-03-01

    Collagen XVIII, a proteoglycan, is a component of basement membranes (BMs). There are three distinct isoforms that differ only by their N-terminal, but with a specific pattern of tissue and developmental expression. Cleavage of its C-terminal produces endostatin, an inhibitor of angiogenesis. In its N-terminal, there is a frizzled motif which seems to be involved in Wnt signaling. Mutations in this gene cause Knobloch syndrome KS), an autosomal recessive disorder characterized by vitreoretinal and macular degeneration and occipital encephalocele. This review discusses the effect of both rare and polymorphic alleles in the human phenotype, showing that deficiency of one of the collagen XVIII isoforms is sufficient to cause KS and that null alleles causing deficiency of all collagen XVIII isoforms are associated with a more severe ocular defect. This review besides illustrating the functional importance of collagen XVIII in eye development and its structure maintenance throughout life, it also shows its role in other tissues and organs, such as nervous system and kidney.

  10. Incidence of the mask phenotype M264V mutation in Labrador Retrievers.

    PubMed

    Conant, E K; Juras, R; Cothran, E G

    2011-12-01

    The introduction of SNP (Single Nucleotide Polymorphism) chips allows for the rapid typing of multiple markers for many individuals at one time. Our lab routinely types dogs using a custom designed combined panel of SNPs for parentage verification and a number of genes for diagnostic tests using an OpenArray platform manufactured by BioTrove (Woburn, MA, USA). By utilizing the same SNP panel across a wide array of canine breeds it is possible to detect trait-associated SNPs in breeds not thought to carry those traits. We genotyped 245 Labrador Retrievers on the canine SNP chip and found 13 animals heterozygous for the M264V mutation associated with autosomal dominant mask trait, and one animal homozygous for this trait. The color genotypes for these animals were further examined. In standard colored Labradors (black, chocolate, and yellow), the mask phenotype would never be distinguishable. As illustrated by this example, we feel this SNP panel is a valuable method for discovering traits not known to exist in a breed.

  11. Expanding the SHOC2 Mutation Associated Phenotype of Noonan Syndrome with Loose Anagen Hair: Structural Brain Anomalies and Myelofibrosis

    PubMed Central

    Gripp, Karen W.; Zand, Dina J.; Demmer, Laurie; Anderson, Carol E.; Dobyns, William B.; Zackai, Elaine H.; Denenberg, Elizabeth; Jenny, Kim; Stabley, Deborah L.; Sol-Church, Katia

    2013-01-01

    Noonan syndrome is a heterogenous rasopathy typically presenting with short stature, characteristic facial features, cardiac abnormalities including pulmonic valve stenosis, ASD and hypertrophic cardiomyopathy (HCM), cryptorchidism, ectodermal abnormalities and learning differences. The phenotype is variable, and limited genotype phenotype correlation exists with SOS1 mutations often associated with normal cognition and stature, RAF1 mutations entailing a high HCM risk, and certain PTPN11 mutations predisposing to juvenile myelomonocytic leukemia. The recently identified SHOC2 mutation (p.Ser2Gly) causes Noonan syndrome with loose anagen hair. We report five patients with this mutation. All had skin hyperpigmentation, sparse light colored hair, increased fine wrinkles, ligamentous laxity, developmental delay and 4/4 had a structural cardiac anomaly. Hypotonia and macrocephaly occurred in 4/5 (80%); 3/5 (60%) had polyhydramnios, increased birth weight or required use of a feeding tube. Distinctive brain abnormalities included relative megalencephaly and enlarged subarachnoid spaces suggestive of benign external hydrocephalus, and a relatively small posterior fossa as indicated by a vertical tentorium. The combination of a large brain with a small posterior fossa likely resulted in the high rate of cerebellar tonsillar ectopia (3/4) (75%). Periventricular nodular heterotopia was seen in one patient with a thick and dysplastic corpus callosum. We report on the first hematologic neoplasm, myelofibrosis, in a 2-year-old patient with SHOC2 mutation. Myelofibrosis is exceedingly rare in children and young adults. The absence of a somatic JAK2 mutation, seen in the majority of patients with myelofibrosis, is noteworthy as it suggests that germline or somatic SHOC2 mutations are causally involved in myelofibrosis. PMID:23918763

  12. Expanding the SHOC2 mutation associated phenotype of Noonan syndrome with loose anagen hair: structural brain anomalies and myelofibrosis.

    PubMed

    Gripp, Karen W; Zand, Dina J; Demmer, Laurie; Anderson, Carol E; Dobyns, William B; Zackai, Elaine H; Denenberg, Elizabeth; Jenny, Kim; Stabley, Deborah L; Sol-Church, Katia

    2013-10-01

    Noonan syndrome is a heterogenous rasopathy typically presenting with short stature, characteristic facial features, cardiac abnormalities including pulmonic valve stenosis, ASD and hypertrophic cardiomyopathy (HCM), cryptorchidism, ectodermal abnormalities, and learning differences. The phenotype is variable, and limited genotype phenotype correlation exists with SOS1 mutations often associated with normal cognition and stature, RAF1 mutations entailing a high HCM risk, and certain PTPN11 mutations predisposing to juvenile myelomonocytic leukemia. The recently identified SHOC2 mutation (p.Ser2Gly) causes Noonan syndrome with loose anagen hair. We report five patients with this mutation. All had skin hyperpigmentation, sparse light colored hair, increased fine wrinkles, ligamentous laxity, developmental delay, and 4/4 had a structural cardiac anomaly. Hypotonia and macrocephaly occurred in 4/5 (80%); 3/5 (60%) had polyhydramnios, increased birth weight or required use of a feeding tube. Distinctive brain abnormalities included relative megalencephaly and enlarged subarachnoid spaces suggestive of benign external hydrocephalus, and a relatively small posterior fossa as indicated by a vertical tentorium. The combination of a large brain with a small posterior fossa likely resulted in the high rate of cerebellar tonsillar ectopia (3/4; 75%). Periventricular nodular heterotopia was seen in one patient with a thick and dysplastic corpus callosum. We report on the first hematologic neoplasm, myelofibrosis, in a 2-year-old patient with SHOC2 mutation. Myelofibrosis is exceedingly rare in children and young adults. The absence of a somatic JAK2 mutation, seen in the majority of patients with myelofibrosis, is noteworthy as it suggests that germline or somatic SHOC2 mutations are causally involved in myelofibrosis.

  13. 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

  14. PKA-Dependent Biophysical Phenotype for V227F-KCNJ2 Mutation in Catecholaminergic Polymorphic Ventricular Tachycardia

    PubMed Central

    Vega, Amanda L.; Tester, David J.; Ackerman, Michael J.; Makielski, Jonathan C.

    2009-01-01

    Background KCNJ2 encodes Kir2.1, a pore-forming subunit of the cardiac inward rectifier current, IK1. KCNJ2 mutations are associated with Andersen-Tawil syndrome (ATS) and also Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT). The aim of this study was to characterize the biophysical and cellular phenotype of a KCNJ2 missense mutation, V227F, found in a patient with CPVT. Methods and Results Kir2.1-wild type (WT) and V227F channels were expressed individually and together in Cos-1 cells to measure IK1 by voltage clamp. Unlike typical ATS-associated KCNJ2 mutations which show dominant negative loss of function, Kir2.1WT+V227F co-expression yielded IK1 indistinguishable from Kir2.1-WT under basal conditions. To simulate catecholamine activity, a PKA-stimulating cocktail comprised of forskolin and 3-isobutyl-1-methylxanthine (IBMX) was used to increase PKA activity. This PKA-simulated catecholaminergic stimulation caused marked reduction of outward IK1 compared to Kir2.1-WT. PKA-induced reduction in IK1 was eliminated by mutating the phosphorylation site at serine 425 (S425N). Conclusions Heteromeric Kir2.1-V227F and WT channels showed an unusual latent loss of function biophysical phenotype that depended upon PKA-dependent Kir2.1 phosphorylation. This biophysical phenotype, distinct from typical ATS mutations, suggests a specific mechanism for PKA dependent IK1 dysfunction for this KCNJ2 mutation which correlates with adrenergic conditions underlying the clinical arrhythmia. PMID:19843922

  15. Broadening of cohesinopathies: exome sequencing identifies mutations in ANKRD11 in two patients with Cornelia de Lange-overlapping phenotype.

    PubMed

    Parenti, I; Gervasini, C; Pozojevic, J; Graul-Neumann, L; Azzollini, J; Braunholz, D; Watrin, E; Wendt, K S; Cereda, A; Cittaro, D; Gillessen-Kaesbach, G; Lazarevic, D; Mariani, M; Russo, S; Werner, R; Krawitz, P; Larizza, L; Selicorni, A; Kaiser, F J

    2016-01-01

    Cornelia de Lange syndrome (CdLS) and KBG syndrome are two distinct developmental pathologies sharing common features such as intellectual disability, psychomotor delay, and some craniofacial and limb abnormalities. Mutations in one of the five genes NIPBL, SMC1A, SMC3, HDAC8 or RAD21, were identified in at least 70% of the patients with CdLS. Consequently, additional causative genes, either unknown or responsible of partially merging entities, possibly account for the remaining 30% of the patients. In contrast, KBG has only been associated with mutations in ANKRD11. By exome sequencing we could identify heterozygous loss-of-function mutations in ANKRD11 in two patients with the clinical diagnosis of CdLS. Both patients show features reminiscent of CdLS such as characteristic facies as well as a small head circumference which is not described for KBG syndrome. Patient A, who carries the mutation in a mosaic state, is a 4-year-old girl with features reminiscent of CdLS. Patient B, a 15-year-old boy, shows a complex phenotype which resembled CdLS during infancy, but has developed to a more KBG overlapping phenotype during childhood. These findings point out the importance of screening ANKRD11 in young CdLS patients who were found to be negative for mutations in the five known CdLS genes.

  16. SOS1 Mutations in Noonan Syndrome: Molecular Spectrum, Structural Insights on Pathogenic Effects, and Genotype–Phenotype Correlations

    PubMed Central

    Lepri, Francesca; De Luca, Alessandro; Stella, Lorenzo; Rossi, Cesare; Baldassarre, Giuseppina; Pantaleoni, Francesca; Cordeddu, Viviana; Williams, Bradley J; Dentici, Maria L; Caputo, Viviana; Venanzi, Serenella; Bonaguro, Michela; Kavamura, Ines; Faienza, Maria F; Pilotta, Alba; Stanzial, Franco; Faravelli, Francesca; Gabrielli, Orazio; Marino, Bruno; Neri, Giovanni; Silengo, Margherita Cirillo; Ferrero, Giovanni B; Torrrente, Isabella; Selicorni, Angelo; Mazzanti, Laura; Digilio, Maria C; Zampino, Giuseppe; Dallapiccola, Bruno; Gelb, Bruce D; Tartaglia, Marco

    2011-01-01

    Noonan syndrome (NS) is among the most common nonchromosomal disorders affecting development and growth. NS is caused by aberrant RAS-MAPK signaling and is genetically heterogeneous, which explains, in part, the marked clinical variability documented for this Mendelian trait. Recently, we and others identified SOS1 as a major gene underlying NS. Here, we explored further the spectrum of SOS1 mutations and their associated phenotypic features. Mutation scanning of the entire SOS1 coding sequence allowed the identification of 33 different variants deemed to be of pathological significance, including 16 novel missense changes and in-frame indels. Various mutation clusters destabilizing or altering orientation of regions of the protein predicted to contribute structurally to the maintenance of autoinhibition were identified. Two previously unappreciated clusters predicted to enhance SOS1's recruitment to the plasma membrane, thus promoting a spatial reorientation of domains contributing to inhibition, were also recognized. Genotype–phenotype analysis confirmed our previous observations, establishing a high frequency of ectodermal anomalies and a low prevalence of cognitive impairment and reduced growth. Finally, mutation analysis performed on cohorts of individuals with nonsyndromic pulmonic stenosis, atrial septal defects, and ventricular septal defects excluded a major contribution of germline SOS1 lesions to the isolated occurrence of these cardiac anomalies. Hum Mutat 32:760–772, 2011. © 2011 Wiley-Liss, Inc. PMID:21387466

  17. A distinct mutation on the alternative splice site of APC exon 9 results in attenuated familial adenomatous polyposis phenotype.

    PubMed

    Fostira, Florentia; Yannoukakos, Drakoulis

    2010-09-01

    A subset of APC mutation carriers shows a milder familial adenomatous polyposis phenotype (attenuated FAP) developing smaller number of polyps and colorectal cancer at an older age. It seems that a different mechanism to carcinogenesis is initiated according to the initial site of the germline mutation. The APC gene of a female patient with AFAP phenotypic features was analysed. A novel mutation located on the alternatively splice site of exon 9 was identified. This is the first reported mutation in the specific site. Transcripts characterization revealed disruption of splicing occurring within exon 9, resulting in the expression of a shorter mRNA transcript, which surprisingly does not affect the ratio between the two wild type transcripts, as well as the production of wild type short isoform by the mutant allele. The short wild type isoform, produced by the mutant allele, needs to be inactivated, on top of the wild type allele, for colorectal cancer to develop. These observations enhance the 'three hit hypothesis' and indicate that a distinct mechanism for the adenoma to carcinoma sequence should be followed, for truncated mutations taking place on the borderline of the alternatively spliced exon 9 of the APC gene, as well.

  18. Non dominant-negative KCNJ2 gene mutations leading to Andersen-Tawil syndrome with an isolated cardiac phenotype.

    PubMed

    Limberg, Maren M; Zumhagen, Sven; Netter, Michael F; Coffey, Alison J; Grace, Andrew; Rogers, Jane; Böckelmann, Doris; Rinné, Susanne; Stallmeyer, Birgit; Decher, Niels; Schulze-Bahr, Eric

    2013-05-01

    Andersen-Tawil syndrome (ATS) is characterized by dysmorphic features, periodic paralyses and abnormal ventricular repolarization. After genotyping a large set of patients with congenital long-QT syndrome, we identified two novel, heterozygous KCNJ2 mutations (p.N318S, p.W322C) located in the C-terminus of the Kir2.1 subunit. These mutations have a different localization than classical ATS mutations which are mostly located at a potential interaction face with the slide helix or at the interface between the C-termini. Mutation carriers were without the key features of ATS, causing an isolated cardiac phenotype. While the N318S mutants regularly reached the plasma membrane, W322C mutants primarily resided in late endosomes. Co-expression of N318S or W322C with wild-type Kir2.1 reduced current amplitudes only by 20-25 %. This mild loss-of-function for the heteromeric channels resulted from defective channel trafficking (W322C) or gating (N318S). Strikingly, and in contrast to the majority of ATS mutations, neither mutant caused a dominant-negative suppression of wild-type Kir2.1, Kir2.2 and Kir2.3 currents. Thus, a mild reduction of native Kir2.x currents by non dominant-negative mutants may cause ATS with an isolated cardiac phenotype.

  19. Seven novel mutations in the methylenetetrahydrofolate reductase gene and genotype/phenotype correlations in severe methylenetetrahydrofolate reductase deficiency

    SciTech Connect

    Goyette, P.; Frosst, P.; Rosenblatt, D.S.; Rozen. R.

    1995-05-01

    5-Methyltetrahydrofolate, the major form of folate in plasma, is a carbon donor for the remethylation of homocysteine to methionine. This form of folate is generated from 5,10-methylenetetrahydrofolate through the action of 5,10-methylenetetrahydrofolate reductase (MTHFR), a cytosolic flavoprotein. Patients with an autosomal recessive severe deficiency of MTHFR have homocystinuria and a wide range of neurological and vascular disturbances. We have recently described the isolation of a cDNA for MTHFR and the identification of two mutations in patients with severe MTHFR deficiency. We report here the characterization of seven novel mutations in this gene: six missense mutations and a 5{prime} splice-site defect that activates a cryptic splice in the coding sequence. We also present a preliminary analysis of the relationship between genotype and phenotype for all nine mutations identified thus far in this gene. A nonsense mutation and two missense mutations (proline to leucine and threonine to methionine) in the homozygous state are associated with extremely low activity (0%-3%) and onset of symptoms within the 1st year of age. Other missense mutations (arginine to cysteine and arginine to glutamine) are associated with higher enzyme activity and later onset of symptoms. 19 refs., 4 figs., 2 tabs.

  20. Compound heterozygous desmoplakin mutations result in a phenotype with a combination of myocardial, skin, hair, and enamel abnormalities.

    PubMed

    Mahoney, My G; Sadowski, Sara; Brennan, Donna; Pikander, Pekka; Saukko, Pekka; Wahl, James; Aho, Heikki; Heikinheimo, Kristiina; Bruckner-Tuderman, Leena; Fertala, Andrzej; Peltonen, Juha; Uitto, Jouni; Peltonen, Sirkku

    2010-04-01

    Desmoplakin (DP) anchors the intermediate filament cytoskeleton to the desmosomal cadherins and thereby confers structural stability to tissues. In this study, we present a patient with extensive mucocutaneous blisters, epidermolytic palmoplantar keratoderma, nail dystrophy, enamel dysplasia, and sparse woolly hair. The patient died at the age of 14 years from undiagnosed cardiomyopathy. The skin showed hyperplasia and acantholysis in the mid- and lower epidermal layers, whereas the heart showed extensive fibrosis and fibrofatty replacement in both ventricles. Immunofluorescence microscopy showed a reduction in the C-terminal domain of DP in the skin and oral mucosa. Sequencing of the DP gene showed undescribed mutations in the maternal and paternal alleles. Both mutations affected exon 24 encoding the C-terminal domain. The paternal mutation, c.6310delA, leads to a premature stop codon. The maternal mutation, c.7964 C to A, results in a substitution of an aspartic acid for a conserved alanine residue at amino acid 2655 (A2655D). Structural modeling indicated that this mutation changes the electrostatic potential of the mutated region of DP, possibly altering functions that depend on intermolecular interactions. To conclude, we describe a combination of DP mutation phenotypes affecting the skin, heart, hair, and teeth. This patient case emphasizes the importance of heart examination of patients with desmosomal genodermatoses.

  1. From Function to Phenotype: Impaired DNA Binding and Clustering Correlates with Clinical Severity in Males with Missense Mutations in MECP2

    PubMed Central

    Sheikh, Taimoor I.; Ausió, Juan; Faghfoury, Hannah; Silver, Josh; Lane, Jane B.; Eubanks, James H.; MacLeod, Patrick; Percy, Alan K.; Vincent, John B.

    2016-01-01

    Mutations in the MECP2 gene cause Rett syndrome (RTT). MeCP2 binds to chromocentric DNA through its methyl CpG-binding domain (MBD) to regulate gene expression. In heterozygous females the variable phenotypic severity is modulated by non-random X-inactivation, thus making genotype-phenotype comparisons unreliable. However, genotype-phenotype correlations in males with hemizygousMECP2 mutations can provide more accurate insights in to the true biological effect of specific mutations. Here, we compared chromatin organization and binding dynamics for twelve MeCP2 missense mutations (including two novel and the five most common MBD missense RTT mutations) and identifiedacorrelation with phenotype in hemizygous males. We observed impaired interaction of MeCP2-DNA for mutations around the MBD-DNA binding interface, and defective chromatin clustering for distal MBD mutations. Furthermore, binding and mobility dynamics show a gradient of impairment depending on the amino acid properties and tertiary structure within the MBD. Interestingly, a wide range of phenotypic/clinical severity, ranging from neonatal encephalopathy to mild psychiatric abnormalities were observed and all are consistent with our functional/molecular results. Overall, clinical severity showed a direct correlation with the functional impairment of MeCP2. These mechanistic and phenotypic correlations of MeCP2 mutations will enable improved and individualized diagnostics, and may lead to personalized therapeutic interventions. PMID:27929079

  2. Genotype–phenotype correlations in nonlethal osteogenesis imperfecta caused by mutations in the helical domain of collagen type I

    PubMed Central

    Rauch, Frank; Lalic, Liljana; Roughley, Peter; Glorieux, Francis H

    2010-01-01

    Osteogenesis imperfecta (OI) is a heritable disorder with bone fragility that is often associated with short stature, tooth abnormalities (dentinogenesis imperfecta), and blue sclera. The most common mutations associated with OI result from the substitution for glycine by another amino acid in the triple helical domain of either the α1 or the α2 chain of collagen type I. In this study, we compared the results of genotype analysis and clinical examination in 161 OI patients (median age: 13 years) who had glycine mutations in the triple helical domain of α1(I) (n=67) or α2(I) (n=94). Serine substitutions were the most frequently encountered type of mutation in both chains. Compared with patients with serine substitutions in α2(I) (n=40), patients with serine substitutions in α1(I) (n=42) on average were shorter (median height z-score −6.0 vs −3.4; P=0.005), indicating that α1(I) mutations cause a more severe phenotype. Height correlated with the location of the mutation in the α2(I) chain but not in the α1(I) chain. Patients with mutations affecting the first 120 amino acids at the amino-terminal end of the collagen type I triple helix had blue sclera but did not have dentinogenesis imperfecta. Among patients from different families sharing the same mutation, about 90 and 75% were concordant for dentinogenesis imperfecta and blue sclera, respectively. These data should be useful to predict disease phenotype in newly diagnosed OI patients. PMID:20087402

  3. Localization studies of rare missense mutations in cystic fibrosis transmembrane conductance regulator (CFTR) facilitate interpretation of genotype-phenotype relationships.

    PubMed

    Krasnov, Kristina V; Tzetis, Maria; Cheng, Jie; Guggino, William B; Cutting, Garry R

    2008-11-01

    We have been investigating the functional consequences of rare disease-associated amino acid substitutions in the cystic fibrosis transmembrane conductance regulator (CFTR). Mutations of the arginine residue at codon 1070 have been associated with different disease consequences; R1070P and R1070Q with "severe" pancreatic insufficient cystic fibrosis (CF) and R1070W with "mild" pancreatic sufficient CF or congenital bilateral absence of the vas deferens. Intriguingly, CFTR bearing each of these mutations is functional when expressed in nonpolarized cells. To determine whether R1070 mutations cause disease by affecting CFTR localization, we created polarized Madin Darby canine kidney (MDCK) cell lines that express either wild-type or mutant CFTR from the same genomic integration site. Confocal microscopy and biotinylation studies revealed that R1070P was not inserted into the apical membrane, R1070W was inserted at levels reduced from wild-type while R1070Q was present in the apical membrane at levels comparable to wild-type. The abnormal localization of CFTR bearing R1070P and R1070W was consistent with deleterious consequences in patients; however, the profile of CFTR R1070Q was inconsistent with a "severe" phenotype. Reanalysis of 16 patients with the R1070Q mutation revealed that 11 carried an in cis nonsense mutation, S466X. All 11 patients carrying the complex allele R1070Q-S466X had severe disease, while 4 out of 5 patients with R1070Q had "mild" disease, thereby reconciling the apparent discrepancy between the localization studies of R1070Q and the phenotype of patients bearing this mutation. Our results emphasize that localization studies in relevant model systems can greatly assist the interpretation of the disease-causing potential of rare missense mutations.

  4. Functional characterization of insulin receptor gene mutations contributing to Rabson-Mendenhall syndrome - phenotypic heterogeneity of insulin receptor gene mutations.

    PubMed

    Jiang, Shan; Fang, Qichen; Zhang, Feng; Wan, Hui; Zhang, Rong; Wang, Congrong; Bao, Yuqian; Zhang, Lei; Ma, Xiaojing; Lu, Junxi; Gao, Fei; Xiang, Kunsan; Jia, Weiping

    2011-01-01

    Rabson-Mendenhall syndrome (RMS) is a rare disorder that presents as severe insulin resistance as a result of mutations present in the insulin receptor (INSR). A Chinese girl with RMS presented with profound diabetes, hyperinsulinemia, acanthosis nigricans, hirsutism, and abnormalities of teeth and nails. Direct sequencing of the patient's INSR detected heterozygote mutations at Arg83Gln (R83Q) and Ala1028Val (A1028V), with the former representing a novel mutation. Functional studies of Chinese hamster ovary (CHO) cells transfected with wild-type (WT) and mutant forms of INSR were performed to evaluate the effects of these mutations on receptor expression and activation. Receptor expression, insulin binding activity, and phosphorylation of the R83Q variant were comparable to WT. In contrast, expression of the A1028V receptor was much lower than that of WT INSR, and impairment of insulin binding and autophosphorylation were nearly commensurate with the decrease in expression detected. Reductions in the phosphorylation of IRS-1, Akt, and Erk1/2 (60%, 40%, and 50% of WT, respectively) indicate that the A1028V receptor contributes to impaired signal transduction. In conclusion, INSR mutations associated with RMS were identified. Moreover, the A1028V mutation associated with a decrease in expression of INSR potentially accounts for loss of function of the INSR.

  5. [Nuclear gene involves in phenotype of non-syndromic deafness associated with mitochondrial 12S rRNA mutation].

    PubMed

    Zhao, Su Ying; Zhang, Hai Jun; Xu, Chun Hong; Shan, Xiang Nian

    2006-02-01

    The human mitochondrial 12S rRNA gene mutation at position 1555 associated with non-syndromic deafness and aminoglycoside-induced deafness. Family of Huaiyin in Jiangsu is one of the biggest non-syndromic deafness family in the world. In this family, deafness is maternally inherited. After establishing immortal lymphoblastoid cell lines of the family by EB virus, we analysed 17 lymphoblastoid cell lines derived, respectively, from symptomatic, asymptomatic and controll members of the family. Compared with control members, symptomatic and asymptomatic members both exhibited significant decreases in the rate of growth as well as in the rates of mitochondrial protein synthesis. But the extent of decreases is different and the severity of mitochondrial defect is related with its clinical phenotype. These results supported that the nuclear factor involves in the phenotypic manifestation of the non-syndromic deafness associated with the A1555G mutation.

  6. Genome duplication and mutations in ACE2 cause multicellular, fast-sedimenting phenotypes in evolved Saccharomyces cerevisiae

    PubMed Central

    Oud, Bart; Guadalupe-Medina, Victor; Nijkamp, Jurgen F.; de Ridder, Dick; Pronk, Jack T.; van Maris, Antonius J. A.; Daran, Jean-Marc

    2013-01-01

    Laboratory evolution of the yeast Saccharomyces cerevisiae in bioreactor batch cultures yielded variants that grow as multicellular, fast-sedimenting clusters. Knowledge of the molecular basis of this phenomenon may contribute to the understanding of natural evolution of multicellularity and to manipulating cell sedimentation in laboratory and industrial applications of S. cerevisiae. Multicellular, fast-sedimenting lineages obtained from a haploid S. cerevisiae strain in two independent evolution experiments were analyzed by whole genome resequencing. The two evolved cell lines showed different frameshift mutations in a stretch of eight adenosines in ACE2, which encodes a transcriptional regulator involved in cell cycle control and mother-daughter cell separation. Introduction of the two ace2 mutant alleles into the haploid parental strain led to slow-sedimenting cell clusters that consisted of just a few cells, thus representing only a partial reconstruction of the evolved phenotype. In addition to single-nucleotide mutations, a whole-genome duplication event had occurred in both evolved multicellular strains. Construction of a diploid reference strain with two mutant ace2 alleles led to complete reconstruction of the multicellular-fast sedimenting phenotype. This study shows that whole-genome duplication and a frameshift mutation in ACE2 are sufficient to generate a fast-sedimenting, multicellular phenotype in S. cerevisiae. The nature of the ace2 mutations and their occurrence in two independent evolution experiments encompassing fewer than 500 generations of selective growth suggest that switching between unicellular and multicellular phenotypes may be relevant for competitiveness of S. cerevisiae in natural environments. PMID:24145419

  7. Behavioral phenotypic properties of a natural occurring rat model of congenital stationary night blindness with Cacna1f mutation.

    PubMed

    An, Jing; Wang, Li; Guo, Qun; Li, Li; Xia, Feng; Zhang, Zuoming

    2012-09-01

    Cacna1f gene mutation could lead to incomplete congenital stationary night blindness (iCSNB) disease. The CSNB-like phenotype rat is a spontaneous rat model caused by Cacna1f gene mutation. The present study explored the phenotypic properties of behavior performance in CSNB rats further. The vision-related behaviors of CSNB rats were assessed with a Morris water maze (MWM), passive avoidance tests, and open-field test. Motor ability was evaluated with a rotarod test and a wire hang test, and mechanical pain and thermalgia were used to evaluate sensory system function. Electroretinograms (ERGs) were recorded to evaluate the function of the retina. The vision-related results showed that longer latencies of escape and reduced probe trial in MWM for CSNB rats. There were more errors in avoidance test; CSNB rats were more active in the open field and presented a different pattern of exploration. The locomotor-related behaviors showed shorter falling latencies in the rotarod test and shorter gripping time in CSNB rats. And mechanical thresholds of pain increased in CSNB rats. The ERGs indicated that both the amplitude and latency of rod and cone systems were impaired in the CSNB rats. In summary, Cacna1f gene mutation changed the performance of various behaviors in the CSNB rat aside from vision-related phenotype. Cacna1f gene might play a role in a wide range of responses in the organism. These results confirm the importance of a comprehensive profile for understanding the behavior phenotype of Cacna1f gene mutation in CSNB rat.

  8. Biallelic Mutations in TMEM126B Cause Severe Complex I Deficiency with a Variable Clinical Phenotype.

    PubMed

    Alston, Charlotte L; Compton, Alison G; Formosa, Luke E; Strecker, Valentina; Oláhová, Monika; Haack, Tobias B; Smet, Joél; Stouffs, Katrien; Diakumis, Peter; Ciara, Elżbieta; Cassiman, David; Romain, Nadine; Yarham, John W; He, Langping; De Paepe, Boel; Vanlander, Arnaud V; Seneca, Sara; Feichtinger, René G; Płoski, Rafal; Rokicki, Dariusz; Pronicka, Ewa; Haller, Ronald G; Van Hove, Johan L K; Bahlo, Melanie; Mayr, Johannes A; Van Coster, Rudy; Prokisch, Holger; Wittig, Ilka; Ryan, Michael T; Thorburn, David R; Taylor, Robert W

    2016-07-07

    Complex I deficiency is the most common biochemical phenotype observed in individuals with mitochondrial disease. With 44 structural subunits and over 10 assembly factors, it is unsurprising that complex I deficiency is associated with clinical and genetic heterogeneity. Massively parallel sequencing (MPS) technologies including custom, targeted gene panels or unbiased whole-exome sequencing (WES) are hugely powerful in identifying the underlying genetic defect in a clinical diagnostic setting, yet many individuals remain without a genetic diagnosis. These individuals might harbor mutations in poorly understood or uncharacterized genes, and their diagnosis relies upon characterization of these orphan genes. Complexome profiling recently identified TMEM126B as a component of the mitochondrial complex I assembly complex alongside proteins ACAD9, ECSIT, NDUFAF1, and TIMMDC1. Here, we describe the clinical, biochemical, and molecular findings in six cases of mitochondrial disease from four unrelated families affected by biallelic (c.635G>T [p.Gly212Val] and/or c.401delA [p.Asn134Ilefs(∗)2]) TMEM126B variants. We provide functional evidence to support the pathogenicity of these TMEM126B variants, including evidence of founder effects for both variants, and establish defects within this gene as a cause of complex I deficiency in association with either pure myopathy in adulthood or, in one individual, a severe multisystem presentation (chronic renal failure and cardiomyopathy) in infancy. Functional experimentation including viral rescue and complexome profiling of subject cell lines has confirmed TMEM126B as the tenth complex I assembly factor associated with human disease and validates the importance of both genome-wide sequencing and proteomic approaches in characterizing disease-associated genes whose physiological roles have been previously undetermined.

  9. The Ames dwarf mutation attenuates Alzheimer's disease phenotype of APP/PS1 mice.

    PubMed

    Puig, Kendra L; Kulas, Joshua A; Franklin, Whitney; Rakoczy, Sharlene G; Taglialatela, Giulio; Brown-Borg, Holly M; Combs, Colin K

    2016-04-01

    APP/PS1 double transgenic mice expressing human mutant amyloid precursor protein (APP) and presenilin-1 (PS1) demonstrate robust brain amyloid beta (Aβ) peptide containing plaque deposition, increased markers of oxidative stress, behavioral dysfunction, and proinflammatory gliosis. On the other hand, lack of growth hormone, prolactin, and thyroid-stimulating hormone due to a recessive mutation in the Prop 1 gene (Prop1df) in Ames dwarf mice results in a phenotype characterized by potentiated antioxidant mechanisms, improved learning and memory, and significantly increased longevity in homozygous mice. Based on this, we hypothesized that a similar hormone deficiency might attenuate disease changes in the brains of APP/PS1 mice. To test this idea, APP/PS1 mice were crossed to the Ames dwarf mouse line. APP/PS1, wild-type, df/+, df/df, df/+/APP/PS1, and df/df/APP/PS1 mice were compared at 6 months of age through behavioral testing and assessing amyloid burden, reactive gliosis, and brain cytokine levels. df/df mice demonstrated lower brain growth hormone and insulin-like growth factor 1 concentrations. This correlated with decreased astrogliosis and microgliosis in the df/df/APP/PS1 mice and, surprisingly, reduced Aβ plaque deposition and Aβ 1-40 and Aβ 1-42 concentrations. The df/df/APP/PS1 mice also demonstrated significantly elevated brain levels of multiple cytokines in spite of the attenuated gliosis. These data indicate that the df/df/APP/PS1 line is a unique resource in which to study aging and resistance to disease and suggest that the affected pituitary hormones may have a role in regulating disease progression.

  10. Targeted mutations in myostatin by zinc-finger nucleases result in double-muscled phenotype in Meishan pigs.

    PubMed

    Qian, Lili; Tang, Maoxue; Yang, Jinzeng; Wang, Qingqing; Cai, Chunbo; Jiang, Shengwang; Li, Hegang; Jiang, Ke; Gao, Pengfei; Ma, Dezun; Chen, Yaoxing; An, Xiaorong; Li, Kui; Cui, Wentao

    2015-09-24

    Myostatin (MSTN) is a dominant inhibitor of skeletal muscle development and growth. Mutations in MSTN gene can lead to muscle hypertrophy or double-muscled (DM) phenotype in cattle, sheep, dog and human. However, there has not been reported significant muscle phenotypes in pigs in association with MSTN mutations. Pigs are an important source of meat production, as well as serve as a preferred animal model for the studies of human disease. To study the impacts of MSTN mutations on skeletal muscle growth in pigs, we generated MSTN-mutant Meishan pigs with no marker gene via zinc finger nucleases (ZFN) technology. The MSTN-mutant pigs developed and grew normally, had increased muscle mass with decreased fat accumulation compared with wild type pigs, and homozygote MSTN mutant (MSTN(-/-)) pigs had apparent DM phenotype, and individual muscle mass increased by 100% over their wild-type controls (MSTN(+/+)) at eight months of age as a result of myofiber hyperplasia. Interestingly, 20% MSTN-mutant pigs had one extra thoracic vertebra. The MSTN-mutant pigs will not only offer a way of fast genetic improvement of lean meat for local fat-type indigenous pig breeds, but also serve as an important large animal model for biomedical studies of musculoskeletal formation, development and diseases.

  11. Targeted mutations in myostatin by zinc-finger nucleases result in double-muscled phenotype in Meishan pigs

    PubMed Central

    Qian, Lili; Tang, Maoxue; Yang, Jinzeng; Wang, Qingqing; Cai, Chunbo; Jiang, Shengwang; Li, Hegang; Jiang, Ke; Gao, Pengfei; Ma, Dezun; Chen, Yaoxing; An, Xiaorong; Li, Kui; Cui, Wentao

    2015-01-01

    Myostatin (MSTN) is a dominant inhibitor of skeletal muscle development and growth. Mutations in MSTN gene can lead to muscle hypertrophy or double-muscled (DM) phenotype in cattle, sheep, dog and human. However, there has not been reported significant muscle phenotypes in pigs in association with MSTN mutations. Pigs are an important source of meat production, as well as serve as a preferred animal model for the studies of human disease. To study the impacts of MSTN mutations on skeletal muscle growth in pigs, we generated MSTN-mutant Meishan pigs with no marker gene via zinc finger nucleases (ZFN) technology. The MSTN-mutant pigs developed and grew normally, had increased muscle mass with decreased fat accumulation compared with wild type pigs, and homozygote MSTN mutant (MSTN−/−) pigs had apparent DM phenotype, and individual muscle mass increased by 100% over their wild-type controls (MSTN+/+) at eight months of age as a result of myofiber hyperplasia. Interestingly, 20% MSTN-mutant pigs had one extra thoracic vertebra. The MSTN-mutant pigs will not only offer a way of fast genetic improvement of lean meat for local fat-type indigenous pig breeds, but also serve as an important large animal model for biomedical studies of musculoskeletal formation, development and diseases. PMID:26400270

  12. Deciphering the mechanism of Q145H SFTPC mutation unmasks a splicing defect and explains the severity of the phenotype.

    PubMed

    Delestrain, Céline; Simon, Stéphanie; Aissat, Abdel; Medina, Rachel; Decrouy, Xavier; Nattes, Elodie; Tarze, Agathe; Costes, Bruno; Fanen, Pascale; Epaud, Ralph

    2017-03-15

    Mutations in the gene encoding surfactant protein C (SFTPC) have led to a broad range of phenotypes from neonatal respiratory distress syndrome to adult interstitial lung disease. We previously identified the c.435G>C variant in the SFTPC gene associated with fatal neonatal respiratory distress syndrome in an infant girl. Although this variation is predicted to change glutamine (Q) at position 145 to histidine (H), its position at the last base of exon 4 and the severity of the phenotype suggested that it might also induce a splicing defect. To test this hypothesis, we used hybrid minigene, biochemical and immunofluorescence tools to decipher the molecular mechanism of the mutation. Immunoblotting and confocal imaging showed similar maturation and localization of wild-type and Q145H proteins, but hybrid minigene analysis showed complete exon 4 skipping. Since the exon 4 is in frame, a putative truncated protein of 160 amino acids would be produced. We have shown that this truncated protein had an altered intracellular trafficking and maturation. The c.435G>C mutation is deleterious not because of its amino acid substitution but because of its subsequent splicing defect and should be referred to as r.325_435del and p.Leu109_Gln145del. The absence of residual full-length transcripts fully explained the severity of the phenotype we observed in the infant.European Journal of Human Genetics advance online publication, 15 March 2017; doi:10.1038/ejhg.2017.36.

  13. Mutational analysis and genotype/phenotype correlation in Turkish Charcot-Marie-Tooth Type 1 and HNPP patients.

    PubMed

    Bissar-Tadmouri, N; Parman, Y; Boutrand, L; Deymeer, F; Serdaroglu, P; Vandenberghe, A; Battaloglu, E

    2000-11-01

    The major Charcot- Marie-Tooth Type 1 (CMT1) locus, CMT1A, and Hereditary neuropathy with liability to pressure palsies (HNPP) cosegregate with a 1.5-Mb duplication and a 1.5-Mb deletion, respectively, in band 17p11.2. Point mutations in peripheral myelin gene 22 (PMP22), myelin protein zero (MPZ), and connexin 32 (Cx32) have been reported in CMT1, and in PMP22 in HNPP patients without deletion. We have screened 54 CMT1 patients, of variable clinical severity, and 25 HNPP patients from Turkey, with no duplication or deletion, for mutations in the PMP22 and Cx32 genes. A novel frameshift mutation affecting the second extracellular domain of PMP22 was found in an HNPP patient, while a point mutation in the second transmembrane domain of the protein was detected in a CMT1 patient. Two point mutations affecting different domains of Cx32 were identified in two CMTX patients. Another patient was found to carry a polymorphism in a non-conserved codon of the Cx32 gene. The clinical phenotypes of the patients correlate well with the effect of the mutation on the protein.

  14. SOS1 mutations in Noonan syndrome: molecular spectrum, structural insights on pathogenic effects, and genotype-phenotype correlations.

    PubMed

    Lepri, Francesca; De Luca, Alessandro; Stella, Lorenzo; Rossi, Cesare; Baldassarre, Giuseppina; Pantaleoni, Francesca; Cordeddu, Viviana; Williams, Bradley J; Dentici, Maria L; Caputo, Viviana; Venanzi, Serenella; Bonaguro, Michela; Kavamura, Ines; Faienza, Maria F; Pilotta, Alba; Stanzial, Franco; Faravelli, Francesca; Gabrielli, Orazio; Marino, Bruno; Neri, Giovanni; Silengo, Margherita Cirillo; Ferrero, Giovanni B; Torrrente, Isabella; Selicorni, Angelo; Mazzanti, Laura; Digilio, Maria C; Zampino, Giuseppe; Dallapiccola, Bruno; Gelb, Bruce D; Tartaglia, Marco

    2011-07-01

    Noonan syndrome (NS) is among the most common nonchromosomal disorders affecting development and growth. NS is caused by aberrant RAS-MAPK signaling and is genetically heterogeneous, which explains, in part, the marked clinical variability documented for this Mendelian trait. Recently, we and others identified SOS1 as a major gene underlying NS. Here, we explored further the spectrum of SOS1 mutations and their associated phenotypic features. Mutation scanning of the entire SOS1 coding sequence allowed the identification of 33 different variants deemed to be of pathological significance, including 16 novel missense changes and in-frame indels. Various mutation clusters destabilizing or altering orientation of regions of the protein predicted to contribute structurally to the maintenance of autoinhibition were identified. Two previously unappreciated clusters predicted to enhance SOS1's recruitment to the plasma membrane, thus promoting a spatial reorientation of domains contributing to inhibition, were also recognized. Genotype-phenotype analysis confirmed our previous observations, establishing a high frequency of ectodermal anomalies and a low prevalence of cognitive impairment and reduced growth. Finally, mutation analysis performed on cohorts of individuals with nonsyndromic pulmonic stenosis, atrial septal defects, and ventricular septal defects excluded a major contribution of germline SOS1 lesions to the isolated occurrence of these cardiac anomalies.

  15. Differential secretion of the mutated protein is a major component affecting phenotypic severity in CRLF1-associated disorders

    PubMed Central

    Herholz, Jana; Meloni, Alessandra; Marongiu, Mara; Chiappe, Francesca; Deiana, Manila; Herrero, Carmen Roche; Zampino, Giuseppe; Hamamy, Hanan; Zalloum, Yusra; Waaler, Per Erik; Crisponi, Giangiorgio; Crisponi, Laura; Rutsch, Frank

    2011-01-01

    Crisponi syndrome (CS) and cold-induced sweating syndrome type 1 (CISS1) are disorders caused by mutations in CRLF1. The two syndromes share clinical characteristics, such as dysmorphic features, muscle contractions, scoliosis and cold-induced sweating, with CS patients showing a severe clinical course in infancy involving hyperthermia, associated with death in most cases in the first years of life. To evaluate a potential genotype/phenotype correlation and whether CS and CISS1 represent two allelic diseases or manifestations at different ages of the same disorder, we carried out a detailed clinical analysis of 19 patients carrying mutations in CRLF1. We studied the functional significance of the mutations found in CRLF1, providing evidence that phenotypic severity of the two disorders mainly depends on altered kinetics of secretion of the mutated CRLF1 protein. On the basis of these findings, we believe that the two syndromes, CS and CISS1, represent manifestations of the same disorder, with different degrees of severity. We suggest renaming the two genetic entities CS and CISS1 with the broader term of Sohar–Crisponi syndrome. PMID:21326283

  16. p.Pro4Arg mutation in LMNA gene: a new atypical progeria phenotype without metabolism abnormalities.

    PubMed

    Guo, Hong; Luo, Na; Hao, Fei; Bai, Yun

    2014-08-01

    Hutchinson-Gilford progeria syndrome (HGPS) is a typical presenile disorder, with mutation in the LMNA gene. Besides HGPS, mutations in LMNA gene have also been reported in atypical progeroid syndrome (APS). The objective of the study was to investigate the phenotype and molecular basis of APS in a Chinese family. LMNA gene mutations were also reviewed to identify the phenotypic and pathogenic differences among APS. Two siblings in a non-consanguineous Chinese family with atypical progeria were reported. The clinical features were observed, including presenile manifestations such as bird-like facial appearance, generalized lipodystrophy involving the extremities and mottled hyperpigmentation on the trunk and extremities. A heterozygous mutation c.11C>G (p.Pro4Arg) of the LMNA gene was detected in the two patients. 28 different variants of the LMNA gene have been reported in APS families, spreading over almost all the 12 exons of the LMNA gene with some hot-spot regions. This is the first detailed description of an APS family without metabolism abnormalities. APS patients share most of the clinical features, but there may be some distinct features in different ethnic groups.

  17. A novel type II collagen gene mutation in a family with spondyloepiphyseal dysplasia and extensive intrafamilial phenotypic diversity

    PubMed Central

    Nakashima, Yasuharu; Sakamoto, Yuma; Nishimura, Gen; Ikegawa, Shiro; Iwamoto, Yukihide

    2016-01-01

    The purpose of this study was to describe a family with spondyloepiphyseal dysplasia caused by a novel type II collagen gene (COL2A1) mutation and the family’s phenotypic diversity. Clinical and radiographic examinations of skeletal dysplasia were conducted on seven affected family members across two generations. The entire coding region of COL2A1, including the flanking intron regions, was analyzed with PCR and direct sequencing. The stature of the subjects ranged from extremely short to within normal height range. Hip deformity and advanced osteoarthritis were noted in all the subjects, ranging from severe coxa plana to mild acetabular dysplasia. Atlantoaxial subluxation combined with a hypoplastic odontoid process was found in three of the subjects. Various degrees of platyspondyly were confirmed in all subjects. Genetically, a novel COL2A1 mutation (c.1349G>C, p.Gly450Ala) was identified in all the affected family members; however, it was not present in the one unaffected family member tested. We described a family with spondyloepiphyseal dysplasia and a novel COL2A1 mutation (c.1349G>C, p.Gly450Ala). Phenotypes were diverse even among individuals with the same mutation and within the same family. PMID:27274858

  18. Amelogenesis Imperfecta Due to a Mutation of the Enamelin Gene: Clinical Case With Genotype-phenotype Correlations

    PubMed Central

    Lindemeyer, Rochelle G.; Gibson, Carolyn W.; Wright, Timothy J.

    2010-01-01

    The major protein components of the enamel matrix include the most abundant amelogenin proteins as well as less plentiful proteins such as enamelin and ameloblastin. The enamel defect in amelogenesis imperfecta (AI) generally results in enamel that is too thin (hypoplastic) or too soft (hypocalcification or hypomaturation). Previous reports indicate that mutations in the human enamelin gene (ENAM) cause hypoplastic AI through autosomaldominant inheritance patterns and patients may also exhibit an anterior open bite. Although crown resorption of unerupted teeth occurs more frequently in AI patients, this finding has not been previously associated with known ENAM mutations. The purpose of this article was to report the genotype-phenotype correlations for a 9-year, 11-month-old boy with a homozygous ENAM mutation (c.1258_1259insAG). PMID:20298654

  19. Recurrent mutation in CDMP1 in a family with Grebe chondrodysplasia: broadening the phenotypic manifestation of syndrome in Pakistani population

    PubMed Central

    Mumtaz, Sara; Riaz, Hafiza Fizzah; Touseef, Mohammad; Basit, Sulman; Haque, Muhammad Faiyaz Ul; Malik, Sajid

    2015-01-01

    Grebe syndrome (OMIM-200700) is a very rare type of acromesomelic dysplasia with autosomal recessive inheritance. We studied a Pakistani family with two affected individuals having typical features of Grebe chondrodysplasia. Patients were observed with short and deformed limbs having a proximo-distal gradient of severity. Hind-limbs were more severely affected than fore-limbs. Digits on autopods were very short and nonfunctional. Index subject also had nearsightedness. However, symptoms in the craniofacial and axial skeleton were minimal. Genetic analysis revealed four base pair insertion mutation (c.1114insGAGT) in gene coding cartilage-derived morphogenetic protein-1 (CDMP1). This mutation was predicted to cause premature stop codon. The clinical presentation in this study broadens the range of phenotypes associated with CDMP1 mutation in Pakistani population. PMID:26870132

  20. Molecular structure of three mutations at the maize sugary1 locus and their allele-specific phenotypic effects.

    PubMed

    Dinges, J R; Colleoni, C; Myers, A M; James, M G

    2001-03-01

    Starch production in all plants examined is altered by mutations of isoamylase-type starch-debranching enzymes (DBE), although how these proteins affect glucan polymer assembly is not understood. Various allelic mutations in the maize (Zea mays) gene sugary1 (su1), which codes for an isoamylase-type DBE, condition distinct kernel phenotypes. This study characterized the recessive mutations su1-Ref, su1-R4582::Mu1, and su1-st, regarding their molecular basis, chemical phenotypes, and effects on starch metabolizing enzymes. The su1-Ref allele results in two specific amino acid substitutions without affecting the Su1 mRNA level. The su1-R4582::Mu1 mutation is a null allele that abolishes transcript accumulation. The su1-st mutation results from insertion of a novel transposon-like sequence, designated Toad, which causes alternative pre-mRNA splicing. Three su1-st mutant transcripts are produced, one that is nonfunctional and two that code for modified SU1 polypeptides. The su1-st mutation is dominant to the null allele su1-R4582::Mu1, but recessive to su1-Ref, suggestive of complex effects involving quaternary structure of the SU1 enzyme. All three su1- alleles severely reduce or eliminate isoamylase-type DBE activity, although su1-st kernels accumulate less phytoglycogen and Suc than su1-Ref or su1-R4582::Mu1 mutants. The chain length distribution of residual amylopectin is significantly altered by su1-Ref and su1-R4582::Mu1, whereas su1-st has modest effects. These results, together with su1 allele-specific effects on other starch- metabolizing enzymes detected in zymograms, suggest that total DBE catalytic activity is the not the sole determinant of Su1 function and that specific interactions between SU1 and other components of the starch biosynthetic system are required.

  1. Molecular Structure of Three Mutations at the Maize sugary1 Locus and Their Allele-Specific Phenotypic Effects1

    PubMed Central

    Dinges, Jason R.; Colleoni, Christophe; Myers, Alan M.; James, Martha G.

    2001-01-01

    Starch production in all plants examined is altered by mutations of isoamylase-type starch-debranching enzymes (DBE), although how these proteins affect glucan polymer assembly is not understood. Various allelic mutations in the maize (Zea mays) gene sugary1 (su1), which codes for an isoamylase-type DBE, condition distinct kernel phenotypes. This study characterized the recessive mutations su1-Ref, su1-R4582::Mu1, and su1-st, regarding their molecular basis, chemical phenotypes, and effects on starch metabolizing enzymes. The su1-Ref allele results in two specific amino acid substitutions without affecting the Su1 mRNA level. The su1-R4582::Mu1 mutation is a null allele that abolishes transcript accumulation. The su1-st mutation results from insertion of a novel transposon-like sequence, designated Toad, which causes alternative pre-mRNA splicing. Three su1-st mutant transcripts are produced, one that is nonfunctional and two that code for modified SU1 polypeptides. The su1-st mutation is dominant to the null allele su1-R4582::Mu1, but recessive to su1-Ref, suggestive of complex effects involving quaternary structure of the SU1 enzyme. All three su1- alleles severely reduce or eliminate isoamylase-type DBE activity, although su1-st kernels accumulate less phytoglycogen and Suc than su1-Ref or su1-R4582::Mu1 mutants. The chain length distribution of residual amylopectin is significantly altered by su1-Ref and su1-R4582::Mu1, whereas su1-st has modest effects. These results, together with su1 allele-specific effects on other starch- metabolizing enzymes detected in zymograms, suggest that total DBE catalytic activity is the not the sole determinant of Su1 function and that specific interactions between SU1 and other components of the starch biosynthetic system are required. PMID:11244120

  2. CARD15/NOD2 Mutational Analysis and Genotype-Phenotype Correlation in 612 Patients with Inflammatory Bowel Disease

    PubMed Central

    Lesage, Suzanne; Zouali, Habib; Cézard, Jean-Pierre; Colombel, Jean-Frédéric; Belaiche, Jacques; Almer, Sven; Tysk, Curt; O’Morain, Colm; Gassull, Miquel; Binder, Vibeke; Finkel, Yigael; Modigliani, Robert; Gower-Rousseau, Corinne; Macry, Jeanne; Merlin, Françoise; Chamaillard, Mathias; Jannot, Anne-Sophie; Thomas, Gilles; Hugot, Jean-Pierre

    2002-01-01

    CARD15/NOD2 encodes a protein involved in bacterial recognition by monocytes. Mutations in CARD15 have recently been found in patients with Crohn disease (CD), a chronic inflammatory condition of the digestive tract. Here, we report the mutational analyses of CARD15 in 453 patients with CD, including 166 sporadic and 287 familial cases, 159 patients with ulcerative colitis (UC), and 103 healthy control subjects. Of 67 sequence variations identified, 9 had an allele frequency >5% in patients with CD. Six of them were considered to be polymorphisms, and three (R702W, G908R, and 1007fs) were confirmed to be independently associated with susceptibility to CD. Also considered as potential disease-causing mutations (DCMs) were 27 rare additional mutations. The three main variants (R702W, G908R, and 1007fs) represented 32%, 18%, and 31%, respectively, of the total CD mutations, whereas the total of the 27 rare mutations represented 19% of DCMs. Altogether, 93% of the mutations were located in the distal third of the gene. No mutations were found to be associated with UC. In contrast, 50% of patients with CD carried at least one DCM, including 17% who had a double mutation. This observation confirmed the gene-dosage effect in CD. The patients with double-dose mutations were characterized by a younger age at onset (16.9 years vs. 19.8 years; P=.01), a more frequent stricturing phenotype (53% vs. 28%; P=.00003; odds ratio 2.92), and a less frequent colonic involvement (43% vs. 62%; P=.003; odds ratio 0.44) than were seen in those patients who had no mutation. The severity of the disease and extraintestinal manifestations were not different for any of the CARD15 genotypes. The proportion of familial and sporadic cases and the proportion of patients with smoking habits were similar in the groups of patients with CD with or without mutation. These findings provide tools for a DNA-based test of susceptibility and for genetic counseling in inflammatory bowel disease. PMID

  3. Genotype-phenotype correlations for EPM2A mutations in Lafora's progressive myoclonus epilepsy: exon 1 mutations associate with an early-onset cognitive deficit subphenotype.

    PubMed

    Ganesh, Subramaniam; Delgado-Escueta, Antonio V; Suzuki, Toshimitsu; Francheschetti, Silvana; Riggio, Concetta; Avanzini, Giuiliano; Rabinowicz, Adrian; Bohlega, Saeed; Bailey, Julia; Alonso, Maria E; Rasmussen, Astrid; Thomson, Alfredo E; Ochoa, Adriana; Prado, Aurelio J; Medina, Marco T; Yamakawa, Kazuhiro

    2002-05-15

    Mutations in the EPM2A gene encoding a dual-specificity phosphatase (laforin) cause an autosomal recessive fatal disorder called Lafora's disease (LD) classically described as an adolescent-onset stimulus-sensitive myoclonus, epilepsy and neurologic deterioration. Here we related mutations in EPM2A with phenotypes of 22 patients (14 families) and identified two subsyndromes: (i) classical LD with adolescent-onset stimulus-sensitive grand mal, absence and myoclonic seizures followed by dementia and neurologic deterioration, and associated mainly with mutations in exon 4 (P = 0.0007); (ii) atypical LD with childhood-onset dyslexia and learning disorder followed by epilepsy and neurologic deterioration, and associated mainly with mutations in exon 1 (P = 0.0015). To understand the two subsyndromes better, we investigated the effect of five missense mutations in the carbohydrate-binding domain (CBD-4; coded by exon 1) and three missense mutations in the dual phosphatase domain (DSPD; coded by exons 3 and 4) on laforin's intracellular localization in HeLa cells. Expression of three mutant proteins (T194I, G279S and Y294N) in DSPD formed ubiquitin-positive cytoplasmic aggregates, suggesting that they were folding mutants set for degradation. In contrast, none of the three CBD-4 mutants showed cytoplasmic clumping. However, CBD-4 mutants W32G and R108C targeted both cytoplasm and nucleus, suggesting that laforin had diminished its usual affinity for polysomes. Our data, thus, represent the first report of a novel childhood syndrome for LD. Our results also provide clues for distinct roles for the CBD-4 and DSP domains of laforin in the etiology of two subsyndromes of LD.

  4. Oto-facial syndrome and esophageal atresia, intellectual disability and zygomatic anomalies - expanding the phenotypes associated with EFTUD2 mutations

    PubMed Central

    2013-01-01

    Background Mutations in EFTUD2 were proven to cause a very distinct mandibulofacial dysostosis type Guion-Almeida (MFDGA, OMIM #610536). Recently, gross deletions and mutations in EFTUD2 were determined to cause syndromic esophageal atresia (EA), as well. We set forth to find further conditions caused by mutations in the EFTUD2 gene (OMIM *603892). Methods and results We performed exome sequencing in two familial cases with clinical features overlapping with MFDGA and EA, but which were previously assumed to represent distinct entities, a syndrome with esophageal atresia, hypoplasia of zygomatic complex, microcephaly, cup-shaped ears, congenital heart defect, and intellectual disability in a mother and her two children [AJMG 143A(11):1135-1142, 2007] and a supposedly autosomal recessive oto-facial syndrome with midline malformations in two sisters [AJMG 132(4):398-401, 2005]. While the analysis of our exome data was in progress, a recent publication made EFTUD2 mutations highly likely in these families. This hypothesis could be confirmed with exome as well as with Sanger sequencing. Also, in three further sporadic patients, clinically overlapping to these two families, de novo mutations within EFTUD2 were identified by Sanger sequencing. Our clinical and molecular workup of the patients discloses a broad phenotypic spectrum, and describes for the first time an instance of germline mosaicism for an EFTUD2 mutation. Conclusions The clinical features of the eight patients described here further broaden the phenotypic spectrum caused by EFTUD2 mutations or deletions. We here show, that it not only includes mandibulofacial dysostosis type Guion-Almeida, which should be reclassified as an acrofacial dysostosis because of thumb anomalies (present in 12/35 or 34% of patients) and syndromic esophageal atresia [JMG 49(12). 737-746, 2012], but also the two new syndromes, namely oto-facial syndrome with midline malformations published by Mégarbané et al. [AJMG 132(4): 398

  5. Novel mutatıons and diverse clinical phenotypes in recombınase-activating gene 1 deficiency

    PubMed Central

    2012-01-01

    Background Severe combined immunodeficiency is within a heterogeneous group of inherited defects throughout the development of T- and/or B-lymphocytes. Mutations in recombinase-activating genes 1 or 2 (RAG1/2) represent approximately 10% of all SCID cases. RAG1/2 are essential for V(D)J rearrangement of the B- and T-cell receptors. Objectives The aim of this study was to review clinical, immunological and molecular findings of Turkish SCID patients with RAG1 defects and to draw attention to novel mutations, genotype-phenotype correlations and the high rate of BCG infections within this group. Methods Eleven patients (F/M: 6/5) were included. Molecular, immunological and clinical data were evaluated. Results Five patients were classified as T-B-NK + SCID, four patients as T + B-NK + SCID (two of these patients were diagnosed as classical Omenn syndrome) and two patients as T + B + NK + SCID with respect to clinical presentations and immunological data. Mean age of the whole study group, mean age at onset of symptoms and mean age at diagnosis were: 33.0 ± 42.8, 3.1 ± 3.3 and 10.4 ± 13.5 months, respectively. Consanguinity rate was 54%. Some novel mutations were found in RAG1 gene in addition to previously reported mutations. Genotype-phenotype correlation was not significantly apparent in most of the cases. BCG infection was observed in 36.4% of patients (two BCG-osis and two BCG-itis). Conclusion Epigenetic factors such as compound genetic defects, enviromental factors, and exposure to recurrent infections may modify phenotypical characteristics of RAG deficiencies. Inoculation of live vaccines such as BCG should be postponed until primary immunodeficiency disease is excluded with appropriate screening tests in suspected cases. PMID:22424479

  6. Mutations in MITF and PAX3 Cause “Splashed White” and Other White Spotting Phenotypes in Horses

    PubMed Central

    Blatter, Marlis; Brooks, Samantha A.; Burger, Dominik; Drögemüller, Cord; Gerber, Vincent; Henke, Diana; Janda, Jozef; Jude, Rony; Magdesian, K. Gary; Matthews, Jacqueline M.; Poncet, Pierre-André; Svansson, Vilhjálmur; Tozaki, Teruaki; Wilkinson-White, Lorna; Penedo, M. Cecilia T.; Rieder, Stefan; Leeb, Tosso

    2012-01-01

    During fetal development neural-crest-derived melanoblasts migrate across the entire body surface and differentiate into melanocytes, the pigment-producing cells. Alterations in this precisely regulated process can lead to white spotting patterns. White spotting patterns in horses are a complex trait with a large phenotypic variance ranging from minimal white markings up to completely white horses. The “splashed white” pattern is primarily characterized by an extremely large blaze, often accompanied by extended white markings at the distal limbs and blue eyes. Some, but not all, splashed white horses are deaf. We analyzed a Quarter Horse family segregating for the splashed white coat color. Genome-wide linkage analysis in 31 horses gave a positive LOD score of 1.6 in a region on chromosome 6 containing the PAX3 gene. However, the linkage data were not in agreement with a monogenic inheritance of a single fully penetrant mutation. We sequenced the PAX3 gene and identified a missense mutation in some, but not all, splashed white Quarter Horses. Genome-wide association analysis indicated a potential second signal near MITF. We therefore sequenced the MITF gene and found a 10 bp insertion in the melanocyte-specific promoter. The MITF promoter variant was present in some splashed white Quarter Horses from the studied family, but also in splashed white horses from other horse breeds. Finally, we identified two additional non-synonymous mutations in the MITF gene in unrelated horses with white spotting phenotypes. Thus, several independent mutations in MITF and PAX3 together with known variants in the EDNRB and KIT genes explain a large proportion of horses with the more extreme white spotting phenotypes. PMID:22511888

  7. A Korean family with KBG syndrome identified by ANKRD11 mutation, and phenotypic comparison of ANKRD11 mutation and 16q24.3 microdeletion.

    PubMed

    Kim, Hyo Jeong; Cho, Eunhae; Park, Jong Bum; Im, Woo Young; Kim, Hyon J

    2015-02-01

    KBG syndrome is a rare disease characterized by intellectual disability, typical craniofacial dysmorphism, macrodontia of the upper central incisors, short stature, and skeletal anomalies. Recently, ANKRD11 was identified as a gene that is responsible for the disease. In addition, microdeletion of 16q24.3, including ANKRD11, has been reported to result in the KBG syndrome phenotype. Herein, we discuss a Korean family with KBG syndrome, as identified by ANKRD11 gene mutation. The patients included a nine-month-old boy and his 21-month-old sister who failed to thrive and have delayed development. Chromosomal microarray was performed to identify the underlying genetic cause, but the results showed no abnormalities. However, the mother of the children was found to have features similar to her children. Therefore, we strongly suspected an autosomal-dominant inherited disease and performed whole exome sequencing. A mutation of ANKRD11 gene was found in all patients, and the frameshift variant c.2395-2398delAAAG was confirmed. Clinical manifestations of the patients were consistent with KBG syndrome. We reviewed all reported cases with confirmed ANKRD11 mutation or 16q24.3 microdeletion including ANKRD11. As a result, we conclude that severe short stature, intellectual disability, and macrodontia are the main characteristics in KBG syndrome related to ANKRD11 mutation.

  8. New mutations, genotype phenotype studies and manifesting carriers in giant axonal neuropathy

    PubMed Central

    Houlden, Henry; Groves, Mike; Miedzybrodzka, Zosia; Roper, Helen; Willis, Tracey; Winer, John; Cole, Gaynor; Reilly, Mary M

    2007-01-01

    Giant axonal neuropathy (GAN; MIM 256850) is a severe childhood onset autosomal recessive sensorimotor neuropathy affecting both the peripheral nerves and the central nervous system. Bomont and colleagues identified a novel ubiquitously expressed gene they named Gigaxonin on chromosome 16q24 as the cause of GAN in a number of families. We analysed five families with GAN for mutations in the Gigaxonin gene and mutations were found in four families; three families had homozygous mutations, one had two compound heterozygous mutations and one family had no mutation identified. All families had the typical clinical features, kinky hair and nerve biopsy. We report some unusual clinical features associated with GAN and Gigaxonin mutations as well as confirm the heterogeneity in GAN and the identification of two families with manifesting carriers. PMID:17578852

  9. Cooperation between phenotypic plasticity and genetic mutations can account for the cumulative selection in evolution

    PubMed Central

    Nishikawa, Ken; Kinjo, Akira R.

    2014-01-01

    We propose the cooperative model of phenotype-driven evolution, in which natural selection operates on a phenotype caused by both genetic and epigenetic factors. The conventional theory of evolutionary synthesis assumes that a phenotypic value (P) is the sum of genotypic value (G) and environmental deviation (E), P=G+E, where E is the fluctuations of the phenotype among individuals in the absence of environmental changes. In contrast, the cooperative model assumes that an evolution is triggered by an environmental change and individuals respond to the change by phenotypic plasticity (epigenetic changes). The phenotypic plasticity, while essentially qualitative, is denoted by a quantitative value F which is modeled as a normal random variable like E, but with a much larger variance. Thus, the fundamental equation of the cooperative model is given as P=G+F where F includes the effect of E. Computer simulations using a genetic algorithm demonstrated that the cooperative model realized much faster evolution than the evolutionary synthesis. This accelerated evolution was found to be due to the cumulative evolution made possible by a ratchet mechanism due to the epigenetic contribution to the phenotypic value. The cooperative model can well account for the phenomenon of genetic assimilation, which, in turn, suggests the mechanism of cumulative selection. The cooperative model may also serve as a theoretical basis to understand various ideas and phenomena of the phenotype-driven evolution such as genetic assimilation, the theory of facilitated phenotypic variation, and epigenetic inheritance over generations. PMID:27493504

  10. Congenital erythropoietic porphyria: mutation update and correlations between genotype and phenotype.

    PubMed

    Ged, C; Moreau-Gaudry, F; Richard, E; Robert-Richard, E; de Verneuil, H

    2009-02-16

    High quality genotype/phenotype analysis is a difficult issue in rare genetic diseases such as congenital erythropoietic porphyria (CEP) or Günther's disease, a heme biosynthesis defect due to uroporphyrinogen III synthase deficiency. The historical background and the main phenotypic features of the disease are depicted together with an update of published mutants and genotype/phenotype correlations. General rules concerning the prediction of disease severity are drawn as a guide for patient management and therapeutic choices. The phenotypic heterogeneity of the disease is presented in relation with a likely influence of modifying factors, either genetic or acquired.

  11. A novel mutation of CLCNKB in a Korean patient of mixed phenotype of Bartter-Gitelman syndrome

    PubMed Central

    Cho, Hee-Won; Lee, Sang Taek; Cheong, Hae Il

    2016-01-01

    Bartter syndrome (BS) is an inherited renal tubular disorder characterized by low or normal blood pressure, hypokalemic metabolic alkalosis, and hyperreninemic hyperaldosteronism. Type III BS is caused by loss-of-function mutations in CLCNKB encoding basolateral ClC-Kb. The clinical phenotype of patients with CLCNKB mutations has been known to be highly variable, and cases that are difficult to categorize as type III BS or other hereditary tubulopathies, such as Gitelman syndrome, have been rarely reported. We report a case of a 10-year-old Korean boy with atypical clinical findings caused by a novel CLCNKB mutation. The boy showed intermittent muscle cramps with laboratory findings of hypokalemia, severe hypomagnesemia, and nephrocalcinosis. These findings were not fully compatible with those observed in cases of BS or Gitelman syndrome. The CLCNKB mutation analysis revealed a heterozygous c.139G>A transition in exon 13 [p.Gly(GGG)465Glu(GAG)]. This change is not a known mutation; however, the clinical findings and in silico prediction results indicated that it is the underlying cause of his presentation. PMID:28018459

  12. CC2D2A mutations in Meckel and Joubert syndromes indicate a genotype-phenotype correlation

    PubMed Central

    Mougou-Zerelli, Soumaya; Thomas, Sophie; Szenker, Emmanuelle; Audollent, Sophie; Elkhartoufi, Nadia; Babarit, Candice; Romano, Stéphane; Salomon, Rémi; Amiel, Jeanne; Esculpavit, Chantal; Gonzales, Marie; Escudier, Estelle; Leheup, Bruno; Loget, Philippe; Odent, Sylvie; Roume, Joëlle; Gérard, Marion; Delezoide, Anne-Lise; Khung, Suonavy; Patrier, Sophie; Cordier, Marie-Pierre; Bouvier, Raymonde; Martinovic, Jéléna; Gubler, Marie-Claire; Boddaert, Nathalie; Munnich, Arnold; Encha-Razavi, Férechté; Valente, Enza Maria; Saad, Ali; Saunier, Sophie; Vekemans, Michel; Attié-Bitach, Tania

    2009-01-01

    The Meckel syndrome (MKS) is a lethal fetal disorder characterized by diffuse renal cystic dysplasia, polydactyly, a brain malformation that is usually occipital encephalocele and/or vermian agenesis, with intrahepatic biliary duct proliferation. Joubert syndrome (JBS) is a viable neurological disorder with a characteristic “molar tooth sign” (MTS) on axial images reflecting cerebellar vermian hypoplasia/dysplasia. Both conditions are classified as ciliopathies with an autosomal recessive mode of inheritance. Allelism of MS and JBS has been reported for TMEM67/MKS3, CEP290/MKS4, and RPGRIP1L/MKS5. Recently, one homozygous splice mutation with a founder effect was reported in the CC2D2A gene in Finnish fetuses with MKS, defining the 6th locus for MKS. Shortly thereafter, CC2D2A mutations were reported in JBS also. The analysis of the CC2D2A gene in our series of MKS fetuses, identified 14 novel truncating mutations in 11 cases. These results confirm the involvement of CC2D2A in MKS and reveal a major contribution of CC2D2A to the disease. We also identified three missense CC2D2A mutations in two JBS cases. Therefore and in accordance with the data reported regarding RPGRIP1L, our results indicate phenotype-genotype correlations, as missense and presumably hypomorphic mutations lead to JBS while all null alleles lead to MKS. PMID:19777577

  13. Identification of Variant-Specific Functions of PIK3CA by Rapid Phenotyping of Rare Mutations

    PubMed Central

    Dogruluk, Turgut; Tsang, Yiu Huen; Espitia, Maribel; Chen, Fengju; Chen, Tenghui; Chong, Zechen; Appadurai, Vivek; Dogruluk, Armel; Eterovic, Agna Karina; Bonnen, Penelope E.; Creighton, Chad J.; Chen, Ken; Mills, Gordon B.; Scott, Kenneth L.

    2015-01-01

    Large-scale sequencing efforts are uncovering the complexity of cancer genomes, which are comprised of causal “driver” mutations that promote tumor progression along with many more pathologically-neutral “passenger” events. The majority of mutations, both in known cancer drivers and uncharacterized genes, are generally of low occurrence, highlighting the need to functionally annotate the long tail of infrequent mutations present in heterogeneous cancers. Here we describe a mutation assessment pipeline enabled by high-throughput engineering of molecularly-barcoded gene variant expression clones identified by tumor sequencing. We first used this platform to functionally assess tail mutations observed in PIK3CA, which encodes the catalytic subunit alpha of the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) frequently mutated in cancer. Orthogonal screening for PIK3CA variant activity using in vitro and in vivo cell growth and transformation assays differentiated driver from passenger mutations, revealing that PIK3CA variant activity correlates imperfectly with its mutation frequency across breast cancer populations. While PIK3CA mutations with frequencies above 5% were significantly more oncogenic than wild-type in all assays, mutations occurring at 0.07 – 5.0% included those with and without oncogenic activities that ranged from weak to strong in at least one assay. Proteomic profiling coupled with therapeutic sensitivity assays on PIK3CA variant-expressing cell models revealed variant-specific activation of PI3K signaling as well as other pathways that include the MEK1/2 module of Mitogen-Activated Protein (MAP) Kinase pathway. Our data indicate that cancer treatments will need to increasingly consider the functional relevance of specific mutations in driver genes rather than considering all mutations in drivers as equivalent. PMID:26627007

  14. Fabry disease: thirty-five mutations in the alpha-galactosidase A gene in patients with classic and variant phenotypes.

    PubMed Central

    Eng, C. M.; Ashley, G. A.; Burgert, T. S.; Enriquez, A. L.; D'Souza, M.; Desnick, R. J.

    1997-01-01

    BACKGROUND: Fabry disease, an X-linked inborn error of glycosphingolipid catabolism, results from mutations in the alpha-galactosidase A (alpha-Gal A) gene located at Xq22.1. To determine the nature and frequency of the molecular lesions causing the classical and milder variant Fabry phenotypes and for precise carrier detection, the alpha-Gal A lesions in 42 unrelated Fabry hemizygotes were determined. MATERIALS AND METHODS: Genomic DNA was isolated from affected probands and their family members. The seven alpha-galactosidase A exons and flanking intronic sequences were PCR amplified and the nucleotide sequence was determined by solid-phase direct sequencing. RESULTS: Two patients with the mild cardiac phenotype had missense mutations, I9IT and F113L, respectively. In 38 classically affected patients, 33 new mutations were identified including 20 missense (MIT, A31V, H46R, Y86C, L89P, D92Y, C94Y, A97V, R100T, Y134S, G138R, A143T, S148R, G163V, D170V, C202Y, Y216D, N263S, W287C, and N298S), two nonsense (Q386X, W399X), one splice site mutation (IVS4 + 2T-->C), and eight small exonic insertions or deletions (304del1, 613del9, 777del1, 1057del2, 1074del2, 1077del1, 1212del3, and 1094ins1), which identified exon 7 as a region prone to gene rearrangements. In addition, two unique complex rearrangements consisting of contiguous small insertions and deletions were found in exons 1 and 2 causing L45R/H46S and L120X, respectively. CONCLUSIONS: These studies further define the heterogeneity of mutations causing Fabry disease, permit precise carrier identification and prenatal diagnosis in these families, and facilitate the identification of candidates for enzyme replacement therapy. Images FIG. 2 PMID:9100224

  15. Spectrum of FOXL2 gene mutations in blepharophimosis-ptosis-epicanthus inversus (BPES) families demonstrates a genotype--phenotype correlation.

    PubMed

    De Baere, E; Dixon, M J; Small, K W; Jabs, E W; Leroy, B P; Devriendt, K; Gillerot, Y; Mortier, G; Meire, F; Van Maldergem, L; Courtens, W; Hjalgrim, H; Huang, S; Liebaers, I; Van Regemorter, N; Touraine, P; Praphanphoj, V; Verloes, A; Udar, N; Yellore, V; Chalukya, M; Yelchits, S; De Paepe, A; Kuttenn, F; Fellous, M; Veitia, R; Messiaen, L

    2001-07-15

    Mutations in FOXL2, a forkhead transcription factor gene, have recently been shown to cause blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) types I and II, a rare genetic disorder. In BPES type I a complex eyelid malformation is associated with premature ovarian failure (POF), whereas in BPES type II the eyelid defect occurs as an isolated entity. In this study, we describe the identification of novel mutations in the FOXL2 gene in BPES types I and II families, in sporadic BPES patients, and in BPES families where the type could not be established. In 67% of the patients studied, we identified a mutation in the FOXL2 gene. In total, 21 mutations (17 of which are novel) and one microdeletion were identified. Thirteen of these FOXL2 mutations are unique. In this study, we demonstrate that there is a genotype--phenotype correlation for either types of BPES by the finding that mutations predicted to result in a truncated protein either lacking or containing the forkhead domain lead to BPES type I. In contrast, duplications within or downstream of the forkhead domain, and a frameshift downstream of them, all predicted to result in an extended protein, cause BPES type II. In addition, in 30 unrelated patients with isolated POF no causal mutations were identified in FOXL2. Our study provides further evidence that FOXL2 haploinsufficiency may cause BPES types I and II by the effect of a null allele and a hypomorphic allele, respectively. Furthermore, we propose that in a fraction of the BPES patients the genetic defect does not reside within the coding region of the FOXL2 gene and may be caused by a position effect.

  16. Biochemical evidence for a mitochondrial genetic modifier in the phenotypic manifestation of Leber's hereditary optic neuropathy-associated mitochondrial DNA mutation.

    PubMed

    Jiang, Pingping; Liang, Min; Zhang, Chaofan; Zhao, Xiaoxu; He, Qiufen; Cui, Limei; Liu, Xiaoling; Sun, Yan-Hong; Fu, Qun; Ji, Yanchun; Bai, Yidong; Huang, Taosheng; Guan, Min-Xin

    2016-08-15

    Leber's hereditary optic neuropathy (LHON) is the most common mitochondrial disease. Mitochondrial modifiers are proposed to modify the phenotypic expression of primary LHON-associated mitochondrial DNA (mtDNA) mutations. In this study, we demonstrated that the LHON susceptibility allele (m.14502T > C, p. 58I > V) in the ND6 gene modulated the phenotypic expression of primary LHON-associated m.11778G > A mutation. Twenty-two Han Chinese pedigrees carrying m.14502T > C and m.11778G > A mutations exhibited significantly higher penetrance of optic neuropathy than those carrying only m.11778G > A mutation. We performed functional assays using the cybrid cell models, generated by fusing mtDNA-less ρ(o) cells with enucleated cells from LHON patients carrying both m.11778G > A and m.14502T > C mutations, only m.14502T > C or m.11778G > A mutation and a control belonging to the same mtDNA haplogroup. These cybrids cell lines bearing m.14502T > C mutation exhibited mild effects on mitochondrial functions compared with those carrying only m.11778G > A mutation. However, more severe mitochondrial dysfunctions were observed in cell lines bearing both m.14502T > C and m.11778G > A mutations than those carrying only m.11778G > A or m.14502T > C mutation. In particular, the m.14502T > C mutation altered assemble of complex I, thereby aggravating the respiratory phenotypes associated with m.11778G > A mutation, resulted in a more defective complex I. Furthermore, more reductions in the levels of mitochondrial ATP and increasing production of reactive oxygen species were also observed in mutant cells bearing both m.14502T > C and m.11778G > A mutation than those carrying only 11778G > A mutation. Our findings provided new insights into the pathophysiology of LHON that were manifested by interaction between primary and secondary mtDNA mutations.

  17. Mutations in voltage-gated potassium channel KCNC3 cause degenerative and developmental central nervous system phenotypes.

    PubMed

    Waters, Michael F; Minassian, Natali A; Stevanin, Giovanni; Figueroa, Karla P; Bannister, John P A; Nolte, Dagmar; Mock, Allan F; Evidente, Virgilio Gerald H; Fee, Dominic B; Müller, Ulrich; Dürr, Alexandra; Brice, Alexis; Papazian, Diane M; Pulst, Stefan M

    2006-04-01

    Potassium channel mutations have been described in episodic neurological diseases. We report that K+ channel mutations cause disease phenotypes with neurodevelopmental and neurodegenerative features. In a Filipino adult-onset ataxia pedigree, the causative gene maps to 19q13, overlapping the SCA13 disease locus described in a French pedigree with childhood-onset ataxia and cognitive delay. This region contains KCNC3 (also known as Kv3.3), encoding a voltage-gated Shaw channel with enriched cerebellar expression. Sequencing revealed two missense mutations, both of which alter KCNC3 function in Xenopus laevis expression systems. KCNC3(R420H), located in the voltage-sensing domain, had no channel activity when expressed alone and had a dominant-negative effect when co-expressed with the wild-type channel. KCNC3(F448L) shifted the activation curve in the negative direction and slowed channel closing. Thus, KCNC3(R420H) and KCNC3(F448L) are expected to change the output characteristics of fast-spiking cerebellar neurons, in which KCNC channels confer capacity for high-frequency firing. Our results establish a role for KCNC3 in phenotypes ranging from developmental disorders to adult-onset neurodegeneration and suggest voltage-gated K+ channels as candidates for additional neurodegenerative diseases.

  18. The Arabidopsis minE mutation causes new plastid and FtsZ1 localization phenotypes in the leaf epidermis.

    PubMed

    Fujiwara, Makoto T; Kojo, Kei H; Kazama, Yusuke; Sasaki, Shun; Abe, Tomoko; Itoh, Ryuuichi D

    2015-01-01

    Plastids in the leaf epidermal cells of plants are regarded as immature chloroplasts that, like mesophyll chloroplasts, undergo binary fission. While mesophyll chloroplasts have generally been used to study plastid division, recent studies have suggested the presence of tissue- or plastid type-dependent regulation of plastid division. Here, we report the detailed morphology of plastids and their stromules, and the intraplastidic localization of the chloroplast division-related protein AtFtsZ1-1, in the leaf epidermis of an Arabidopsis mutant that harbors a mutation in the chloroplast division site determinant gene AtMinE1. In atminE1, the size and shape of epidermal plastids varied widely, which contrasts with the plastid phenotype observed in atminE1 mesophyll cells. In particular, atminE1 epidermal plastids occasionally displayed grape-like morphology, a novel phenotype induced by a plastid division mutation. Observation of an atminE1 transgenic line harboring an AtMinE1 promoter::AtMinE1-yellow fluorescent protein fusion gene confirmed the expression and plastidic localization of AtMinE1 in the leaf epidermis. Further examination revealed that constriction of plastids and stromules mediated by the FtsZ1 ring contributed to the plastid pleomorphism in the atminE1 epidermis. These results illustrate that a single plastid division mutation can have dramatic consequences for epidermal plastid morphology, thereby implying that plastid division and morphogenesis are differentially regulated in epidermal and mesophyll plastids.

  19. Neurological phenotype in Waardenburg syndrome type 4 correlates with novel SOX10 truncating mutations and expression in developing brain.

    PubMed Central

    Touraine, R L; Attié-Bitach, T; Manceau, E; Korsch, E; Sarda, P; Pingault, V; Encha-Razavi, F; Pelet, A; Augé, J; Nivelon-Chevallier, A; Holschneider, A M; Munnes, M; Doerfler, W; Goossens, M; Munnich, A; Vekemans, M; Lyonnet, S

    2000-01-01

    Waardenburg syndrome type 4 (WS4), also called Shah-Waardenburg syndrome, is a rare neurocristopathy that results from the absence of melanocytes and intrinsic ganglion cells of the terminal hindgut. WS4 is inherited as an autosomal recessive trait attributable to EDN3 or EDNRB mutations. It is inherited as an autosomal dominant condition when SOX10 mutations are involved. We report on three unrelated WS4 patients with growth retardation and an as-yet-unreported neurological phenotype with impairment of both the central and autonomous nervous systems and occasionally neonatal hypotonia and arthrogryposis. Each of the three patients was heterozygous for a SOX10 truncating mutation (Y313X in two patients and S251X [corrected] in one patient). The extended spectrum of the WS4 phenotype is relevant to the brain expression of SOX10 during human embryonic and fetal development. Indeed, the expression of SOX10 in human embryo was not restricted to neural-crest-derived cells but also involved fetal brain cells, most likely of glial origin. These data emphasize the important role of SOX10 in early development of both neural-crest-derived tissues, namely melanocytes, autonomic and enteric nervous systems, and glial cells of the central nervous system. PMID:10762540

  20. Novel mutation and three other sequence variants segregating with phenotype at keratoconus 13q32 susceptibility locus

    PubMed Central

    Czugala, Marta; Karolak, Justyna A; Nowak, Dorota M; Polakowski, Piotr; Pitarque, Jose; Molinari, Andrea; Rydzanicz, Malgorzata; Bejjani, Bassem A; Yue, Beatrice Y J T; Szaflik, Jacek P; Gajecka, Marzena

    2012-01-01

    Keratoconus (KTCN), a non-inflammatory corneal disorder characterized by stromal thinning, represents a major cause of corneal transplantations. Genetic and environmental factors have a role in the etiology of this complex disease. Previously reported linkage analysis revealed that chromosomal region 13q32 is likely to contain causative gene(s) for familial KTCN. Consequently, we have chosen eight positional candidate genes in this region: MBNL1, IPO5, FARP1, RNF113B, STK24, DOCK9, ZIC5 and ZIC2, and sequenced all of them in 51 individuals from Ecuadorian KTCN families and 105 matching controls. The mutation screening identified one mutation and three sequence variants showing 100% segregation under a dominant model with KTCN phenotype in one large Ecuadorian family. These substitutions were found in three different genes: c.2262A>C (p.Gln754His) and c.720+43A>G in DOCK9; c.2377-132A>C in IPO5 and c.1053+29G>C in STK24. PolyPhen analyses predicted that c.2262A>C (Gln754His) is possibly damaging for the protein function and structure. Our results suggest that c.2262A>C (p.Gln754His) mutation in DOCK9 may contribute to the KTCN phenotype in the large KTCN-014 family. PMID:22045297

  1. CEBPA-double-mutated acute myeloid leukemia displays a unique phenotypic profile: a reliable screening method and insight into biological features.

    PubMed

    Mannelli, Francesco; Ponziani, Vanessa; Bencini, Sara; Bonetti, Maria Ida; Benelli, Matteo; Cutini, Ilaria; Gianfaldoni, Giacomo; Scappini, Barbara; Pancani, Fabiana; Piccini, Matteo; Rondelli, Tommaso; Caporale, Roberto; Gelli, Anna Maria Grazia; Peruzzi, Benedetta; Chiarini, Marco; Borlenghi, Erika; Spinelli, Orietta; Giupponi, Damiano; Zanghì, Pamela; Bassan, Renato; Rambaldi, Alessandro; Rossi, Giuseppe; Bosi, Alberto

    2017-03-01

    Mutations in CCAAT/enhancer binding protein α (CEBPA) occur in 5-10% of cases of acute myeloid leukemia. CEBPA-double-mutated cases usually bear biallelic N- and C-terminal mutations and are associated with a favorable clinical outcome. Identification of CEBPA mutants is challenging because of the variety of mutations, intrinsic characteristics of the gene and technical issues. Several screening methods (fragment-length analysis, gene expression array) have been proposed especially for large-scale clinical use; although efficient, they are limited by specific concerns. We investigated the phenotypic profile of blast and maturing bone marrow cell compartments at diagnosis in 251 cases of acute myeloid leukemia. In this cohort, 16 (6.4%) patients had two CEBPA mutations, whereas ten (4.0%) had a single mutation. First, we highlighted that the CEBPA-double-mutated subset displays recurrent phenotypic abnormalities in all cell compartments. By mutational analysis after cell sorting, we demonstrated that this common phenotypic signature depends on CEBPA-double-mutated multi-lineage involvement. From a multidimensional study of phenotypic data, we developed a classifier including ten core and widely available parameters. The selected markers on blasts (CD34, CD117, CD7, CD15, CD65), neutrophil (SSC, CD64), monocytic (CD14, CD64) and erythroid (CD117) compartments were able to cluster CEBPA-double-mutated cases. In a validation set of 259 AML cases from three independent centers, our classifier showed excellent performance with 100% specificity and 100% sensitivity. We have, therefore, established a reliable screening method, based upon multidimensional analysis of widely available phenotypic parameters. This method provides early results and is suitable for large-scale detection of CEBPA-double-mutated status, allowing gene sequencing to be focused in selected cases.

  2. REEP1 Mutation Spectrum and Genotype/Phenotype Correlation in Hereditary Spastic Paraplegia Type 31

    ERIC Educational Resources Information Center

    Beetz, Christian; Schule, Rebecca; Deconinck, Tine; Tran-Viet, Khanh-Nhat; Zhu, Hui; Kremer, Berry P. H.; Frints, Suzanna G. M.; van Zelst-Stams, Wendy A. G.; Byrne, Paula; Otto, Susanne; Nygren, Anders O. H.; Baets, Jonathan; Smets, Katrien; Ceulemans, Berten; Dan, Bernard; Nagan, Narasimhan; Kassubek, Jan; Klimpe, Sven; Klopstock, Thomas; Stolze, Henning; Smeets, Hubert J. M.; Schrander-Stumpel, Constance T. R. M.; Hutchinson, Michael; van de Warrenburg, Bart P.; Braastad, Corey; Deufel, Thomas; Pericak-Vance, Margaret; Schols, Ludger; de Jonghe, Peter; Zuchner, Stephan

    2008-01-01

    Mutations in the receptor expression enhancing protein 1 (REEP1) have recently been reported to cause autosomal dominant hereditary spastic paraplegia (HSP) type SPG31. In a large collaborative effort, we screened a sample of 535 unrelated HSP patients for "REEP1" mutations and copy number variations. We identified 13 novel and 2 known "REEP1"…

  3. Identification of mutations from phenotype-driven ENU mutagenesis in mouse chromosome 7.

    PubMed

    Culiat, Cymbeline T; Klebig, Mitchell L; Liu, Zhaowei; Monroe, Heidi; Stanford, Beverly; Desai, Jayashree; Tandan, Samvit; Hughes, Lori; Kerley, Marilyn K; Carpenter, Donald A; Johnson, Dabney K; Rinchik, Eugene M; Li, Qingbo

    2005-08-01

    We have used the new high-throughput mutation-scanning technique temperature-gradient capillary electrophoresis (TGCE) for the identification of point mutations induced by N-ethyl-N-nitrosourea (ENU) in the mouse genome. TGCE detects the presence of heteroduplex molecules formed between a wild-type gene segment and the corresponding homologous segment containing an induced mutation or a naturally occurring single nucleotide polymorphism (SNP). Partially denatured heteroduplex molecules are resolved from homoduplexes by virtue of their differential mobilities during capillary electrophoresis conducted in a finely controlled temperature gradient. Simultaneous heteroduplex analysis of 96 amplicons ranging from 150 to 600 bp in size is achieved in approximately 45 min without the need for predetermining the melting profile of each fragment. Initially, we exploited known mouse mutations to develop TGCE protocols for analyzing unpurified PCR samples amplified from crude tail-DNA preparations. TGCE was then applied to the rapid identification of three new ENU-induced mutations recovered from regional mutagenesis screens of a segment of mouse Chromosome 7. Enzyme assays and quantitative reverse transcription-PCR (qRT-PCR) methods validated these new mutations. Our data demonstrate that rapid mutation scanning with TGCE, followed by sequence verification only of detected positives, is an efficient approach to the identification of point mutations in the mouse genome.

  4. Large deletion of the GJB6 gene in deaf patients heterozygous for the GJB2 gene mutation: genotypic and phenotypic analysis.

    PubMed

    Feldmann, Delphine; Denoyelle, Françoise; Chauvin, Pierre; Garabédian, Eréa-Noël; Couderc, Rémy; Odent, Sylvie; Joannard, Alain; Schmerber, Sébastien; Delobel, Bruno; Leman, Jacques; Journel, Hubert; Catros, Hélène; Le Maréchal, Cédric; Dollfus, Hélène; Eliot, Marie-Madeleine; Delaunoy, Jean-Pierre; David, Albert; Calais, Catherine; Drouin-Garraud, Valérie; Obstoy, Marie-Françoise; Bouccara, Didier; Sterkers, Olivier; Huy, Patrice Tran Ba; Goizet, Cyril; Duriez, Françoise; Fellmann, Florence; Hélias, Jocelyne; Vigneron, Jacqueline; Montaut, Bétina; Lewin, Patricia; Petit, Christine; Marlin, Sandrine

    2004-06-15

    Recent investigations identified a large deletion of the GJB6 gene in trans to a mutation of GJB2 in deaf patients. We looked for GJB2 mutations and GJB6 deletions in 255 French patients presenting with a phenotype compatible with DFNB1. 32% of the patients had biallelic GJB2 mutations and 6% were a heterozygous for a GJB2 mutation and a GJB6 deletion. Biallelic GJB2 mutations and combined GJB2/GJB6 anomalies were more frequent in profoundly deaf children. Based on these results, we are now assessing GJB6 deletion status in cases of prelingual hearing loss.

  5. Phenotypic patterns of desminopathy associated with three novel mutations in the desmin gene

    PubMed Central

    Olivé, Montse; Armstrong, Judith; Miralles, Francesc; Pou, Adolf; Fardeau, Michel; Gonzalez, Laura; Martínez, Francesca; Fischer, Dirk; Matos, Juan Antonio Martínez; Shatunov, Alexey; Goldfarb, Lev; Ferrer, Isidre

    2016-01-01

    Desminopathy represents a subgroup of myofibrillar myopathies caused by mutations in the desmin gene. Three novel disease-associated mutations in the desmin gene were identified in unrelated Spanish families affected by cardioskeletal myopathy. A selective pattern of muscle involvement, which differed from that observed in myofibrillar myopathy resulting from mutations in the myotilin gene, was observed in each of the three families with novel mutations and each of three desminopathy patients with known desmin mutations. Prominent joint retractions at the ankles and characteristic nasal speech were observed early in the course of illness. These findings suggest that muscle imaging in combination with routine clinical and pathological examination may be helpful in distinguishing desminopathy from other forms of myofibrillar myopathy and ordering appropriate molecular investigations. PMID:17418574

  6. Presence of rd8 mutation does not alter the ocular phenotype of late-onset retinal degeneration mouse model

    PubMed Central

    Sahu, Bhubanananda; Alapati, Akhila; Suk, John; Bartsch, Dirk-Uwe; Jablonski, Monica M.; Ayyagari, Radha

    2015-01-01

    -type and Ctrp5+/− mice with the rd8 mutation (Wtrd8/rd8 and Ctrp5+/−;rd8/rd8, respectively) revealed an integrated retinal architecture with well-defined outer segments/inner segments (OS/IS), outer nuclear layer (ONL), outer plexiform layer (OPL), and inner nuclear layer (INL). The presence of pseudorosette structures reported in the rd8 mice between the ONL and the INL in the ventral quadrant of the retina was not observed in all genotypes studied. Further, the external limiting membrane was continuous in the Ctrp5+/−;rd8/rd8 and Wtrd8/rd8 mice. Evaluation of the retinal phenotype revealed that the Ctrp5+/−;wt/wt mice developed characteristic L-ORD pathology including age-dependent accumulation of AF spots, development of sub-retinal, sub-RPE, and basal laminar deposits, and Bruch’s membrane abnormalities at older age, while these changes were not observed in the age-matched littermate WTwt/wt mice. Conclusions The Wtrd8/rd8 and Ctrp5+/−;rd8/rd8 mice raised on C57BL/6J did not develop early onset retinal changes that are characteristic of the rd8 phenotype, supporting the hypothesis that manifestation of rd8-associated pathology depends on the genetic background. The retinal pathology observed in mice with the Ctrp5+/−;wt/wt genotype is consistent with the L-ORD phenotype observed in patients and with the phenotype we described previously. The lack of rd8-associated retinal pathology in the Ctrp5+/−;wt/wt mouse model raised on the C57BL/6J background and the development of the L-ORD phenotype in these mice in the presence and absence of the rd8 mutation suggests that the pathology observed in the Ctrp5+/−;wt/wt mice is primarily associated with the S163R mutation in the Ctrp5 gene. PMID:25814825

  7. Somatic deleterious mutation rate in a woody plant: estimation from phenotypic data

    PubMed Central

    Bobiwash, K; Schultz, S T; Schoen, D J

    2013-01-01

    We conducted controlled crosses in populations of the long-lived clonal shrub, Vaccinium angustifolium (lowbush blueberry) to estimate inbreeding depression and mutation parameters associated with somatic deleterious mutation. Inbreeding depression level was high, with many plants failing to set fruit after self-pollination. We also compared fruit set from autogamous pollinations (pollen collected from within the same inflorescence) with fruit set from geitonogamous pollinations (pollen collected from the same plant but from inflorescences separated by several meters of branch growth). The difference between geitonogamous versus autogamous fitness within single plants is referred to as ‘autogamy depression' (AD). AD can be caused by somatic deleterious mutation. AD was significantly different from zero for fruit set. We developed a maximum-likelihood procedure to estimate somatic mutation parameters from AD, and applied it to geitonogamous and autogamous fruit set data from this experiment. We infer that, on average, approximately three sublethal, partially dominant somatic mutations exist within the crowns of the plants studied. We conclude that somatic mutation in this woody plant results in an overall genomic deleterious mutation rate that exceeds the rate measured to date for annual plants. Some implications of this result for evolutionary biology and agriculture are discussed. PMID:23778990

  8. Maternal Genetic Mutations as Gestational and Early Life Influences in Producing Psychiatric Disease-Like Phenotypes in Mice

    PubMed Central

    Gleason, Georgia; Zupan, Bojana; Toth, Miklos

    2011-01-01

    Risk factors for psychiatric disorders have traditionally been classified as genetic or environmental. Risk (candidate) genes, although typically possessing small effects, represent a clear starting point to elucidate downstream cellular/molecular pathways of disease. Environmental effects, especially during development, can also lead to altered behavior and increased risk for disease. An important environmental factor is the mother, demonstrated by the negative effects elicited by maternal gestational stress and altered maternal care. These maternal effects can also have a genetic basis (e.g., maternal genetic variability and mutations). The focus of this review is “maternal genotype effects” that influence the emotional development of the offspring resulting in life-long psychiatric disease-like phenotypes. We have recently found that genetic inactivation of the serotonin 1A receptor (5-HT1AR) and the fmr1 gene (encoding the fragile X mental retardation protein) in mouse dams results in psychiatric disease-like phenotypes in their genetically unaffected offspring. 5-HT1AR deficiency in dams results in anxiety and increased stress responsiveness in their offspring. Offspring of 5-HT1AR deficient dams display altered development of the hippocampus, which could be linked to their anxiety-like phenotype. Maternal inactivation of fmr1, like its inactivation in the offspring, results in a hyperactivity-like condition and is associated with receptor alterations in the striatum. These data indicate a high sensitivity of the offspring to maternal mutations and suggest that maternal genotype effects can increase the impact of genetic risk factors in a population by increasing the risk of the genetically normal offspring as well as by enhancing the effects of offspring mutations. PMID:21629836

  9. Claudin-19 Mutations and Clinical Phenotype in Spanish Patients with Familial Hypomagnesemia with Hypercalciuria and Nephrocalcinosis

    PubMed Central

    Claverie-Martín, Félix; García-Nieto, Víctor; Loris, Cesar; Ariceta, Gema; Nadal, Inmaculada; Espinosa, Laura; Fernández-Maseda, Ángeles; Antón-Gamero, Montserrat; Avila, África; Madrid, Álvaro; González-Acosta, Hilaria; Córdoba-Lanus, Elizabeth; Santos, Fernando; Gil-Calvo, Marta; Espino, Mar; García-Martinez, Elena; Sanchez, Ana; Muley, Rafael

    2013-01-01

    Familial hypomagnesemia with hypercalciuria and nephrocalcinosis is an autosomal recessive tubular disorder characterized by excessive renal magnesium and calcium excretion and chronic kidney failure. This rare disease is caused by mutations in the CLDN16 and CLDN19 genes. These genes encode the tight junction proteins claudin-16 and claudin-19, respectively, which regulate the paracellular ion reabsortion in the kidney. Patients with mutations in the CLDN19 gene also present severe visual impairment. Our goals in this study were to examine the clinical characteristics of a large cohort of Spanish patients with this disorder and to identify the disease causing mutations. We included a total of 31 patients belonging to 27 unrelated families and studied renal and ocular manifestations. We then analyzed by direct DNA sequencing the coding regions of CLDN16 and CLDN19 genes in these patients. Bioinformatic tools were used to predict the consequences of mutations. Clinical evaluation showed ocular defects in 87% of patients, including mainly myopia, nystagmus and macular colobomata. Twenty two percent of patients underwent renal transplantation and impaired renal function was observed in another 61% of patients. Results of the genetic analysis revealed CLDN19 mutations in all patients confirming the clinical diagnosis. The majority of patients exhibited the previously described p.G20D mutation. Haplotype analysis using three microsatellite markers showed a founder effect for this recurrent mutation in our cohort. We also identified four new pathogenic mutations in CLDN19, p.G122R, p.I41T, p.G75C and p.G75S. A strategy based on microsequencing was designed to facilitate the genetic diagnosis of this disease. Our data indicate that patients with CLDN19 mutations have a high risk of progression to chronic renal disease. PMID:23301036

  10. Novel TTC37 Mutations in a Patient with Immunodeficiency without Diarrhea: Extending the Phenotype of Trichohepatoenteric Syndrome.

    PubMed

    Rider, Nicholas L; Boisson, Bertrand; Jyonouchi, Soma; Hanson, Eric P; Rosenzweig, Sergio D; Cassanova, Jean-Laurent; Orange, Jordan S

    2015-01-01

    Unbiased genetic diagnosis has increasingly associated seemingly unrelated somatic and immunological phenotypes. We report a male infant who presented within the first year of life with physical growth impairment, feeding difficulties, hyperemesis without diarrhea, and abnormal hair findings suggestive of trichorrhexis nodosa. With advancing age, moderate global developmental delay, susceptibility to frequent viral illnesses, otitis media, and purulent conjunctivitis were identified. Because of the repeated infections, an immunological evaluation was pursued and identified impaired antibody memory responses following pneumococcal vaccine administration. Immunoglobulin replacement therapy and nutritional support were employed as mainstays of therapy. The child is now aged 12 years and still without diarrhea. Whole exome sequencing identified compound heterozygous mutations in the TTC37 gene, a known cause of the trichohepatoenteric syndrome (THES). This case extends the known phenotype of THES and defines a potential subset for inclusion as an immune overlap syndrome.

  11. Novel TTC37 Mutations in a Patient with Immunodeficiency without Diarrhea: Extending the Phenotype of Trichohepatoenteric Syndrome

    PubMed Central

    Rider, Nicholas L.; Boisson, Bertrand; Jyonouchi, Soma; Hanson, Eric P.; Rosenzweig, Sergio D.; Casanova, Jean-Laurent; Orange, Jordan S.

    2015-01-01

    Unbiased genetic diagnosis has increasingly associated seemingly unrelated somatic and immunological phenotypes. We report a male infant who presented within the first year of life with physical growth impairment, feeding difficulties, hyperemesis without diarrhea, and abnormal hair findings suggestive of trichorrhexis nodosa. With advancing age, moderate global developmental delay, susceptibility to frequent viral illnesses, otitis media, and purulent conjunctivitis were identified. Because of the repeated infections, an immunological evaluation was pursued and identified impaired antibody memory responses following pneumococcal vaccine administration. Immunoglobulin replacement therapy and nutritional support were employed as mainstays of therapy. The child is now aged 12 years and still without diarrhea. Whole exome sequencing identified compound heterozygous mutations in the TTC37 gene, a known cause of the trichohepatoenteric syndrome (THES). This case extends the known phenotype of THES and defines a potential subset for inclusion as an immune overlap syndrome. PMID:25688341

  12. Mutations in KIAA0586 Cause Lethal Ciliopathies Ranging from a Hydrolethalus Phenotype to Short-Rib Polydactyly Syndrome.

    PubMed

    Alby, Caroline; Piquand, Kevin; Huber, Céline; Megarbané, André; Ichkou, Amale; Legendre, Marine; Pelluard, Fanny; Encha-Ravazi, Ferechté; Abi-Tayeh, Georges; Bessières, Bettina; El Chehadeh-Djebbar, Salima; Laurent, Nicole; Faivre, Laurence; Sztriha, László; Zombor, Melinda; Szabó, Hajnalka; Failler, Marion; Garfa-Traore, Meriem; Bole, Christine; Nitschké, Patrick; Nizon, Mathilde; Elkhartoufi, Nadia; Clerget-Darpoux, Françoise; Munnich, Arnold; Lyonnet, Stanislas; Vekemans, Michel; Saunier, Sophie; Cormier-Daire, Valérie; Attié-Bitach, Tania; Thomas, Sophie

    2015-08-06

    KIAA0586, the human ortholog of chicken TALPID3, is a centrosomal protein that is essential for primary ciliogenesis. Its disruption in animal models causes defects attributed to abnormal hedgehog signaling; these defects include polydactyly and abnormal dorsoventral patterning of the neural tube. Here, we report homozygous mutations of KIAA0586 in four families affected by lethal ciliopathies ranging from a hydrolethalus phenotype to short-rib polydactyly. We show defective ciliogenesis, as well as abnormal response to SHH-signaling activation in cells derived from affected individuals, consistent with a role of KIAA0586 in primary cilia biogenesis. Whereas centriolar maturation seemed unaffected in mutant cells, we observed an abnormal extended pattern of CEP290, a centriolar satellite protein previously associated with ciliopathies. Our data show the crucial role of KIAA0586 in human primary ciliogenesis and subsequent abnormal hedgehog signaling through abnormal GLI3 processing. Our results thus establish that KIAA0586 mutations cause lethal ciliopathies.

  13. Congenital muscular dystrophy phenotype with neuromuscular spindles excess in a 5-year-old girl caused by HRAS mutation.

    PubMed

    Bolocan, Anamaria; Quijano-Roy, Susana; Seferian, Andreea M; Baumann, Clarisse; Allamand, Valérie; Richard, Pascale; Estournet, Brigitte; Carlier, Robert; Cavé, Hélène; Gartioux, Corine; Blin, Nathalie; Le Moing, Anne-Gaëlle; Gidaro, Teresa; Germain, Dominique P; Fardeau, Michel; Voit, Thomas; Servais, Laurent; Romero, Norma Beatriz

    2014-11-01

    We report on a 5-year-old girl who presented with an association of symptoms reminiscent of an Ullrich-like congenital muscular dystrophy including congenital hypotonia, proximal joint contractures, hyperlaxity of distal joints, normal cognitive development, and kyphoscoliosis. There was an excess of neuromuscular spindles on the skeletal muscle biopsy. This very peculiar feature on muscle biopsy has been reported only in patients with mutations in the HRAS gene. Sequence analysis of the subject's HRAS gene from blood leukocytes and skeletal muscle revealed a previously described heterozygous missense mutation (c.187G>A, p. Glu63Lys). The present report thus extends the differential diagnosis of congenital muscular dystrophy with major "retractile" phenotypes and adds congenital muscular dystrophy to the clinical spectrum of HRAS-related disorders.

  14. PLA2G6 Mutations Related to Distinct Phenotypes: A New Case with Early-onset Parkinsonism

    PubMed Central

    Giri, Anamika; Guven, Gamze; Hanagasi, Hasmet; Hauser, Ann-Kathrin; Erginul-Unaltuna, Nihan; Bilgic, Basar; Gurvit, Hakan; Heutink, Peter; Gasser, Thomas; Lohmann, Ebba; Simón-Sánchez, Javier

    2016-01-01

    Background PLA2G6-associated neurodegeneration (PLAN) is a recessive neurodegenerative disorder characterized by three distinct phenotypes: infantile neuroaxonal dystrophy (INAD), atypical neuroaxonal dystrophy (atypical NAD), and PLA2G6-related dystonia–parkinsonism. Methods A consanguineous index case from Turkey was diagnosed with early-onset Parkinsonism at the Istanbul Faculty of Medicine. She and her unaffected brother were subjected to whole-genome sequencing. Results In this report, we describe a 33-year-old index case with parental consanguinity and early-onset Parkinsonism. Whole-genome sequencing of this individual revealed that a homozygous p.R747W mutation in PLA2G6 segregates with the disease in this family Discussion This result supports the importance of prioritizing this gene in mutational analysis of autosomal recessive Parkinsonism, and confirms the clinical heterogeneity of PLAN. PMID:27127721

  15. A study of familial MELAS: evaluation of A3243G mutation, clinical phenotype, and magnetic resonance spectroscopy-monitored progression.

    PubMed

    Chen, Chunnuan; Xiong, Nian; Wang, Yuhui; Xiong, Jing; Huang, Jinsha; Zhang, Zhentao; Wang, Tao

    2012-01-01

    The clinical manifestations of mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes syndrome (MELAS syndrome) are nonspecific and can easily be misdiagnosed. Magnetic resonance spectroscopy (MRS)-based detection of lactate in the brain has been found to be of diagnostic help in MELAS syndrome, however, the issue of whether MRS features vary by stage remains unresolved. We assessed the causative mutation and radiological features of a family of MELAS. Four of the family members harbored the A3243G mutation, probably of maternal inheritance. However, the clinical phenotypic expression was different in these patients. MRS showed a lactate peak, decreased N-acetylaspartate, choline, and creatine, which became more pronounced with progression of the disease, demonstrating that brain-MRS-based detection of lactate may be a suitable way to monitor the progression and treatment of MELAS.

  16. Cyclic ichthyosis with epidermolytic hyperkeratosis: A phenotype conferred by mutations in the 2B domain of keratin K1.

    PubMed Central

    Sybert, V P; Francis, J S; Corden, L D; Smith, L T; Weaver, M; Stephens, K; McLean, W H

    1999-01-01

    Bullous congenital ichthyosiform erythroderma (BCIE) is characterized by blistering and erythroderma in infancy and by erythroderma and ichthyosis thereafter. Epidermolytic hyperkeratosis is a hallmark feature of light and electron microscopy. Here we report on four individuals from two families with a unique clinical disorder with histological findings of epidermolytic hyperkeratosis. Manifesting erythema and superficial erosions at birth, which improved during the first few months of life, affected individuals later developed palmoplantar hyperkeratosis with patchy erythema and scale elsewhere on the body. Three affected individuals exhibit dramatic episodic flares of annular, polycyclic erythematous plaques with scale, which coalesce to involve most of the body surface. The flares last weeks to months. In the interim periods the skin may be normal, except for palmoplantar hyperkeratosis. Abnormal keratin-filament aggregates were observed in suprabasal keratinocytes from both probands, suggesting that the causative mutation might reside in keratin K1 or keratin K10. In one proband, sequencing of K1 revealed a heterozygous mutation, 1436T-->C, predicting a change of isoleucine to threonine in the highly conserved helix-termination motif. In the second family, a heterozygous mutation, 1435A-->T, was found in K1, predicting an isoleucine-to-phenylalanine substitution in the same codon. Both mutations were excluded in both a control population and all unaffected family members tested. These findings reveal that a clinical phenotype distinct from classic BCIE but with similar histology can result from K1 mutations and that mutations at this codon give rise to a clinically unique condition. PMID:10053007

  17. The Zebrafish Model Organism Database: new support for human disease models, mutation details, gene expression phenotypes and searching.

    PubMed

    Howe, Douglas G; Bradford, Yvonne M; Eagle, Anne; Fashena, David; Frazer, Ken; Kalita, Patrick; Mani, Prita; Martin, Ryan; Moxon, Sierra Taylor; Paddock, Holly; Pich, Christian; Ramachandran, Sridhar; Ruzicka, Leyla; Schaper, Kevin; Shao, Xiang; Singer, Amy; Toro, Sabrina; Van Slyke, Ceri; Westerfield, Monte

    2017-01-04

    The Zebrafish Model Organism Database (ZFIN; http://zfin.org) is the central resource for zebrafish (Danio rerio) genetic, genomic, phenotypic and developmental data. ZFIN curators provide expert manual curation and integration of comprehensive data involving zebrafish genes, mutants, transgenic constructs and lines, phenotypes, genotypes, gene expressions, morpholinos, TALENs, CRISPRs, antibodies, anatomical structures, models of human disease and publications. We integrate curated, directly submitted, and collaboratively generated data, making these available to zebrafish research community. Among the vertebrate model organisms, zebrafish are superbly suited for rapid generation of sequence-targeted mutant lines, characterization of phenotypes including gene expression patterns, and generation of human disease models. The recent rapid adoption of zebrafish as human disease models is making management of these data particularly important to both the research and clinical communities. Here, we describe recent enhancements to ZFIN including use of the zebrafish experimental conditions ontology, 'Fish' records in the ZFIN database, support for gene expression phenotypes, models of human disease, mutation details at the DNA, RNA and protein levels, and updates to the ZFIN single box search.

  18. The Zebrafish Model Organism Database: new support for human disease models, mutation details, gene expression phenotypes and searching

    PubMed Central

    Howe, Douglas G.; Bradford, Yvonne M.; Eagle, Anne; Fashena, David; Frazer, Ken; Kalita, Patrick; Mani, Prita; Martin, Ryan; Moxon, Sierra Taylor; Paddock, Holly; Pich, Christian; Ramachandran, Sridhar; Ruzicka, Leyla; Schaper, Kevin; Shao, Xiang; Singer, Amy; Toro, Sabrina; Van Slyke, Ceri; Westerfield, Monte

    2017-01-01

    The Zebrafish Model Organism Database (ZFIN; http://zfin.org) is the central resource for zebrafish (Danio rerio) genetic, genomic, phenotypic and developmental data. ZFIN curators provide expert manual curation and integration of comprehensive data involving zebrafish genes, mutants, transgenic constructs and lines, phenotypes, genotypes, gene expressions, morpholinos, TALENs, CRISPRs, antibodies, anatomical structures, models of human disease and publications. We integrate curated, directly submitted, and collaboratively generated data, making these available to zebrafish research community. Among the vertebrate model organisms, zebrafish are superbly suited for rapid generation of sequence-targeted mutant lines, characterization of phenotypes including gene expression patterns, and generation of human disease models. The recent rapid adoption of zebrafish as human disease models is making management of these data particularly important to both the research and clinical communities. Here, we describe recent enhancements to ZFIN including use of the zebrafish experimental conditions ontology, ‘Fish’ records in the ZFIN database, support for gene expression phenotypes, models of human disease, mutation details at the DNA, RNA and protein levels, and updates to the ZFIN single box search. PMID:27899582

  19. An Individual with Blepharophimosis-Ptosis-Epicanthus Inversus Syndrome (BPES) and Additional Features Expands the Phenotype Associated with Mutations in KAT6B

    PubMed Central

    Yu, Hung-Chun; Geiger, Elizabeth A.; Medne, Livija; Zackai, Elaine H.; Shaikh, Tamim H.

    2015-01-01

    Blepharophimosis-Ptosis-Epicanthus Inversus Syndrome (BPES) is an autosomal dominant disorder caused by mutations in FOXL2. We identified an individual with BPES and additional phenotypic features who did not have a FOXL2 mutation. We used whole exome sequencing to identify a de novo mutation in KAT6B (lysine acetyltransferase 6B) in this individual. The mutation was a 2 bp insertion leading to a frameshift which resulted in a premature stop codon. The resulting truncated protein does not have the C-terminal serine/methionine transcription activation domain necessary for interaction with other transcriptional and epigenetic regulators. This mutation likely has a dominant-negative or gain-of-function effect, similar to those observed in other genetic disorders resulting from KAT6B mutations, including Say-Barber-Biesecker-Young-Simpson (SBBYSS) and Genitopatellar syndrome (GTPTS). Thus, our subject’s phenotype broadens the spectrum of clinical findings associated with mutations in KAT6B. Furthermore, our results suggest that individuals with BPES without a FOXL2 mutation should be tested for KAT6B mutations. The transcriptional and epigenetic regulation mediated by KAT6B appears crucial to early developmental processes, which when perturbed can lead to a wide spectrum of phenotypic outcomes. PMID:24458743

  20. An individual with blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) and additional features expands the phenotype associated with mutations in KAT6B.

    PubMed

    Yu, Hung-Chun; Geiger, Elizabeth A; Medne, Livija; Zackai, Elaine H; Shaikh, Tamim H

    2014-04-01

    Blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) is an autosomal dominant disorder caused by mutations in FOXL2. We identified an individual with BPES and additional phenotypic features who did not have a FOXL2 mutation. We used whole exome sequencing to identify a de novo mutation in KAT6B (lysine acetyltransferase 6B) in this individual. The mutation was a 2-bp insertion leading to a frameshift which resulted in a premature stop codon. The resulting truncated protein does not have the C-terminal serine/methionine transcription activation domain necessary for interaction with other transcriptional and epigenetic regulators. This mutation likely has a dominant-negative or gain-of-function effect, similar to those observed in other genetic disorders resulting from KAT6B mutations, including Say-Barber-Biesecker-Young-Simpson (SBBYSS) and genitopatellar syndrome (GTPTS). Thus, our subject's phenotype broadens the spectrum of clinical findings associated with mutations in KAT6B. Furthermore, our results suggest that individuals with BPES without a FOXL2 mutation should be tested for KAT6B mutations. The transcriptional and epigenetic regulation mediated by KAT6B appears crucial to early developmental processes, which when perturbed can lead to a wide spectrum of phenotypic outcomes.

  1. Painful small fiber neuropathy with gastroparesis: A new phenotype with a novel mutation in the SCN10A gene.

    PubMed

    Dabby, Ron; Sadeh, Menachem; Broitman, Yelena; Yosovich, Keren; Dickman, Ram; Leshinsky-Silver, Esther

    2016-04-01

    Gain-of-function mutations in the SCN10A gene (encoding the Nav1.8 voltage gated sodium channel) have been reported in a small number of patients. All presented with predominantly painful sensory neuropathy, congruent with the expression of Nav1.8 in nociceptive sensory neurons of the dorsal root ganglion. Only a few had mild autonomic symptoms, including dry eyes and mouth, orthostatic dizziness, palpitations, diarrhea and constipation. The underlying mechanism of the autonomic symptoms in these patients is unclear. We describe a 37-year-old woman with severe progressive gastroparesis and diffuse painful small fiber sensory neuropathy that started at age 32. Due to the severe dysphagia she could not ingest solid food, and lost eight kilograms. The gastroparesis was documented by esophageal manometry and gastric scintigraphy. The neuropathic pain started distally and then intensified and spread to most body areas. The patient harbored a novel heterozygous mutation: c.G4915A:p.D1639N in the SCN10A gene. To the best of our knowledge, this is the first description of such a phenotype due to a Nav1.8 mutation. Thus, our study expands the clinical spectrum of Nav1.8 associated disorders, and suggests that mutations in this sodium channel should be considered in patients with gastrointestinal motility dysfunction and painful neuropathy.

  2. A novel SMARCAL1 mutation associated with a mild phenotype of Schimke immuno-osseous dysplasia (SIOD)

    PubMed Central

    2014-01-01

    Background Schimke immuno-osseous dysplasia (SIOD, OMIM #242900) is an autosomal-recessive pleiotropic disorder characterized by spondyloepiphyseal dysplasia, renal dysfunction and T-cell immunodeficiency. SIOD is caused by mutations in the gene SMARCAL1. Case presentation We report the clinical and genetic diagnosis of a 5-years old girl with SIOD, referred to our Center because of nephrotic-range proteinuria occasionally detected during the follow-up for congenital hypothyroidism. Mutational analysis of SMARCAL1 gene was performed by polymerase chain reaction (PCR) and bidirectional sequencing. Sequence analysis revealed that patient was compound heterozygous for two SMARCAL1 mutations: a novel missense change (p.Arg247Pro) and a well-known nonsense mutation (p.Glu848*). Conclusion This report provided the clinical and genetic description of a mild phenotype of Schimke immuno-osseous dysplasia associated with nephrotic proteinuria, decreasing after combined therapy with ACE inhibitors and sartans. Our experience highlighted the importance of detailed clinical evaluation, appropriate genetic counseling and molecular testing, to provide timely treatment and more accurate prognosis. PMID:24589093

  3. Intermediate Phenotype between ADULT Syndrome and EEC Syndrome Caused by R243Q Mutation in TP63

    PubMed Central

    Ueda, Koichi; Satoh, Chisei; Maekawa, Ryuta; Yoshiura, Koh-ichiro; Iseki, Sachiko

    2016-01-01

    Summary: A patient who had ectrodactyly, dry skin, exfoliative dermatitis, and hypodontia with peg-shaped teeth, but not cleft lip and palate, is described. Ectrodactyly with a tooth anomaly is recognized in both acro-dermato-ungual-lacrimal-tooth (ADULT) syndrome and ectrodactyly-ectodermal dysplasia-cleft (EEC) syndrome. These 2 syndromes are caused by heterozygous mutations in the transcriptional factor gene p63. Mutation analysis of p63 gene showed a heterozygous mutation c.728G>A, p.Arg243Gln (previously referred to as R204Q) in the patient, but not in his parents. Therefore, this was a sporadic case of the p63 mutation–associated disorder. Although the mutation has been mostly reported in EEC syndrome patients, the present case did not have cleft lip and palate. Furthermore, the present case did not exhibit freckling or some of the other ectodermal dysplasia phenotypes typical of ADULT syndrome. The concept of ELA syndrome proposed by Prontera in 2011 resolves the problem confronted in diagnosing the present case. ELA syndrome is an acronym of EEC/limb–mammary syndrome/ADULT syndromes, and these 3 syndromes are united into a unique entity. This system can classify p63 mutation–associated disorders simply without interfering with treatment. PMID:28293528

  4. Novel CDKL5 Mutations in Czech Patients with Phenotypes of Atypical Rett Syndrome and Early-Onset Epileptic Encephalopathy.

    PubMed

    Záhoráková, D; Langová, M; Brožová, K; Laštůvková, J; Kalina, Z; Rennerová, L; Martásek, P

    2016-01-01

    The X-linked CDKL5 gene, which encodes cyclin-dependent kinase-like 5 protein, has been implicated in early-onset encephalopathy and atypical Rett syndrome with early-onset seizures. The CDKL5 protein is a kinase required for neuronal development and morphogenesis, but its precise functions are still largely unexplored. Individuals with CDKL5 mutations present with severe global developmental delay, intractable epilepsy, and Rett-like features. A clear genotype-phenotype correlation has not been established due to an insufficient number of reported cases. The aim of this study was to analyse the CDKL5 gene in Czech patients with early-onset seizures and Rett-like features. We performed mutation screening in a cohort of 83 individuals using high-resolution melting analysis, DNA sequencing and multiplex ligation- dependent probe amplification. Molecular analyses revealed heterozygous pathogenic mutations in three girls with severe intellectual disability and intractable epilepsy starting at the age of two months. All three identified mutations, c.637G>A, c.902_977+29del105, and c.1757_1758delCT, are novel, thus significantly extending the growing spectrum of known pathogenic CDKL5 sequence variants. Our results support the importance of genetic testing of the CDKL5 gene in patients with early-onset epileptic encephalopathy and Rett-like features with early-onset seizures. This is the first study referring to molecular defects of CDKL5 in Czech cases.

  5. Reciprocal mouse and human limb phenotypes caused by gain- and loss-of-function mutations affecting Lmbr1.

    PubMed Central

    Clark, R M; Marker, P C; Roessler, E; Dutra, A; Schimenti, J C; Muenke, M; Kingsley, D M

    2001-01-01

    The major locus for dominant preaxial polydactyly in humans has been mapped to 7q36. In mice the dominant Hemimelic extra toes (Hx) and Hammertoe (Hm) mutations map to a homologous chromosomal region and cause similar limb defects. The Lmbr1 gene is entirely within the small critical intervals recently defined for both the mouse and human mutations and is misexpressed at the exact time that the mouse Hx phenotype becomes apparent during limb development. This result suggests that Lmbr1 may underlie preaxial polydactyly in both mice and humans. We have used deletion chromosomes to demonstrate that the dominant mouse and human limb defects arise from gain-of-function mutations and not from haploinsufficiency. Furthermore, we created a loss-of-function mutation in the mouse Lmbr1 gene that causes digit number reduction (oligodactyly) on its own and in trans to a deletion chromosome. The loss of digits that we observed in mice with reduced Lmbr1 activity is in contrast to the gain of digits observed in Hx mice and human polydactyly patients. Our results suggest that the Lmbr1 gene is required for limb formation and that reciprocal changes in levels of Lmbr1 activity can lead to either increases or decreases in the number of digits in the vertebrate limb. PMID:11606546

  6. Conditional Loss of Arx From the Developing Dorsal Telencephalon Results in Behavioral Phenotypes Resembling Mild Human ARX Mutations

    PubMed Central

    Simonet, Jacqueline C.; Sunnen, C. Nicole; Wu, Jue; Golden, Jeffrey A.; Marsh, Eric D.

    2015-01-01

    Mutations in the Aristaless-Related Homeobox (ARX) gene cause structural anomalies of the brain, epilepsy, and neurocognitive deficits in children. During forebrain development, Arx is expressed in both pallial and subpallial progenitor cells. We previously demonstrated that elimination of Arx from subpallial-derived cortical interneurons generates an epilepsy phenotype with features overlapping those seen in patients with ARX mutations. In this report, we have selectively removed Arx from pallial progenitor cells that give rise to the cerebral cortical projection neurons. While no discernable seizure activity was recorded, these mice exhibited a peculiar constellation of behaviors. They are less anxious, less social, and more active when compared with their wild-type littermates. The overall cortical thickness was reduced, and the corpus callosum and anterior commissure were hypoplastic, consistent with a perturbation in cortical connectivity. Taken together, these data suggest that some of the structural and behavioral anomalies, common in patients with ARX mutations, are specifically due to alterations in pallial progenitor function. Furthermore, our data demonstrate that some of the neurobehavioral features found in patients with ARX mutations may not be due to on-going seizures, as is often postulated, given that epilepsy was eliminated as a confounding variable in these behavior analyses. PMID:24794919

  7. Long-Term Clinical Outcome and Carrier Phenotype in Autosomal Recessive Hypophosphatemia Caused by a Novel DMP1 Mutation

    PubMed Central

    Mäkitie, Outi; Pereira, Renata C; Kaitila, Ilkka; Turan, Serap; Bastepe, Murat; Laine, Tero; Kröger, Heikki; Cole, William G; Jüppner, Harald

    2010-01-01

    Homozygous inactivating mutations in DMP1 (dentin matrix protein 1), the gene encoding a noncollagenous bone matrix protein expressed in osteoblasts and osteocytes, cause autosomal recessive hypophosphatemia (ARHP). Herein we describe a family with ARHP owing to a novel homozygous DMP1 mutation and provide a detailed description of the associated skeletal dysplasia and carrier phenotype. The two adult patients with ARHP, a 78-year-old man and his 66-year-old sister, have suffered from bone pain and lower extremity varus deformities since early childhood. With increasing age, both patients developed severe joint pain, contractures, and complete immobilization of the spine. Radiographs showed short and deformed long bones, significant cranial hyperostosis, enthesopathies, and calcifications of the paraspinal ligaments. Biochemistries were consistent with hypophosphatemia owing to renal phosphate wasting; markers of bone turnover and serum fibroblast growth factor 23 (FGF-23) levels were increased significantly. Nucleotide sequence analysis of DMP1 revealed a novel homozygous mutation at the splice acceptor junction of exon 6 (IVS5-1G > A). Two heterozygous carriers of the mutation also showed mild hypophosphatemia, and bone biopsy in one of these individuals showed focal areas of osteomalacia. In bone, DMP1 expression was absent in the homozygote but normal in the heterozygote, whereas FGF-23 expression was increased in both subjects but higher in the ARHP patient. The clinical and laboratory observations in this family confirm that DMP1 has an important role in normal skeletal development and mineral homeostasis. The skeletal phenotype in ARHP may be significantly more severe than in other forms of hypophosphatemic rickets. © 2010 American Society for Bone and Mineral Research. PMID:20499351

  8. Clinical and immunopathological corneal phenotype in homozygotes for the BIGH3 R124H mutation.

    PubMed

    Diaper, C J M; Schorderet, D F; Chaubert, P; Munier, F L

    2005-01-01

    A family was previously reported as suffering from severe granular dystrophy. The phenotypic picture suggested a mix of homozygous and heterozygous family members. Genetic analysis confirms the homozygousity in the patients most severely affected, but shows the disease state to be one of Avellino corneal dystrophy. The previous case reports are extended immunohistological staining using polyclonal antibodies raised against keratofepithelin. This genotype/phenotype correlation study is consistent with incomplete dominance.

  9. Splicing factor gene mutations in the myelodysplastic syndromes: impact on disease phenotype and therapeutic applications.

    PubMed

    Pellagatti, Andrea; Boultwood, Jacqueline

    2017-01-01

    Splicing factor gene mutations are the most frequent mutations found in patients with the myeloid malignancy myelodysplastic syndrome (MDS), suggesting that spliceosomal dysfunction plays a major role in disease pathogenesis. The aberrantly spliced target genes and deregulated cellular pathways associated with the commonly mutated splicing factor genes in MDS (SF3B1, SRSF2 and U2AF1) are being identified, illuminating the molecular mechanisms underlying MDS. Emerging data from mouse modeling studies indicate that the presence of splicing factor gene mutations can lead to bone marrow hematopoietic stem/myeloid progenitor cell expansion, impaired hematopoiesis and dysplastic differentiation that are hallmarks of MDS. Importantly, recent evidence suggests that spliceosome inhibitors and splicing modulators may have therapeutic value in the treatment of splicing factor mutant myeloid malignancies.

  10. Phenotypic diversity of breast cancer-related mutations in metalloproteinase-disintegrin ADAM12.

    PubMed

    Qi, Yue; Duhachek-Muggy, Sara; Li, Hui; Zolkiewska, Anna

    2014-01-01

    Six different somatic missense mutations in the human ADAM12 gene have been identified so far in breast cancer. Five of these mutations involve highly conserved residues in the extracellular domain of the transmembrane ADAM12-L protein. Two of these extracellular mutations, D301H and G479E, have been previously characterized in the context of mouse ADAM12. Three other mutations, T596A, R612Q, and G668A, have been reported more recently, and their effects on ADAM12-L protein structure/function are not known. Here, we show that ADAM12-L bearing the G668A mutation is largely retained in the endoplasmic reticulum in its nascent, full-length form, with an intact N-terminal pro-domain. The T596A and R612Q mutants are efficiently trafficked to the cell surface and proteolytically processed to remove their pro-domains. However, the T596A mutant shows decreased catalytic activity at the cell surface, while the R612Q mutant is fully active and comparable to the wild-type ADAM12-L. The D301H and G479E mutants, consistent with the corresponding D299H and G477E mutants of mouse ADAM12 described earlier, are not proteolytically processed and do not exhibit catalytic activity at the cell surface. Among all six breast cancer-associated mutations in ADAM12-L, mutations that preserve the activity--R612Q and L792F--occur in triple-negative breast cancers, while loss-of-function mutations--D301H, G479E, T596A, and G668A--are found in non-triple negative cancers. This apparent association between the catalytic activity of the mutants and the type of breast cancer supports a previously postulated role of an active ADAM12-L in the triple negative breast cancer disease.

  11. Mutations of the KIT (Mast/Stem cell growth factor receptor) proto-oncogene account for a continuous range of phenotypes in human piebaldism

    SciTech Connect

    Spritz, R.A.; Holmes, S.A. ); Ramesar, R.; Greenberg, J.; Beighton, P.; Curtis, D.

    1992-11-01

    Piebaldism is a rare autosomal dominant disorder of pigmentation, characterized by congenital patches of white skin and hair from which melanocytes are absent. The authors have previously shown that piebaldism can result from missense and frameshift mutations of the KIT proto-oncogene, which encodes the cellular receptor tyrosine kinase for the mast/stem cell growth factor. Here, the authors report two novel KIT mutations associated with human piebaldism. A proximal frameshift is associated with a mild piebald phenotype, and a splice-junction mutation is associated with a highly variable piebald phenotype. They discuss the apparent relationship between the predicted impact of specific KIT mutations on total KIT-dependent signal transduction and the severity of the resultant piebald phenotypes. 35 refs., 5 figs.

  12. TGFBR2 mutations alter smooth muscle cell phenotype and predispose to thoracic aortic aneurysms and dissections

    PubMed Central

    Inamoto, Sakiko; Kwartler, Callie S.; Lafont, Andrea L.; Liang, Yao Yun; Fadulu, Van Tran; Duraisamy, Senthil; Willing, Marcia; Estrera, Anthony; Safi, Hazim; Hannibal, Mark C.; Carey, John; Wiktorowicz, John; Tan, Filemon K.; Feng, Xin-Hua; Pannu, Hariyadarshi; Milewicz, Dianna M.

    2010-01-01

    Aims Transforming growth factor-β (TGF-β) signaling is critical for the differentiation of smooth muscle cells (SMCs) into quiescent cells expressing a full repertoire of contractile proteins. Heterozygous mutations in TGF-β receptor type II (TGFBR2) disrupt TGF-β signaling and lead to genetic conditions that predispose to thoracic aortic aneurysms and dissections (TAADs). The aim of this study is to determine the molecular mechanism by which TGFBR2 mutations cause TAADs. Methods and results Using aortic SMCs explanted from patients with TGFBR2 mutations, we show decreased expression of SMC contractile proteins compared with controls. Exposure to TGF-β1 fails to increase expression of contractile genes in mutant SMCs, whereas control cells further increase expression of these genes. Analysis of fixed and frozen aortas from patients with TGFBR2 mutations confirms decreased in vivo expression of contractile proteins relative to unaffected aortas. Fibroblasts explanted from patients with TGFBR2 mutations fail to transform into mature myofibroblasts with TGF-β1 stimulation as assessed by expression of contractile proteins. Conclusions These data support the conclusion that heterozygous TGFBR2 mutations lead to decreased expression of SMC contractile protein in both SMCs and myofibroblasts. The failure of TGFBR2-mutant SMCs to fully express SMC contractile proteins predicts defective contractile function in these cells and aligns with a hypothesis that defective SMC contractile function contributes to the pathogenesis of TAAD. PMID:20628007

  13. Genotype-phenotype correlation in hereditary hemorrhagic telangiectasia: mutations and manifestations.

    PubMed

    Bayrak-Toydemir, Pinar; McDonald, Jamie; Markewitz, Boaz; Lewin, Susan; Miller, Franklin; Chou, Lan-Szu; Gedge, Friederike; Tang, Wei; Coon, Hillary; Mao, Rong

    2006-03-01

    Hereditary hemorrhagic telangiectasia (HHT) is a genetically heterogeneous vascular dysplasia with multiple telangiectases and arteriovenous malformations and it is caused by mutations in endoglin gene (ENG) (HHT1) and activin A receptor type II-like 1 gene (ACVRL1) (HHT2). We evaluated 111 patients with HHT from 34 families by history, examination, screening for vascular malformations, and sequencing of both genes. We found mutations in 26 of the 34 kindreds (76%) analyzed-54% were in ENG and 46% were in ACVRL1. Mutations in ACVRL1 cluster largely in exons 7 and 8, but ENG mutations were widely distributed within that gene. We found that epistaxis had an earlier onset in patients with HHT1 than those with HHT2, but the severity by middle ages was similar. Pulmonary arteriovenous malformations were more frequent and on the average of larger size in HHT1. Hepatic vascular malformations were more common in patients with HHT2. Cerebral arteriovenous malformations were more common in patients with HHT1, but spinal arteriovenous malformations were seen only in patients with HHT2. Truncating mutations in ENG were associated with more affected organs and more severe hemorrhaging than were missense mutations. We conclude that HHT2 has a later onset than HHT1 and the former may disproportionately involve smaller vessels in tissues with more significant vascular remodeling.

  14. Genome-Wide Association Studies Identify Two Novel BMP15 Mutations Responsible for an Atypical Hyperprolificacy Phenotype in Sheep

    PubMed Central

    Demars, Julie; Fabre, Stéphane; Sarry, Julien; Rossetti, Raffaella; Gilbert, Hélène; Persani, Luca; Tosser-Klopp, Gwenola; Mulsant, Philippe; Nowak, Zuzanna; Drobik, Wioleta; Martyniuk, Elzbieta; Bodin, Loys

    2013-01-01

    Some sheep breeds are naturally prolific, and they are very informative for the studies of reproductive genetics and physiology. Major genes increasing litter size (LS) and ovulation rate (OR) were suspected in the French Grivette and the Polish Olkuska sheep populations, respectively. To identify genetic variants responsible for the highly prolific phenotype in these two breeds, genome-wide association studies (GWAS) followed by complementary genetic and functional analyses were performed. Highly prolific ewes (cases) and normal prolific ewes (controls) from each breed were genotyped using the Illumina OvineSNP50 Genotyping Beadchip. In both populations, an X chromosome region, close to the BMP15 gene, harbored clusters of markers with suggestive evidence of association at significance levels between 1E−05 and 1E−07. The BMP15 candidate gene was then sequenced, and two novel non-conservative mutations called FecXGr and FecXO were identified in the Grivette and Olkuska breeds, respectively. The two mutations were associated with the highly prolific phenotype (pFecXGr = 5.98E−06 and pFecXO = 2.55E−08). Homozygous ewes for the mutated allele showed a significantly increased prolificacy (FecXGr/FecXGr, LS = 2.50±0.65 versus FecX+/FecXGr, LS = 1.93±0.42, p<1E−03 and FecXO/FecXO, OR = 3.28±0.85 versus FecX+/FecXO, OR = 2.02±0.47, p<1E−03). Both mutations are located in very well conserved motifs of the protein and altered the BMP15 signaling activity in vitro using a BMP-responsive luciferase test in COV434 granulosa cells. Thus, we have identified two novel mutations in the BMP15 gene associated with increased LS and OR. Notably, homozygous FecXGr/FecXGr Grivette and homozygous FecXO/FecXO Olkuska ewes are hyperprolific in striking contrast with the sterility exhibited by all other known homozygous BMP15 mutations. Our results bring new insights into the key role played by the BMP15 protein in ovarian function and could

  15. De novo loss-of-function mutations in X-linked SMC1A cause severe ID and therapy-resistant epilepsy in females: expanding the phenotypic spectrum.

    PubMed

    Jansen, S; Kleefstra, T; Willemsen, M H; de Vries, P; Pfundt, R; Hehir-Kwa, J Y; Gilissen, C; Veltman, J A; de Vries, B B A; Vissers, L E L M

    2016-11-01

    De novo missense mutations and in-frame coding deletions in the X-linked gene SMC1A (structural maintenance of chromosomes 1A), encoding part of the cohesin complex, are known to cause Cornelia de Lange syndrome in both males and females. For a long time, loss-of-function (LoF) mutations in SMC1A were considered incompatible with life, as such mutations had not been reported in neither male nor female patients. However, recently, the authors and others reported LoF mutations in females with intellectual disability (ID) and epilepsy. Here we present the detailed phenotype of two females with de novo LoF mutations in SMC1A, including a de novo mutation of single base deletion [c.2364del, p.(Asn788Lysfs*10)], predicted to result in a frameshift, and a de novo deletion of exon 16, resulting in an out-of-frame mRNA splice product [p.(Leu808Argfs*6)]. By combining our patients with the other recently reported females carrying SMC1A LoF mutations, we ascertained a phenotypic spectrum of (severe) ID, therapy-resistant epilepsy, absence/delay of speech, hypotonia and small hands and feet. Our data show the existence of a novel phenotypic entity - distinct from CdLS - and caused by de novo SMC1A LoF mutations.

  16. Succinic Semialdehyde Dehydrogenase Deficiency in a Chinese Boy: A Novel ALDH5A1 Mutation With Severe Phenotype.

    PubMed

    Tay, Chee Geap; Ariffin, Hany; Yap, Sufin; Rahmat, Kartini; Sthaneshwar, Pavai; Ong, Lai Choo

    2015-06-01

    Succinic semialdehyde dehydrogenase deficiency is a rare autosomal recessive disorder affecting catabolism of the neurotransmitter gamma-aminobutyric acid (GABA), with a wide range of clinical phenotype. We report a Malaysian Chinese boy with a severe early onset phenotype due to a previously unreported mutation. Urine organic acid chromatogram revealed elevated 4-hydroxybutyric acid. Magnetic resonance imaging (MRI) of the brain demonstrated cerebral atrophy with atypical putaminal involvement. Molecular genetic analysis showed a novel homozygous 3-bp deletion at the ALDH5A1 gene c.1501_1503del (p.Glu501del). Both parents were confirmed to be heterozygotes for the p.Glu501del mutation. The clinical course was complicated by the development of subdural hemorrhage probably as a result of rocking the child to sleep for erratic sleep-wake cycles. This case illustrates the need to recognize that trivial or unintentional shaking of such children, especially in the presence of cerebral atrophy, can lead to subdural hemorrhage.

  17. Phenotypic expressions of a Gly154Arg mutation in type II collagen in two unrelated patients with spondyloepimetaphyseal dysplasia (SEMD)

    SciTech Connect

    Kaitila, I.; Marttinen, E.; Koerkkoe, J.; Ala-Kokko, L.

    1996-05-03

    Type II collagenopathies consist of chondrodysplasia ranging from lethal to mild in severity. A large number of mutations has been found in the COL2A1 gene. Glycine substitutions have been the most common types of mutation. Genotype-phenotype correlations in type II collagenopathies have not been established, partly because of insufficient clinical and radiographic description of the patients. We found a glycine-to-arginine substitution at position 154 in type II collagen in two unrelated isolated propositi with spondyloepimetaphyseal dysplasia and provide a comparative clinical and radiographic analysis from birth to young adulthood for this condition. The clinical phenotype was disproportionate short stature with varus/valgus deformities of the lower limbs requiring corrective osteotomies, and lumbar lordosis. The skeletal radiographs showed an evolution from short tubular bones, delayed epiphyseal development, and mild vertebral involvement to severe metaphyseal dysplasia with dappling irregularities, and hip {open_quotes}dysplasia.{close_quotes} The metaphyseal abnormalities disappeared by adulthood. 27 refs., 11 figs., 1 tab.

  18. Unusual phenotype of congenital adrenal hyperplasia (CAH) with a novel mutation of the CYP21A2 gene.

    PubMed

    Raisingani, Manish; Contreras, Maria F; Prasad, Kris; Pappas, John G; Kluge, Michelle L; Shah, Bina; David, Raphael

    2016-07-01

    Gonadotropin independent sexual precocity (SP) may be due to congenital adrenal hyperplasia (CAH), and its timing usually depends on the type of mutation in the CYP21A2 gene. Compound heterozygotes are common and express phenotypes of varying severity. The objective of this case report was to investigate the hormonal pattern and unusual genetic profile in a 7-year-old boy who presented with pubic hair, acne, an enlarged phallus, slightly increased testicular volume and advanced bone age. Clinical, hormonal and genetic studies were undertaken in the patient as well as his parents. We found elevated serum 17-hydroxyprogesterone (17-OHP) and androstenedione that were suppressed with dexamethasone, and elevated testosterone that actually rose after giving dexamethasone, indicating activity of the hypothalamic-pituitary-gonadal (HPG) axis. An initial search for common mutations was negative, but a more detailed genetic analysis of the CYP21A2 gene revealed two mutations including R341W, a non-classical mutation inherited from his mother, and g.823G>A, a novel not previously reported consensus donor splice site mutation inherited from his father, which is predicted to be salt wasting. However, the child had a normal plasma renin activity. He was effectively treated with low-dose dexamethasone and a GnRH agonist. His father was an unaffected carrier, but his mother had evidence of mild non-classical CAH. In a male child presenting with gonadotropin independent SP it is important to investigate adrenal function with respect to the androgen profile, and to carry out appropriate genetic studies.

  19. DCLRE1C (ARTEMIS) mutations causing phenotypes ranging from atypical severe combined immunodeficiency to mere antibody deficiency

    PubMed Central

    Volk, Timo; Pannicke, Ulrich; Reisli, Ismail; Bulashevska, Alla; Ritter, Julia; Björkman, Andrea; Schäffer, Alejandro A.; Fliegauf, Manfred; Sayar, Esra H.; Salzer, Ulrich; Fisch, Paul; Pfeifer, Dietmar; Di Virgilio, Michela; Cao, Hongzhi; Yang, Fang; Zimmermann, Karin; Keles, Sevgi; Caliskaner, Zafer; Güner, S¸ükrü; Schindler, Detlev; Hammarström, Lennart; Rizzi, Marta; Hummel, Michael; Pan-Hammarström, Qiang; Schwarz, Klaus; Grimbacher, Bodo

    2015-01-01

    Null mutations in genes involved in V(D)J recombination cause a block in B- and T-cell development, clinically presenting as severe combined immunodeficiency (SCID). Hypomorphic mutations in the non-homologous end-joining gene DCLRE1C (encoding ARTEMIS) have been described to cause atypical SCID, Omenn syndrome, Hyper IgM syndrome and inflammatory bowel disease—all with severely impaired T-cell immunity. By whole-exome sequencing, we investigated the molecular defect in a consanguineous family with three children clinically diagnosed with antibody deficiency. We identified perfectly segregating homozygous variants in DCLRE1C in three index patients with recurrent respiratory tract infections, very low B-cell numbers and serum IgA levels. In patients, decreased colony survival after irradiation, impaired proliferative response and reduced counts of naïve T cells were observed in addition to a restricted T-cell receptor repertoire, increased palindromic nucleotides in the complementarity determining regions 3 and long stretches of microhomology at switch junctions. Defective V(D)J recombination was complemented by wild-type ARTEMIS protein in vitro. Subsequently, homozygous or compound heterozygous DCLRE1C mutations were identified in nine patients from the same geographic region. We demonstrate that DCLRE1C mutations can cause a phenotype presenting as only antibody deficiency. This novel association broadens the clinical spectrum associated with ARTEMIS mutations. Clinicians should consider the possibility that an immunodeficiency with a clinically mild initial presentation could be a combined immunodeficiency, so as to provide appropriate care for affected patients. PMID:26476407

  20. DCLRE1C (ARTEMIS) mutations causing phenotypes ranging from atypical severe combined immunodeficiency to mere antibody deficiency.

    PubMed

    Volk, Timo; Pannicke, Ulrich; Reisli, Ismail; Bulashevska, Alla; Ritter, Julia; Björkman, Andrea; Schäffer, Alejandro A; Fliegauf, Manfred; Sayar, Esra H; Salzer, Ulrich; Fisch, Paul; Pfeifer, Dietmar; Di Virgilio, Michela; Cao, Hongzhi; Yang, Fang; Zimmermann, Karin; Keles, Sevgi; Caliskaner, Zafer; Güner, S Ükrü; Schindler, Detlev; Hammarström, Lennart; Rizzi, Marta; Hummel, Michael; Pan-Hammarström, Qiang; Schwarz, Klaus; Grimbacher, Bodo

    2015-12-20

    Null mutations in genes involved in V(D)J recombination cause a block in B- and T-cell development, clinically presenting as severe combined immunodeficiency (SCID). Hypomorphic mutations in the non-homologous end-joining gene DCLRE1C (encoding ARTEMIS) have been described to cause atypical SCID, Omenn syndrome, Hyper IgM syndrome and inflammatory bowel disease-all with severely impaired T-cell immunity. By whole-exome sequencing, we investigated the molecular defect in a consanguineous family with three children clinically diagnosed with antibody deficiency. We identified perfectly segregating homozygous variants in DCLRE1C in three index patients with recurrent respiratory tract infections, very low B-cell numbers and serum IgA levels. In patients, decreased colony survival after irradiation, impaired proliferative response and reduced counts of naïve T cells were observed in addition to a restricted T-cell receptor repertoire, increased palindromic nucleotides in the complementarity determining regions 3 and long stretches of microhomology at switch junctions. Defective V(D)J recombination was complemented by wild-type ARTEMIS protein in vitro. Subsequently, homozygous or compound heterozygous DCLRE1C mutations were identified in nine patients from the same geographic region. We demonstrate that DCLRE1C mutations can cause a phenotype presenting as only antibody deficiency. This novel association broadens the clinical spectrum associated with ARTEMIS mutations. Clinicians should consider the possibility that an immunodeficiency with a clinically mild initial presentation could be a combined immunodeficiency, so as to provide appropriate care for affected patients.

  1. A novel mutation in a large family causes a unique phenotype of Mucolipidosis IV.

    PubMed

    AlBakheet, AlBandary; Qari, Aliya; Colak, Dilek; Rasheed, Anas; Kaya, Namik; Al-Sayed, Moeenaldeen

    2013-09-10

    Mucolipidosis type IV is a rare autosomal recessive lysosomal storage disorder reported among Ashkenazi Jews and to a lesser extent in other ethnic groups. Several mutations have been reported in MCOLN1 which is the only known gene associated with the disorder. Here we report the first Saudi patient with Mucolipidosis type IV from a consanguineous family with two branches having a total of five patients carrying a novel transition mutation, c.1307A>G (p.Y436C) in exon 11. The clinical course of the patient was nonspecific and a lysosomal storage disorder was not highly suspected due to lack of coarse facial features, organomegaly and skeletal findings of dysostosis multiplex. The detailed bioinformatics analysis on the deleterious effects of the mutation is discussed. Emphasis is made on the importance of brain magnetic resonance imaging (MRI) findings and serum gastrin level as key clues to the diagnosis of this often subtle neurodevelopmental disorder.

  2. A molecular model for the genetic and phenotypic characteristics of the mouse lethal yellow (Ay) mutation.

    PubMed

    Michaud, E J; Bultman, S J; Klebig, M L; van Vugt, M J; Stubbs, L J; Russell, L B; Woychik, R P

    1994-03-29

    Lethal yellow (Ay) is a mutation at the mouse agouti locus in chromosome 2 that causes a number of dominant pleiotropic effects, including a completely yellow coat color, obesity, an insulin-resistant type II diabetic condition, and an increased propensity to develop a variety of spontaneous and induced tumors. Additionally, homozygosity for Ay results in preimplantation lethality, which terminates development by the blastocyst stage. The Ay mutation is the result of a 170-kb deletion that removes all but the promoter and noncoding first exon of another gene called Raly, which lies in the same transcriptional orientation as agouti and maps 280 kb proximal to the 3' end of the agouti gene. We present a model for the structure of the Ay allele that can explain the dominant pleiotropic effects associated with this mutation, as well as the recessive lethality, which is unrelated to the agouti gene.

  3. A MITF Mutation Associated with a Dominant White Phenotype and Bilateral Deafness in German Fleckvieh Cattle

    PubMed Central

    Philipp, Ute; Lupp, Bettina; Mömke, Stefanie; Stein, Veronika; Tipold, Andrea; Eule, Johanna Corinna; Rehage, Jürgen; Distl, Ottmar

    2011-01-01

    A dominantly inherited syndrome associated with hypopigmentation, heterochromia irides, colobomatous eyes and bilateral hearing loss has been ascertained in Fleckvieh cattle (German White Fleckvieh syndrome). This syndrome has been mapped to bovine chromosome (BTA) 22 using a genome-wide association study with the bovine high density single nucleotide polymorphism array. An R210I missense mutation has been identified within microphthalmia-associated transcription factor (MITF) as responsible for this syndrome. The mutation is located in the highly conserved basic region of the protein and causes a negative-dominant effect. SOX10 and PAX3 promoter binding site mutations in MITF could be ruled out as causative for the German White Fleckvieh syndrome. Molecular characterization of this newly detected bovine syndrome means a large animal model is now available for the Tietz syndrome in humans. PMID:22174915

  4. Autosomal Dominant Hypoparathyroidism Caused by Germline Mutation in GNA11: Phenotypic and Molecular Characterization

    PubMed Central

    Li, Dong; Opas, Evan E.; Tuluc, Florin; Metzger, Daniel L.; Hou, Cuiping; Hakonarson, Hakon

    2014-01-01

    Context: Most cases of autosomal dominant hypoparathyroidism (ADH) are caused by gain-of-function mutations in CASR or dominant inhibitor mutations in GCM2 or PTH. Objective: Our objectives were to identify the genetic basis for ADH in a multigenerational family and define the underlying disease mechanism. Subjects: Here we evaluated a multigenerational family with ADH in which affected subjects had normal sequences in these genes and were shorter than unaffected family members. Methods: We collected clinical and biochemical data from 6 of 11 affected subjects and performed whole-exome sequence analysis on DNA from two affected sisters and their affected father. Functional studies were performed after expression of wild-type and mutant Gα11 proteins in human embryonic kidney-293-CaR cells that stably express calcium-sensing receptors. Results: Whole-exome-sequencing followed by Sanger sequencing revealed a heterozygous mutation, c.179G>T; p.R60L, in GNA11, which encodes the α-subunit of G11, the principal heterotrimeric G protein that couples calcium-sensing receptors to signal activation in parathyroid cells. Functional studies of Gα11 R60L showed increased accumulation of intracellular concentration of free calcium in response to extracellular concentration of free calcium with a significantly decreased EC50 compared with wild-type Gα11. By contrast, R60L was significantly less effective than the oncogenic Q209L form of Gα11 as an activator of the MAPK pathway. Compared to subjects with CASR mutations, patients with GNA11 mutations lacked hypercalciuria and had normal serum magnesium levels. Conclusions: Our findings indicate that the germline gain-of-function mutation of GNA11 is a cause of ADH and implicate a novel role for GNA11 in skeletal growth. PMID:24823460

  5. Phenotypes and PRRT2 mutations in Chinese families with benign familial infantile epilepsy and infantile convulsions with paroxysmal choreoathetosis

    PubMed Central

    2013-01-01

    Background Mutations in the PRRT2 gene have been identified as the major cause of benign familial infantile epilepsy (BFIE), paroxysmal kinesigenic dyskinesia (PKD) and infantile convulsions with paroxysmal choreoathetosis/dyskinesias (ICCA). Here, we analyzed the phenotypes and PRRT2 mutations in Chinese families with BFIE and ICCA. Methods Clinical data were collected from 22 families with BFIE and eight families with ICCA. PRRT2 mutations were screened using PCR and direct sequencing. Results Ninety-five family members were clinically affected in the 22 BFIE families. During follow-up, two probands had one seizure induced by diarrhea at the age of two years. Thirty-one family members were affected in the eight ICCA families, including 11 individuals with benign infantile epilepsy, nine with PKD, and 11 with benign infantile epilepsy followed by PKD. Two individuals in one ICCA family had PKD or ICCA co-existing with migraine. One affected member in another ICCA family had experienced a fever-induced seizure at 7 years old. PRRT2 mutations were detected in 13 of the 22 BFIE families. The mutation c.649_650insC (p.R217PfsX8) was found in nine families. The mutations c.649delC (p.R217EfsX12) and c.904_905insG (p.D302GfsX39) were identified in three families and one family, respectively. PRRT2 mutations were identified in all eight ICCA families, including c.649_650insC (p.R217PfsX8), c.649delC (p.R217EfsX12), c.514_517delTCTG (p.S172RfsX3) and c.1023A > T (X341C). c.1023A > T is a novel mutation predicted to elongate the C-terminus of the protein by 28 residues. Conclusions Our data demonstrated that PRRT2 is the major causative gene of BFIE and ICCA in Chinese families. Site c.649 is a mutation hotspot: c.649_650insC is the most common mutation, and c.649delC is the second most common mutation in Chinese families with BFIE and ICCA. As far as we know, c.1023A > T is the first reported mutation in exon 4 of PRRT2. c.649delC was previously reported in

  6. The Arabidopsis minE mutation causes new plastid and FtsZ1 localization phenotypes in the leaf epidermis

    PubMed Central

    Fujiwara, Makoto T.; Kojo, Kei H.; Kazama, Yusuke; Sasaki, Shun; Abe, Tomoko; Itoh, Ryuuichi D.

    2015-01-01

    Plastids in the leaf epidermal cells of plants are regarded as immature chloroplasts that, like mesophyll chloroplasts, undergo binary fission. While mesophyll chloroplasts have generally been used to study plastid division, recent studies have suggested the presence of tissue- or plastid type-dependent regulation of plastid division. Here, we report the detailed morphology of plastids and their stromules, and the intraplastidic localization of the chloroplast division-related protein AtFtsZ1-1, in the leaf epidermis of an Arabidopsis mutant that harbors a mutation in the chloroplast division site determinant gene AtMinE1. In atminE1, the size and shape of epidermal plastids varied widely, which contrasts with the plastid phenotype observed in atminE1 mesophyll cells. In particular, atminE1 epidermal plastids occasionally displayed grape-like morphology, a novel phenotype induced by a plastid division mutation. Observation of an atminE1 transgenic line harboring an AtMinE1 promoter::AtMinE1-yellow fluorescent protein fusion gene confirmed the expression and plastidic localization of AtMinE1 in the leaf epidermis. Further examination revealed that constriction of plastids and stromules mediated by the FtsZ1 ring contributed to the plastid pleomorphism in the atminE1 epidermis. These results illustrate that a single plastid division mutation can have dramatic consequences for epidermal plastid morphology, thereby implying that plastid division and morphogenesis are differentially regulated in epidermal and mesophyll plastids. PMID:26500667

  7. Mutations in Two Genes Encoding Different Subunits of a Receptor Signaling Complex Result in an Identical Disease Phenotype

    PubMed Central

    Paloneva, Juha; Manninen, Tuula; Christman, Grant; Hovanes, Karine; Mandelin, Jami; Adolfsson, Rolf; Bianchin, Marino; Bird, Thomas; Miranda, Roxana; Salmaggi, Andrea; Tranebjærg, Lisbeth; Konttinen, Yrjö; Peltonen, Leena

    2002-01-01

    Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL), also known as “Nasu-Hakola disease,” is a globally distributed recessively inherited disease leading to death during the 5th decade of life and is characterized by early-onset progressive dementia and bone cysts. Elsewhere, we have identified PLOSL mutations in TYROBP (DAP12), which codes for a membrane receptor component in natural-killer and myeloid cells, and also have identified genetic heterogeneity in PLOSL, with some patients carrying no mutations in TYROBP. Here we complete the molecular pathology of PLOSL by identifying TREM2 as the second PLOSL gene. TREM2 forms a receptor signaling complex with TYROBP and triggers activation of the immune responses in macrophages and dendritic cells. Patients with PLOSL have no defects in cell-mediated immunity, suggesting a remarkable capacity of the human immune system to compensate for the inactive TYROBP-mediated activation pathway. Our data imply that the TYROBP-mediated signaling pathway plays a significant role in human brain and bone tissue and provide an interesting example of how mutations in two different subunits of a multisubunit receptor complex result in an identical human disease phenotype. PMID:12080485

  8. A probable new syndrome with the storage disease phenotype caused by the VPS33A gene mutation.

    PubMed

    Dursun, Ali; Yalnizoglu, Dilek; Gerdan, Omer F; Yucel-Yilmaz, Didem; Sagiroglu, Mahmut S; Yuksel, Bayram; Gucer, Safak; Sivri, Serap; Ozgul, Riza K

    2017-01-01

    We present a novel multisystem disease in two siblings with clinical features resembling a lysosomal storage disease. These included coarse face, dysostosis multiplex, respiratory difficulty, proteinuria with glomerular foamy cells, neurological involvement with developmental delays, pyramidal signs, and severe chronic anemia. Detailed enzymatic analysis for lysosomal diseases and whole-exome sequencing studies excluded known lysosomal storage diseases in the proband. Subsequently, genome-wide genotyping and exome sequencing analysis of the family indicated two large homozygous regions on chromosomes 5 and 12, and strongly suggested that a homozygous p. R498W missense mutation in the VPS33A gene might be responsible for this novel disease. Segregation analysis in family members and mutation prediction tools' results also supported the damaging effect of the missense mutation on the function of the Vps33a protein, which plays a role in the vesicular transport system. Electron microscopic studies of the cornea of the proband showed findings supportive of dysfunction in vesicular transport. The clinical phenotype and genetic studies support the suggestion that the siblings most probably have a novel disease very likely caused by a VPS33A gene defect.

  9. Mutation spectrum and genotype-phenotype correlations in a large French cohort of MYH9-Related Disorders.

    PubMed

    Saposnik, Béatrice; Binard, Sylvie; Fenneteau, Odile; Nurden, Alan; Nurden, Paquita; Hurtaud-Roux, Marie-Françoise; Schlegel, Nicole

    2014-07-01

    MYH9-Related Disorders are a group of rare autosomal dominant platelet disorders presenting as nonsyndromic forms characterized by macrothrombocytopenia with giant platelets and leukocyte inclusion bodies or as syndromic forms combining these hematological features with deafness and/or nephropathy and/or cataracts. They are caused by mutations in the MYH9 gene encoding the nonmuscle myosin heavy chain II-A (NMMHC-IIA). Until now, at least 49 MYH9 mutations have been reported in isolated cases or small series but only rarely in large series. We report the results of an 8-year study of a large cohort of 109 patients from 37 sporadic cases and 39 unrelated families. We have identified 43 genetic variants, 21 of which are novel to our patients. A majority, 33 (76.7%), were missense mutations and six exons were preferentially targeted, as previously published. The other alterations were three deletions of one nucleotide, one larger deletion of 21 nucleotides, and one duplication. For the first time, a substitution T>A was found in the donor splice site of intron 40 (c.5765+2T>A). Seven patients, four from the same family, had two genetic variants. The analysis of the genotype-phenotype relationships enabled us to improve the knowledge of this heterogeneous but important rare disease.

  10. Two novel distinct COL1A2 mutations highlight the complexity of genotype-phenotype correlations in osteogenesis imperfecta and related connective tissue disorders.

    PubMed

    Reuter, Miriam S; Schwabe, Georg C; Ehlers, Christian; Marschall, Christoph; Reis, André; Thiel, Christian; Graul-Neumann, Luitgard

    2013-12-01

    Osteogenesis imperfecta is a heritable connective tissue disorder characterized by variable symptoms including predisposition to fractures. Despite the identification of numerous mutations, a reliable genotype-phenotype correlation has remained notoriously difficult. We now describe two patients with osteogenesis imperfecta and novel, so far undescribed mutations in the COL1A2 gene, further highlighting this complexity. A 3-year-old patient presented with features reminiscent of a connective tissue disorder, with joint hypermobility, Wormian bones, streaky lucencies in the long bones and relative macrocephaly. The patient carried a heterozygous c.1316G > A (p.Gly439Asp) mutation in the COL1A2 gene located in a triple-helix region, in which glycine substitutions have been assumed to cause perinatal lethal OI (Sillence type II). A second family with type I osteogenesis imperfecta carried a heterozygous nonsense mutation c.4060C > T (p.Gln1354X) within the last exon of COL1A2. Whereas other heterozygous nonsense mutations in COL1A2 do not lead to a phenotype, in this case the mRNA is presumed to escape nonsense-mediated decay. Therefore the predicted COL1A2 propeptide lacks the last 13 C-terminal amino acids, suggesting that the OI phenotype results from decelerated assembly and overmodification of the collagen triple helix. The presented COL1A2 mutations exemplify the complexity of COL1A2 genotype-phenotype correlation in genetic counselling in OI.

  11. Neuropathological Phenotype of a Distinct Form of Lissencephaly Associated with Mutations in "TUBA1A"

    ERIC Educational Resources Information Center

    Fallet-Bianco, Catherine; Loeuillet, Laurence; Poirier, Karine; Loget, Philippe; Chapon, Francoise; Pasquier, Laurent; Saillour, Yoann; Beldjord, Cherif; Chelly, Jamel; Francis, Fiona

    2008-01-01

    Lissencephalies are congenital malformations responsible for epilepsy and mental retardation in children. A number of distinct lissencephaly syndromes have been characterized, according to the aspect and the topography of the cortical malformation, the involvement of other cerebral structures and the identified genetic defect. A mutation in…

  12. A hypermutation phenotype and somatic MSH6 mutations in recurrent human malignant gliomas after alkylator chemotherapy.

    PubMed

    Hunter, Chris; Smith, Raffaella; Cahill, Daniel P; Stephens, Philip; Stevens, Claire; Teague, Jon; Greenman, Chris; Edkins, Sarah; Bignell, Graham; Davies, Helen; O'Meara, Sarah; Parker, Adrian; Avis, Tim; Barthorpe, Syd; Brackenbury, Lisa; Buck, Gemma; Butler, Adam; Clements, Jody; Cole, Jennifer; Dicks, Ed; Forbes, Simon; Gorton, Matthew; Gray, Kristian; Halliday, Kelly; Harrison, Rachel; Hills, Katy; Hinton, Jonathon; Jenkinson, Andy; Jones, David; Kosmidou, Vivienne; Laman, Ross; Lugg, Richard; Menzies, Andrew; Perry, Janet; Petty, Robert; Raine, Keiran; Richardson, David; Shepherd, Rebecca; Small, Alexandra; Solomon, Helen; Tofts, Calli; Varian, Jennifer; West, Sofie; Widaa, Sara; Yates, Andy; Easton, Douglas F; Riggins, Gregory; Roy, Jennifer E; Levine, Kymberly K; Mueller, Wolf; Batchelor, Tracy T; Louis, David N; Stratton, Michael R; Futreal, P Andrew; Wooster, Richard

    2006-04-15

    Malignant gliomas have a very poor prognosis. The current standard of care for these cancers consists of extended adjuvant treatment with the alkylating agent temozolomide after surgical resection and radiotherapy. Although a statistically significant increase in survival has been reported with this regimen, nearly all gliomas recur and become insensitive to further treatment with this class of agents. We sequenced 500 kb of genomic DNA corresponding to the kinase domains of 518 protein kinases in each of nine gliomas. Large numbers of somatic mutations were observed in two gliomas recurrent after alkylating agent treatment. The pattern of mutations in these cases showed strong similarity to that induced by alkylating agents in experimental systems. Further investigation revealed inactivating somatic mutations of the mismatch repair gene MSH6 in each case. We propose that inactivating somatic mutations of MSH6 confer resistance to alkylating agents in gliomas in vivo and concurrently unleash accelerated mutagenesis in resistant clones as a consequence of continued exposure to alkylating agents in the presence of defective mismatch repair. The evidence therefore suggests that when MSH6 is inactivated in gliomas, alkylating agents convert from induction of tumor cell death to promotion of neoplastic progression. These observations highlight the potential of large scale sequencing for revealing and elucidating mutagenic processes operative in individual human cancers.

  13. Interaction between murine spf-ash mutation and genetic background yields different metabolic phenotypes

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The spf-ash mutation in mice results in reduced hepatic and intestinal ornithine transcarbamylase. However, a reduction in enzyme activity only translates in reduced ureagenesis and hyperammonemia when an unbalanced nitrogen load is imposed. Six-week-old wild-type control and spf-ash mutant male mic...

  14. Phenotypical Characteristics of Idiopathic Infantile Nystagmus with and without Mutations in "FRMD7"

    ERIC Educational Resources Information Center

    Thomas, Shery; Proudlock, Frank A.; Sarvananthan, Nagini; Roberts, Eryl O.; Awan, Musarat; McLean, Rebecca; Surendran, Mylvaganam; Kumar, A. S. Anil; Farooq, Shegufta J.; Degg, Chris; Gale, Richard P.; Reinecke, Robert D.; Woodruff, Geoffrey; Langmann, Andrea; Lindner, Susanne; Jain, Sunila; Tarpey, Patrick; Raymond, F. Lucy; Gottlob, Irene

    2008-01-01

    Idiopathic infantile nystagmus (IIN) consists of involuntary oscillations of the eyes. The familial form is most commonly X-linked. We recently found mutations in a novel gene "FRMD7" (Xq26.2), which provided an opportunity to investigate a genetically defined and homogeneous group of patients with nystagmus. We compared clinical features and eye…

  15. NSD1 Mutations Are the Major Cause of Sotos Syndrome and Occur in Some Cases of Weaver Syndrome but Are Rare in Other Overgrowth Phenotypes

    PubMed Central

    Douglas, Jenny; Hanks, Sandra; Temple, I. Karen; Davies, Sally; Murray, Alexandra; Upadhyaya, Meena; Tomkins, Susan; Hughes, Helen E.; Cole, Trevor R. P.; Rahman, Nazneen

    2003-01-01

    Sotos syndrome is a childhood overgrowth syndrome characterized by a distinctive facial appearance, height and head circumference >97th percentile, advanced bone age, and developmental delay. Weaver syndrome is characterized by the same criteria but has its own distinctive facial gestalt. Recently, a 2.2-Mb chromosome 5q35 microdeletion, encompassing NSD1, was reported as the major cause of Sotos syndrome, with intragenic NSD1 mutations identified in a minority of cases. We evaluated 75 patients with childhood overgrowth, for intragenic mutations and large deletions of NSD1. The series was phenotypically scored into four groups, prior to the molecular analyses: the phenotype in group 1 (n=37) was typical of Sotos syndrome; the phenotype in group 2 (n=13) was Sotos-like but with some atypical features; patients in group 3 (n=7) had Weaver syndrome, and patients in group 4 (n=18) had an overgrowth condition that was neither Sotos nor Weaver syndrome. We detected three deletions and 32 mutations (13 frameshift, 8 nonsense, 2 splice-site, and 9 missense) that are likely to impair NSD1 functions. The truncating mutations were spread throughout NSD1, but there was evidence of clustering of missense mutations in highly conserved functional domains between exons 13 and 23. There was a strong correlation between presence of an NSD1 alteration and clinical phenotype, in that 28 of 37 (76%) patients in group 1 had NSD1 mutations or deletions, whereas none of the patients in group 4 had abnormalities of NSD1. Three patients with Weaver syndrome had NSD1 mutations, all between amino acids 2142 and 2184. We conclude that intragenic mutations of NSD1 are the major cause of Sotos syndrome and account for some Weaver syndrome cases but rarely occur in other childhood overgrowth phenotypes. PMID:12464997

  16. A multicenter experience on the prevalence of ARMC5 mutations in patients with primary bilateral macronodular adrenal hyperplasia: from genetic characterization to clinical phenotype.

    PubMed

    Albiger, N M; Regazzo, D; Rubin, B; Ferrara, A M; Rizzati, S; Taschin, E; Ceccato, F; Arnaldi, G; Pecori Giraldi, F; Stigliano, A; Cerquetti, L; Grimaldi, F; De Menis, E; Boscaro, M; Iacobone, M; Occhi, G; Scaroni, C

    2017-03-01

    ARMC5 mutations have recently been identified as a common genetic cause of primary bilateral macronodular adrenal hyperplasia (PBMAH). We aimed to assess the prevalence of ARMC5 germline mutations and correlate genotype with phenotype in a large cohort of PBMAH patients. A multicenter study was performed, collecting patients from different endocrinology units in Italy. Seventy-one PBMAH patients were screened for small mutations and large rearrangements in the ARMC5 gene: 53 were cortisol-secreting (two with a family history of adrenal hyperplasia) and 18 were non-secreting cases of PBMAH. Non-mutated and mutated patients' clinical phenotypes were compared and related to the type of mutation. A likely causative germline ARMC5 mutation was only identified in cortisol-secreting PBMAH patients (one with a family history of adrenal hyperplasia and ten apparently sporadic cases). Screening in eight first-degree relatives of three index cases revealed four carriers of an ARMC5 mutation. Evidence of a second hit at somatic level was identified in five nodules. Mutated patients had higher cortisol levels (p = 0.062), and more severe hypertension and diabetes (p < 0.05). Adrenal glands were significantly larger, with a multinodular phenotype, in the mutant group (p < 0.01). No correlation emerged between type of mutation and clinical parameters. ARMC5 mutations are frequent in cortisol-secreting PBMAH and seem to be associated with a particular pattern of the adrenal masses. Their identification may have implications for the clinical care of PBMAH cases and their relatives.

  17. Cystic fibrosis mutations with widely variable phenotype: the D1152H example.

    PubMed

    Mussaffi, H; Prais, D; Mei-Zahav, M; Blau, H

    2006-03-01

    D1152H is a type IV cystic fibrosis transmembrane regulator (CFTR) mutation associated with abnormal chloride gating. Although comprising 5-6% of mutations on genetic screening, clinical reports of cystic fibrosis (CF) are rare, suggesting that the disease is mild, atypical, or even absent. We describe our experience, which contrasts with this assumption, in a retrospective case series encompassing 91 CF patients (74 Jewish) aged 8 months to 56 years, from 2000-2005. Nine patients of varied Jewish ethnic origins were homozygous (2 patients) or compound heterozygous for D1152H with 11 of 182 potential alleles (6%). Five were diagnosed at age 33-49 years. Of 4 infants, 1 was diagnosed by prenatal screening, 1 had a prenatal dilated bowel, and 1 had pulmonary symptoms. Sweat chloride was 28-120 meq/l. Three adults had chronic mucoid Pseudomonas aeruginosa in sputum, and a forced expired volume in 1 sec (FEV1) of 20-55%. One was on bilevel positive airway pressure (BIPAP) ventilation. The infants had pulmonary symptoms that responded well to therapy. All 9 patients had good nutrition, 6 were pancreatic-sufficient, and 3 adults had subclinical pancreatic insufficiency. Three adults had recurrent pancreatitis. None had a bowel obstruction. Two of 3 adult males were fertile. Although asymptomatic at times, the D1152H mutation is associated with a broad clinical spectrum. This information is crucial for genetic counseling. Lung disease may be evident from infancy, and is severe in some adults, although all have outlived the median life expectancy of CF. Hopefully, with early diagnosis and therapy, prognosis can be good. A multicenter study of this mutation is warranted.

  18. Endogenous DNA replication stress results in expansion of dNTP pools and a mutator phenotype

    PubMed Central

    Davidson, Marta B; Katou, Yuki; Keszthelyi, Andrea; Sing, Tina L; Xia, Tian; Ou, Jiongwen; Vaisica, Jessica A; Thevakumaran, Neroshan; Marjavaara, Lisette; Myers, Chad L; Chabes, Andrei; Shirahige, Katsuhiko; Brown, Grant W

    2012-01-01

    The integrity of the genome depends on diverse pathways that regulate DNA metabolism. Defects in these pathways result in genome instability, a hallmark of cancer. Deletion of ELG1 in budding yeast, when combined with hypomorphic alleles of PCNA results in spontaneous DNA damage during S phase that elicits upregulation of ribonucleotide reductase (RNR) activity. Increased RNR activity leads to a dramatic expansion of deoxyribonucleotide (dNTP) pools in G1 that allows cells to synthesize significant fractions of the genome in the presence of hydroxyurea in the subsequent S phase. Consistent with the recognized correlation between dNTP levels and spontaneous mutation, compromising ELG1 and PCNA results in a significant increase in mutation rates. Deletion of distinct genome stability genes RAD54, RAD55, and TSA1 also results in increased dNTP levels and mutagenesis, suggesting that this is a general phenomenon. Together, our data point to a vicious circle in which mutations in gatekeeper genes give rise to genomic instability during S phase, inducing expansion of the dNTP pool, which in turn results in high levels of spontaneous mutagenesis. PMID:22234187

  19. Molecular basis of the attenuated phenotype of human APOBEC3B DNA mutator enzyme

    PubMed Central

    Caval, Vincent; Bouzidi, Mohamed S.; Suspène, Rodolphe; Laude, Hélène; Dumargne, Marie-Charlotte; Bashamboo, Anu; Krey, Thomas; Vartanian, Jean-Pierre; Wain-Hobson, Simon

    2015-01-01

    The human APOBEC3A and APOBEC3B genes (A3A and A3B) encode DNA mutator enzymes that deaminate cytidine and 5-methylcytidine residues in single-stranded DNA (ssDNA). They are important sources of mutations in many cancer genomes which show a preponderance of CG->TA transitions. Although both enzymes can hypermutate chromosomal DNA in an experimental setting, only A3A can induce double strand DNA breaks, even though the catalytic domains of A3B and A3A differ by only 9% at the protein level. Accordingly we sought the molecular basis underlying A3B attenuation through the generation of A3A-A3B chimeras and mutants. It transpires that the N-terminal domain facilitates A3B activity while a handful of substitutions in the catalytic C-terminal domain impacting ssDNA binding serve to attenuate A3B compared to A3A. Interestingly, functional attenuation is also observed for the rhesus monkey rhA3B enzyme compared to rhA3A indicating that this genotoxic dichotomy has been selected for and maintained for some 38 million years. Expression of all human ssDNA cytidine deaminase genes is absent in mature sperm indicating they contribute to somatic mutation and cancer but not human diversity. PMID:26384561

  20. Hyperferritinaemia-cataract syndrome: Worldwide mutations and phenotype of an increasingly diagnosed genetic disorder

    PubMed Central

    2010-01-01

    The hereditary hyperferritinaemia-cataract syndrome (HHCS) is characterised by an autosomal dominant cataract and high levels of serum ferritin without iron overload. The cataract develops due to L-ferritin deposits in the lens and its pulverulent aspect is pathognomonic. The syndrome is caused by mutations within the iron-responsive element of L-ferritin. These mutations prevent efficient binding of iron regulatory proteins 1 and 2 to the IRE in L-ferritin mRNA, resulting in an unleashed ferritin translation. This paper reviews all 31 mutations (27 single nucleotide transitions and four deletions) that have been described since 1995. Laboratory test showing hyperferritinaemia, normal serum iron and normal transferrin saturation are indicative for HHCS after exclusion of other causes of increased ferritin levels (inflammation, malignancy, alcoholic liver disease) and should prompt an ophthalmological consultation for diagnostic confirmation. Invasive diagnostics such as liver biopsy are not indicated. HHCS is an important differential diagnosis of hyperferritinaemia. Haematologists, gastroenterologists and ophthalmologists should be aware of this syndrome to spare patients from further invasive diagnosis (liver biopsy), and also from a false diagnosis of hereditary haemochromatosis followed by venesections. Patients diagnosed with HHCS should be counselled regarding the relative harmlessness of this genetic disease, with early cataract surgery as the only clinical consequence. PMID:20511138

  1. NOD2/CARD15 mutations in Polish and Bosnian populations with and without Crohn’s disease: prevalence and genotype-phenotype analysis

    PubMed Central

    Salkic, Nermin N.; Adler, Grazyna; Zawada, Iwona; Alibegovic, Ervin; Karakiewicz, Beata; Kozlowska-Wiechowska, Anna; Wasilewicz, Michał; Sulzyc-Bielicka, Violetta; Bielicki, Dariusz

    2015-01-01

    Data on prevalence and phenotypic consequences of nucleotide-binding oligomerisation domain 2/caspase recruitment domains 15 (NOD2/CARD15) variants in Crohn’s disease (CD) population in Poland and Bosnia and Herzegovina (B&H) are nonexistent. We aimed to determine the prevalence of NOD2/CARD15 mutations and their association with disease phenotype in Polish and Bosnian patients with CD and in healthy controls. We prospectively recruited 86 CD patients and 83 controls in Poland and 30 CD patients and 30 controls in B&H, 229 in total. We determined the prevalence of NOD2/CARD15 mutations and their association with the disease phenotype according to Montreal classification. Participants were genotyped for Leu1007fsinsC and Gly908Arg mutations. At least one CD-associated allele was found in 29/86 (33.7%) of Polish CD patients and in 9/83 (10.8%) of healthy controls (p<0.001). In both CD patients and controls in Bosnian sample, at least one NOD2 mutation was found in equal number of patients (3/30; 10%) with all of the NOD2 mutation positive CD patients being homozygous, while controls being heterozygous. In Polish sample, perianal disease was less frequent in CD patients with any NOD2 mutation (1/21; 4.8%) compared to those without (11/41; 26.8%; p=0.046). Higher percentage of patients with NOD2 mutations had history of CD related surgery when compared with those without mutations (66.7% vs. 43.3%; p=0.05). The risk for CD is increased in patients with NOD2 mutations (Poland) and especially in the presence of homozygous NOD2 mutations (Poland and Bosnia). The presence of variant NOD2 alleles is associated with increased need for surgery and reduced occurrence of perianal disease. PMID:26042516

  2. NOD2/CARD15 mutations in Polish and Bosnian populations with and without Crohn's disease: prevalence and genotype-phenotype analysis.

    PubMed

    Salkic, Nermin N; Adler, Grazyna; Zawada, Iwona; Alibegovic, Ervin; Karakiewicz, Beata; Kozlowska-Wiechowska, Anna; Wasilewicz, Michał; Sulzyc-Bielicka, Violetta; Bielicki, Dariusz

    2015-05-25

    Data on prevalence and phenotypic consequences of nucleotide-binding oligomerisation domain 2/caspase recruitment domains 15 (NOD2/CARD15) variants in Crohn's disease (CD) population in Poland and Bosnia and Herzegovina (B&H) are nonexistent. We aimed to determine the prevalence of NOD2/CARD15 mutations and their association with disease phenotype in Polish and Bosnian patients with CD and in healthy controls. We prospectively recruited 86 CD patients and 83 controls in Poland and 30 CD patients and 30 controls in B&H, 229 in total. We determined the prevalence of NOD2/CARD15 mutations and their association with the disease phenotype according to Montreal classification. Participants were genotyped for Leu1007fsinsC and Gly908Arg mutations. At least one CD-associated allele was found in 29/86 (33.7%) of Polish CD patients and in 9/83 (10.8%) of healthy controls (p<0.001). In both CD patients and controls in Bosnian sample, at least one NOD2 mutation was found in equal number of patients (3/30; 10%) with all of the NOD2 mutation positive CD patients being homozygous, while controls being heterozygous. In Polish sample, perianal disease was less frequent in CD patients with any NOD2 mutation (1/21; 4.8%) compared to those without (11/41; 26.8%; p=0.046). Higher percentage of patients with NOD2 mutations had history of CD related surgery when compared with those without mutations (66.7% vs. 43.3%; p=0.05). The risk for CD is increased in patients with NOD2 mutations (Poland) and especially in the presence of homozygous NOD2 mutations (Poland and Bosnia). The presence of variant NOD2 alleles is associated with increased need for surgery and reduced occurrence of perianal disease.

  3. Phenotypical characteristics of idiopathic infantile nystagmus with and without mutations in FRMD7.

    PubMed

    Thomas, Shery; Proudlock, Frank A; Sarvananthan, Nagini; Roberts, Eryl O; Awan, Musarat; McLean, Rebecca; Surendran, Mylvaganam; Kumar, A S Anil; Farooq, Shegufta J; Degg, Chris; Gale, Richard P; Reinecke, Robert D; Woodruff, Geoffrey; Langmann, Andrea; Lindner, Susanne; Jain, Sunila; Tarpey, Patrick; Raymond, F Lucy; Gottlob, Irene

    2008-05-01

    Idiopathic infantile nystagmus (IIN) consists of involuntary oscillations of the eyes. The familial form is most commonly X-linked. We recently found mutations in a novel gene FRMD7 (Xq26.2), which provided an opportunity to investigate a genetically defined and homogeneous group of patients with nystagmus. We compared clinical features and eye movement recordings of 90 subjects with mutation in the gene (FRMD7 group) to 48 subjects without mutations but with clinical IIN (non-FRMD7 group). Fifty-eight female obligate carriers of the mutation were also investigated. The median visual acuity (VA) was 0.2 logMAR (Snellen equivalent 6/9) in both groups and most patients had good stereopsis. The prevalence of strabismus was also similar (FRMD7: 7.8%, non-FRMD7: 10%). The presence of anomalous head posture (AHP) was significantly higher in the non-FRMD7 group (P < 0.0001). The amplitude of nystagmus was more strongly dependent on the direction of gaze in the FRMD7 group being lower at primary position (P < 0.0001), compared to non-FRMD7 group (P = 0.83). Pendular nystagmus waveforms were also more frequent in the FRMD7 group (P = 0.003). Fifty-three percent of the obligate female carriers of an FRMD7 mutation were clinically affected. The VA's in affected females were slightly better compared to affected males (P = 0.014). Subnormal optokinetic responses were found in a subgroup of obligate unaffected carriers, which may be interpreted as a sub-clinical manifestation. FRMD7 is a major cause of X-linked IIN. Most clinical and eye movement characteristics were similar in the FRMD7 group and non-FRMD7 group with most patients having good VA and stereopsis and low incidence of strabismus. Fewer patients in the FRMD7 group had AHPs, their amplitude of nystagmus being lower in primary position. Our findings are helpful in the clinical identification of IIN and genetic counselling of nystagmus patients.

  4. A multi-species comparative structural bioinformatics analysis of inherited mutations in α-D-Mannosidase reveals strong genotype-phenotype correlation

    PubMed Central

    2009-01-01

    Background Lysosomal α-mannosidase is an enzyme that acts to degrade N-linked oligosaccharides and hence plays an important role in mannose metabolism in humans and other mammalian species, especially livestock. Mutations in the gene (MAN2B1) encoding lysosomal α-D-mannosidase cause improper coding, resulting in dysfunctional or non-functional protein, causing the disease α-mannosidosis. Mapping disease mutations to the structure of the protein can help in understanding the functional consequences of these mutations and thus indirectly, the finer aspects of the pathology and clinical manifestations of the disease, including phenotypic severity as a function of the genotype. Results A comprehensive homology modeling study of all the wild-type and inherited mutations of lysosomal α-mannosidase in four different species, human, cow, cat and guinea pig, reveals a significant correlation between the severity of the genotype and the phenotype in α-mannosidosis. We used the X-ray crystallographic structure of bovine lysosomal α-mannosidase as template, containing only two disulphide bonds and some ligands, to build structural models of wild-type structures with four disulfide linkages and all bound ligands. These wild-type models were then used as templates for disease mutations. All the truncations and substitutions involving the residues in and around the active site and those that destabilize the fold led to severe genotypes resulting in lethal phenotypes, whereas the mutations lying away from the active site were milder in both their genotypic and phenotypic expression. Conclusion Based on the co-location of mutations from different organisms and their proximity to the enzyme active site, we have extrapolated observed mutations from one species to homologous positions in other organisms, as a predictive approach for detecting likely α-mannosidosis. Besides predicting new disease mutations, this approach also provides a way for detecting mutation hotspots in the

  5. Detection of 15 novel mutations in 52 children from 40 families with the Marfan or Loeys-Dietz syndrome and phenotype-genotype correlations.

    PubMed

    Pees, C; Michel-Behnke, I; Hagl, M; Laccone, F

    2014-12-01

    We report about 52 pediatric patients of 40 different families with confirmed Marfan syndrome (MFS) in 49 patients and Loeys-Dietz syndrome (LDS) in 3 patients. We found 39 different mutations, 15 of them being novel. Phenotype-genotype correlation in the 49 MFS patients showed that the majority of patients carrying mutations in exons 1-21 had ectopic lens (80%). Patients having mutations in exons 23-32 had a higher probability of aortic root dilation, in 50% even above a z score of 3. We found three children with neonatal MFS form, two of them with novel mutations. Of the three LDS patients, only one presented with the typical phenotype of LDS type 1.

  6. Role of a short tandem leucine/arginine repeat in strong mutator phenotype acquisition in a clinical isolate of Salmonella Typhimurium.

    PubMed

    Le Bars, Hervé; Bousarghin, Latifa; Bonnaure-Mallet, Martine; Jolivet-Gougeon, Anne

    2013-01-01

    In this prospective study, a strong mutator strain of Salmonella Typhimurium was isolated from a collection of 130 human clinical strains of Salmonella. Sequence analysis of the mutS, mutL, and mutH genes, which encode three proteins that are essential for initiation of methyl-directed DNA mismatch repair, revealed insertion of a short tandem repeat (STR) of leucine/alanine in the histidine kinase-like ATPase domain of MutL. The role of this STR in the acquisition of the strong mutator phenotype was confirmed by the construction of an isogenic mutant (6bpinsmutL) from a normomutator strain of Salmonella Heidelberg. This result adds to the sparse body of knowledge about strong mutators and highlights the role of this STR as a hotspot for the acquisition of a strong mutator phenotype in Salmonella.

  7. Extending the phenotypic spectrum of keratitis-ichthyosis-deafness syndrome: report of a patient with GJB2 (G12R) Connexin 26 mutation and unusual clinical findings.

    PubMed

    Lazic, Tamara; Li, Qiaoli; Frank, Michael; Uitto, Jouni; Zhou, Linda H

    2012-01-01

    Keratitis-ichthyosis-deafness (KID) syndrome is a rare ectodermal dysplasia, characterized mainly by the presence of hyperkeratotic skin lesions, neurosensory hearing loss, and vascularizing keratitis. Most mutations that have been discovered as a cause of KID syndrome are autosomal dominant, found in exon 2 of the Connexin (Cx) 26 gene. A G12R (p.Gly12Arg) is a GJB2 mutation reported in only two patients with KID syndrome to date. This article describes a patient with the G12R mutation and KID syndrome with interesting additional features, which include a porokeratotic eccrine ostial and dermal duct nevus, follicular occlusion triad, and unusual persistent oral mucosal papules. We compare this patient's phenotype with the only two other patients described with the same (G12R) mutation. The phenotypic heterogeneity of KID syndrome, inexplicable according to our current understanding of these proteins, speaks to the complexity of the connexin system and its overlapping expression patterns in different tissues.

  8. Mutational spectrum of the CYP1B1 gene in Pakistani patients with primary congenital glaucoma: Novel variants and genotype-phenotype correlations

    PubMed Central

    Sheikh, Shakeel Ahmed; Narsani, Ashok Kumar; Shaikh, Hina; Gilal, Imtiaz Ahmed; Shah, Khairuddin; Qasim, Muhammad; Memon, Azam Iqbal; Kewalramani, Pitambar; Shaikh, Naila

    2014-01-01

    Purpose This study aimed to investigate the role of CYP1B1 mutations in primary congenital glaucoma (PCG) in Pakistani patients. Methods After consent was received, 20 families with at least more than one member affected with primary congenital glaucoma were enrolled in the study. The disease was confirmed with standard ophthalmological investigations. Genomic DNA was extracted from whole blood for localization of linkage and sequencing. Bioinformatics tools were used to assess the predicted pathological role of novel variants. Results Ten out of 20 families (50%, 10/20) showed homozygosity with CYP1B1-linked short tandem repeat (STR) markers. On direct sequencing of the CYP1B1 gene in the linked families, six mutations, including two novel pathogenic variants, were identified. p. R390H was the most frequently found mutation in five families (50%, 5/10), whereas c.868_869insC, p.E229K, and p.A115P were found once in three families. Two novel mutations, a missense mutation (p.G36D) and an in-frame deletion mutation (p.G67-A70del), were segregated with disease phenotype in two families. Age of disease onset was congenital in all mutations; however, disease severity and response to clinical interventions varied among the mutations and families. Haplotype analysis using five polymorphisms revealed a distinct haplotype for a common mutation. Conclusions This is the largest cohort of Pakistani patients with PCG to be genetically screened for CYP1B1 mutations. Identifying common mutation and genotype-phenotype correlations may help in genetic testing and better prognosis for the disease. Novel mutations identified in the study may help in better understanding the pathophysiology of CYP1B1-associated glaucoma. PMID:25018621

  9. Increased rate of missense/in-frame mutations in individuals with NF1-related pulmonary stenosis: a novel genotype-phenotype correlation.

    PubMed

    Ben-Shachar, Shay; Constantini, Shlomi; Hallevi, Hen; Sach, Emma K; Upadhyaya, Meena; Evans, Gareth D; Huson, Susan M

    2013-05-01

    Neurofibromatosis type 1 (NF1) and its related disorders (NF1-Noonan syndrome (NFNS) and Watson syndrome (WS)) are caused by heterozygous mutations in the NF1 gene. Pulmonary stenosis (PS) occurs more commonly in NF1 and its related disorders than in the general population. This study investigated whether PS is associated with specific types of NF1 gene mutations in NF1, NFNS and WS. The frequency of different NF1 mutation types in a cohort of published and unpublished cases with NF1/NFNS/WS and PS was examined. Compared with NF1 in general, NFNS patients had higher rates of PS (9/35=26% vs 25/2322=1.1%, P value<0.001). Stratification according to mutation type showed that the increased PS rate appears to be driven by the NFNS group with non-truncating mutations. Eight of twelve (66.7%) NFNS cases with non-truncating mutations had PS compared with a 1.1% PS frequency in NF1 in general (P<0.001); there was no increase in the frequency of PS in NFNS patients with truncating mutations. Eight out of eleven (73%) individuals with NF1 and PS, were found to have non-truncating mutations, a much higher frequency than the 19% reported in NF1 cohorts (P<0.015). Only three cases of WS have been published with intragenic mutations, two of three had non-truncating mutations. Therefore, PS in NF1 and its related disorders is clearly associated with non-truncating mutations in the NF1 gene providing a new genotype-phenotype correlation. The data indicate a specific role of non-truncating mutations on the NF1 cardiac phenotype.

  10. GNAO1-associated epileptic encephalopathy and movement disorders: c.607G>A variant represents a probable mutation hotspot with a distinct phenotype.

    PubMed

    Arya, Ravindra; Spaeth, Christine; Gilbert, Donald L; Leach, James L; Holland, Katherine D

    2017-02-15

    We describe a case of GNAO1-associated epilepsy and chorea in a patient with a de novo pathogenic mutation. This patient is unique in being the first reported male with this phenotype, and we propose that this genetic variant may represent a mutation hotspot that characterizes a unique phenotype. This 5.2-years-old boy presented with seizures, chorea, and severe global developmental delay. Brain imaging showed progressive diffuse cerebral atrophy. EEG monitoring revealed multifocal and diffuse discharges, along with generalized-onset seizures. Genetic testing found a de novo pathogenic variant in the GNAO1 gene (c.607G>A; p.Gly203Arg). A review of the literature showed two other patients with similar phenotype and the same genetic variant. In contrast, other patients with neurological involvement had private mutations in the GNAO1 gene. The neurological phenotypes associated with GNAO1 mutations appear to lie on a spectrum, and it is possible that the c.607G>A (p.Gly203Arg) variant characterizes a phenotype with both severe epilepsy and chorea. [Published with video sequence on www.epilepticdisorders.com].

  11. High Incidence of Noonan Syndrome Features Including Short Stature and Pulmonic Stenosis in Patients carrying NF1 Missense Mutations Affecting p.Arg1809: Genotype–Phenotype Correlation

    PubMed Central

    Rojnueangnit, Kitiwan; Xie, Jing; Gomes, Alicia; Sharp, Angela; Callens, Tom; Chen, Yunjia; Liu, Ying; Cochran, Meagan; Abbott, Mary‐Alice; Atkin, Joan; Babovic‐Vuksanovic, Dusica; Barnett, Christopher P.; Crenshaw, Melissa; Bartholomew, Dennis W.; Basel, Lina; Bellus, Gary; Ben‐Shachar, Shay; Bialer, Martin G.; Bick, David; Blumberg, Bruce; Cortes, Fanny; David, Karen L.; Destree, Anne; Duat‐Rodriguez, Anna; Earl, Dawn; Escobar, Luis; Eswara, Marthanda; Ezquieta, Begona; Frayling, Ian M.; Frydman, Moshe; Gardner, Kathy; Gripp, Karen W.; Hernández‐Chico, Concepcion; Heyrman, Kurt; Ibrahim, Jennifer; Janssens, Sandra; Keena, Beth A; Llano‐Rivas, Isabel; Leppig, Kathy; McDonald, Marie; Misra, Vinod K.; Mulbury, Jennifer; Narayanan, Vinodh; Orenstein, Naama; Galvin‐Parton, Patricia; Pedro, Helio; Pivnick, Eniko K.; Powell, Cynthia M.; Randolph, Linda; Raskin, Salmo; Rosell, Jordi; Rubin, Karol; Seashore, Margretta; Schaaf, Christian P.; Scheuerle, Angela; Schultz, Meredith; Schorry, Elizabeth; Schnur, Rhonda; Siqveland, Elizabeth; Tkachuk, Amanda; Tonsgard, James; Upadhyaya, Meena; Verma, Ishwar C.; Wallace, Stephanie; Williams, Charles; Zackai, Elaine; Zonana, Jonathan; Lazaro, Conxi; Claes, Kathleen; Korf, Bruce; Martin, Yolanda; Legius, Eric

    2015-01-01

    ABSTRACT Neurofibromatosis type 1 (NF1) is one of the most frequent genetic disorders, affecting 1:3,000 worldwide. Identification of genotype–phenotype correlations is challenging because of the wide range clinical variability, the progressive nature of the disorder, and extreme diversity of the mutational spectrum. We report 136 individuals with a distinct phenotype carrying one of five different NF1 missense mutations affecting p.Arg1809. Patients presented with multiple café‐au‐lait macules (CALM) with or without freckling and Lisch nodules, but no externally visible plexiform neurofibromas or clear cutaneous neurofibromas were found. About 25% of the individuals had Noonan‐like features. Pulmonic stenosis and short stature were significantly more prevalent compared with classic cohorts (P < 0.0001). Developmental delays and/or learning disabilities were reported in over 50% of patients. Melanocytes cultured from a CALM in a segmental NF1‐patient showed two different somatic NF1 mutations, p.Arg1809Cys and a multi‐exon deletion, providing genetic evidence that p.Arg1809Cys is a loss‐of‐function mutation in the melanocytes and causes a pigmentary phenotype. Constitutional missense mutations at p.Arg1809 affect 1.23% of unrelated NF1 probands in the UAB cohort, therefore this specific NF1 genotype–phenotype correlation will affect counseling and management of a significant number of patients. PMID:26178382

  12. A strong loss-of-function mutation in RAN1 results in constitutive activation of the ethylene response pathway as well as a rosette-lethal phenotype

    NASA Technical Reports Server (NTRS)

    Woeste, K. E.; Kieber, J. J.; Evans, M. L. (Principal Investigator)

    2000-01-01

    A recessive mutation was identified that constitutively activated the ethylene response pathway in Arabidopsis and resulted in a rosette-lethal phenotype. Positional cloning of the gene corresponding to this mutation revealed that it was allelic to responsive to antagonist1 (ran1), a mutation that causes seedlings to respond in a positive manner to what is normally a competitive inhibitor of ethylene binding. In contrast to the previously identified ran1-1 and ran1-2 alleles that are morphologically indistinguishable from wild-type plants, this ran1-3 allele results in a rosette-lethal phenotype. The predicted protein encoded by the RAN1 gene is similar to the Wilson and Menkes disease proteins and yeast Ccc2 protein, which are integral membrane cation-transporting P-type ATPases involved in copper trafficking. Genetic epistasis analysis indicated that RAN1 acts upstream of mutations in the ethylene receptor gene family. However, the rosette-lethal phenotype of ran1-3 was not suppressed by ethylene-insensitive mutants, suggesting that this mutation also affects a non-ethylene-dependent pathway regulating cell expansion. The phenotype of ran1-3 mutants is similar to loss-of-function ethylene receptor mutants, suggesting that RAN1 may be required to form functional ethylene receptors. Furthermore, these results suggest that copper is required not only for ethylene binding but also for the signaling function of the ethylene receptors.

  13. High Incidence of Noonan Syndrome Features Including Short Stature and Pulmonic Stenosis in Patients carrying NF1 Missense Mutations Affecting p.Arg1809: Genotype-Phenotype Correlation.

    PubMed

    Rojnueangnit, Kitiwan; Xie, Jing; Gomes, Alicia; Sharp, Angela; Callens, Tom; Chen, Yunjia; Liu, Ying; Cochran, Meagan; Abbott, Mary-Alice; Atkin, Joan; Babovic-Vuksanovic, Dusica; Barnett, Christopher P; Crenshaw, Melissa; Bartholomew, Dennis W; Basel, Lina; Bellus, Gary; Ben-Shachar, Shay; Bialer, Martin G; Bick, David; Blumberg, Bruce; Cortes, Fanny; David, Karen L; Destree, Anne; Duat-Rodriguez, Anna; Earl, Dawn; Escobar, Luis; Eswara, Marthanda; Ezquieta, Begona; Frayling, Ian M; Frydman, Moshe; Gardner, Kathy; Gripp, Karen W; Hernández-Chico, Concepcion; Heyrman, Kurt; Ibrahim, Jennifer; Janssens, Sandra; Keena, Beth A; Llano-Rivas, Isabel; Leppig, Kathy; McDonald, Marie; Misra, Vinod K; Mulbury, Jennifer; Narayanan, Vinodh; Orenstein, Naama; Galvin-Parton, Patricia; Pedro, Helio; Pivnick, Eniko K; Powell, Cynthia M; Randolph, Linda; Raskin, Salmo; Rosell, Jordi; Rubin, Karol; Seashore, Margretta; Schaaf, Christian P; Scheuerle, Angela; Schultz, Meredith; Schorry, Elizabeth; Schnur, Rhonda; Siqveland, Elizabeth; Tkachuk, Amanda; Tonsgard, James; Upadhyaya, Meena; Verma, Ishwar C; Wallace, Stephanie; Williams, Charles; Zackai, Elaine; Zonana, Jonathan; Lazaro, Conxi; Claes, Kathleen; Korf, Bruce; Martin, Yolanda; Legius, Eric; Messiaen, Ludwine

    2015-11-01

    Neurofibromatosis type 1 (NF1) is one of the most frequent genetic disorders, affecting 1:3,000 worldwide. Identification of genotype-phenotype correlations is challenging because of the wide range clinical variability, the progressive nature of the disorder, and extreme diversity of the mutational spectrum. We report 136 individuals with a distinct phenotype carrying one of five different NF1 missense mutations affecting p.Arg1809. Patients presented with multiple café-au-lait macules (CALM) with or without freckling and Lisch nodules, but no externally visible plexiform neurofibromas or clear cutaneous neurofibromas were found. About 25% of the individuals had Noonan-like features. Pulmonic stenosis and short stature were significantly more prevalent compared with classic cohorts (P < 0.0001). Developmental delays and/or learning disabilities were reported in over 50% of patients. Melanocytes cultured from a CALM in a segmental NF1-patient showed two different somatic NF1 mutations, p.Arg1809Cys and a multi-exon deletion, providing genetic evidence that p.Arg1809Cys is a loss-of-function mutation in the melanocytes and causes a pigmentary phenotype. Constitutional missense mutations at p.Arg1809 affect 1.23% of unrelated NF1 probands in the UAB cohort, therefore this specific NF1 genotype-phenotype correlation will affect counseling and management of a significant number of patients.

  14. Exploring the complete mutational space of the LDL receptor LA5 domain using molecular dynamics: linking SNPs with disease phenotypes in familial hypercholesterolemia.

    PubMed

    Angarica, Vladimir Espinosa; Orozco, Modesto; Sancho, Javier

    2016-03-15

    Familial hypercholesterolemia (FH), a genetic disorder with a prevalence of 0.2%, represents a high-risk factor to develop cardiovascular and cerebrovascular diseases. The majority and most severe FH cases are associated to mutations in the receptor for low-density lipoproteins receptor (LDL-r), but the molecular basis explaining the connection between mutation and phenotype is often unknown, which hinders early diagnosis and treatment of the disease. We have used atomistic simulations to explore the complete SNP mutational space (227 mutants) of the LA5 repeat, the key domain for interacting with LDL that is coded in the exon concentrating the highest number of mutations. Four clusters of mutants of different stability have been identified. The majority of the 50 FH known mutations (33) appear distributed in the unstable clusters, i.e. loss of conformational stability explains two-third of FH phenotypes. However, one-third of FH phenotypes (17 mutations) do not destabilize the LR5 repeat. Combining our simulations with available structural data from different laboratories, we have defined a consensus-binding site for the interaction of the LA5 repeat with LDL-r partner proteins and have found that most (16) of the 17 stable FH mutations occur at binding site residues. Thus, LA5-associated FH arises from mutations that cause either the loss of stability or a decrease in domain's-binding affinity. Based on this finding, we propose the likely phenotype of each possible SNP in the LA5 repeat and outline a procedure to make a full computational diagnosis for FH.

  15. Exploring the complete mutational space of the LDL receptor LA5 domain using molecular dynamics: linking SNPs with disease phenotypes in familial hypercholesterolemia

    PubMed Central

    Angarica, Vladimir Espinosa; Orozco, Modesto; Sancho, Javier

    2016-01-01

    Familial hypercholesterolemia (FH), a genetic disorder with a prevalence of 0.2%, represents a high-risk factor to develop cardiovascular and cerebrovascular diseases. The majority and most severe FH cases are associated to mutations in the receptor for low-density lipoproteins receptor (LDL-r), but the molecular basis explaining the connection between mutation and phenotype is often unknown, which hinders early diagnosis and treatment of the disease. We have used atomistic simulations to explore the complete SNP mutational space (227 mutants) of the LA5 repeat, the key domain for interacting with LDL that is coded in the exon concentrating the highest number of mutations. Four clusters of mutants of different stability have been identified. The majority of the 50 FH known mutations (33) appear distributed in the unstable clusters, i.e. loss of conformational stability explains two-third of FH phenotypes. However, one-third of FH phenotypes (17 mutations) do not destabilize the LR5 repeat. Combining our simulations with available structural data from different laboratories, we have defined a consensus-binding site for the interaction of the LA5 repeat with LDL-r partner proteins and have found that most (16) of the 17 stable FH mutations occur at binding site residues. Thus, LA5-associated FH arises from mutations that cause either the loss of stability or a decrease in domain's-binding affinity. Based on this finding, we propose the likely phenotype of each possible SNP in the LA5 repeat and outline a procedure to make a full computational diagnosis for FH. PMID:26755827

  16. The retinal phenotype of Grk1−/− is compromised by a Crb1rd8 mutation

    PubMed Central

    Pak, Joseph S.; Lee, Eun-Jin

    2015-01-01

    Purpose Well-established laboratory mouse lines are important in creating genetically engineered knockout mouse models; however, these routinely used inbred strains are prone to spontaneous and deleterious mutations. One of these strains, the commonly used C57BL/6N (B6N), was discovered to carry a point mutation in the Crumbs homolog 1 (Crb1rd8) gene, which codes for a developmental protein involved in tight junction formation at the outer limiting membrane (OLM). This mutation disrupts photoreceptor polarity and leads to retinal degeneration. It was hypothesized that the G-protein receptor kinase 1 knockouts (Grk1−/−), which were based on the B6N strain, would exhibit abnormal morphological phenotypes in their offspring not related to GRK1’s major phosphorylation function. The hypothesis was tested by examining Grk1−/− with or without the Crb1rd8 mutation. Methods The mice strains tested were C57BL/6J (B6J), B6N, and Grk1−/− on either a B6J (Grk1−/−;B6J) or B6N background (Grk1−/−;B6N) and were verified with PCR genotype analysis for Grk1−/− and Crb rd8. The mice were bred and raised in complete darkness until 1 or 3 months of age and then exposed to 1,000 lux light for 24 h, followed by processing for immunohistochemistry (IHC) analysis on the retinal structure to investigate the morphological effects of light exposure. Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) was performed to detect photoreceptor apoptosis. Results The microanatomy of the retinal sections revealed disorganization of the outer nuclear layer (ONL) in the B6N and Grk1−/−;B6N mice and a significant decrease in the thickness of the ONL in the 3-month-old Grk1−/−;B6N mice. The adherens-junction-associated protein, Zona occludens-1 (ZO-1), formed a continuous line at the OLM in the 1- and 3-month-old control B6J and Grk1−/−;B6J mice. In contrast, the B6N and Grk1−/−;B6N retinas showed discontinuous and fragmented staining

  17. AB175. The first large-scale study of VHL gene mutation spectrum and genotype-phenotype correlationship of VHL disease in China

    PubMed Central

    Peng, Shuanghe; Gong, Kan

    2015-01-01

    Objective VHL disease is the most common hereditary renal cancer, and it is an autosomal-dominant inherited familial cancer syndrome caused by germline mutations of the VHL tumor suppressor gene. The golden standard for diagnosing VHL disease is to find the VHL gene mutation in patients’ genes. In the world, the United States had summarized 469 VHL families from the United States, Europe and Japan to summarize VHL gene mutation spectrum and the genotype-phenotype correlationship. However, no such large number of samples’ analysis had been done in China. The purpose of this study is to finish the first large-scale study of VHL gene mutation spectrum and genotype-phenotype correlationship of VHL disease in China. Methods We have gathered 172 Chinese VHL families including 89 families diagnosed in our hospital and 83 families from other domestic hospitals gathered by literature summary. Then we made statistical analysis of data from 172 Chinese VHL families. Results In the 172 Chinese VHL families, germline mutations were identified in 165 (96%) families. Point mutations were found in 103 (62%) families, large deletions were found in 32 (19%) families, micro-deletions or micro-insertions were found in 21 (13%) families, and splice mutations were found in 9 (6%) families. We found 9 hot mutation codons that affected more than 4 families each, and they were codon65, codon76, codon78, codon80, codon86, codon88, codon161, codon162 and codon167. The onset of pheochromocytoma in VHL patients was related to mutations in VHL gene locus 482, 482, 499, 499. Mutations in VHL gene locus 257, 257, 481 was negatively related to the onset of pheochromocytoma. The occurrence of retinal angioma associated with VHL gene large deletions. Mutations in VHL gene locus 226, 233, 239, 257, 263, 481, 486, 499, 500 was related to the onset of renal cell carcinoma. Conclusions We have finished the first large-scale study of VHL gene mutation spectrum and genotype-phenotype correlationship

  18. Aberrant let7a/HMGA2 signaling activity with unique clinical phenotype in JAK2-mutated myeloproliferative neoplasms.

    PubMed

    Chen, Chih-Cheng; You, Jie-Yu; Lung, Jrhau; Huang, Cih-En; Chen, Yi-Yang; Leu, Yu-Wei; Ho, Hsing-Ying; Li, Chian-Pei; Lu, Chang-Hsien; Lee, Kuan-Der; Hsu, Chia-Chen; Gau, Jyh-Pyng

    2017-03-01

    High mobility group AT-hook 2 (HMGA2) is an architectural transcription factor that is negatively regulated by let-7 microRNA through binding to it's 3'-untranslated region. Transgenic mice expressing Hmga2 with a truncation of its 3'-untranslated region has been shown to exhibit a myeloproliferative phenotype. To decipher the let-7-HMGA2 axis in myeloproliferative neoplasms, we employed an in vitro model supplemented with clinical correlation. Ba/F3 cells with inducible JAK2V617F expression (Ton.JAK2.V617F cells) showed upregulation of HMGA2 with concurrent let-7a repression. Ton.JAK2.V617F cells treated with a let-7a inhibitor exhibited further escalation of Hmga2 expression, while a let-7a mimic diminished the Hmga2 transcript level. Hmga2 overexpression conferred JAK2-mutated cells with a survival advantage through inhibited apoptosis. A pan-JAK inhibitor, INC424, increased the expression of let-7a, downregulated the level of Hmga2, and led to increased apoptosis in Ton.JAK2.V617F cells in a dose-dependent manner. In samples from 151 patients with myeloproliferative neoplasms, there was a modest inverse correlation between the expression levels of let-7a and HMGA2 Overexpression of HMGA2 was detected in 29 (19.2%) of the cases, and it was more commonly seen in patients with essential thrombocythemia than in those with polycythemia vera (26.9% vs 12.7%, P=0.044). Patients with upregulated HMGA2 showed an increased propensity for developing major thrombotic events, and they were more likely to harbor one of the 3 driver myeloproliferative neoplasm mutations in JAK2, MPL and CALR Our findings suggest that, in a subset of myeloproliferative neoplasm patients, the let-7-HMGA2 axis plays a prominent role in the pathogenesis of the disease that leads to unique clinical phenotypes.

  19. Acromelic frontonasal dysostosis and ZSWIM6 mutation: phenotypic spectrum and mosaicism

    PubMed Central

    Ousager, L.B.; Miller, K.A.; Zhou, Y.; Elalaoui, S.C.; Sefiani, A.; Bak, G.S; Hove, H.; Hansen, L.K.; Fagerberg, C.R.; Tajir, M.; Wilkie, A.O.M.

    2016-01-01

    Acromelic frontonasal dysostosis (AFND) is a distinctive and rare frontonasal malformation that presents in combination with brain and limb abnormalities. A single recurrent heterozygous missense substitution in ZSWIM6, encoding a protein of unknown function, was previously shown to underlie this disorder in four unrelated cases. Here we describe four additional individuals from three families, comprising two sporadic subjects (one of whom had no limb malformation) and a mildly affected female with a severely affected son. In the latter family we demonstrate parental mosaicism through deep sequencing of DNA isolated from a variety of tissues, which each contain different levels of mutation. This has important implications for genetic counselling. PMID:26706854

  20. Screening of a large cohort of Leber congenital amaurosis and retinitis pigmentosa patients identifies novel LCA5 mutations and new genotype-phenotype correlations

    PubMed Central

    Sui, Ruifang; van den Born, L. Ingeborgh; Berson, Eliot L.; Ocaka, Louise A.; Davidson, Alice E.; Heckenlively, John R.; Branham, Kari; Ren, Huanan; Lopez, Irma; Maria, Maleeha; Azam, Maleeha; Henkes, Arjen; Blokland, Ellen; Qamar, Raheel; Webster, Andrew R.; Andreasson, Sten; de Baere, Elfride; Bennett, Jean; Chader, Gerald J.; Berger, Wolfgang; Golovleva, Irina; Greenberg, Jacquie; den Hollander, Anneke I.; Klaver, Caroline C.W.; Klevering, B. Jeroen; Lorenz, Birgit; Preising, Markus N.; Ramsear, Raj; Roberts, Lisa; Roepman, Ronald; Rohrschneider, Klaus; Wissinger, Bernd

    2014-01-01

    To investigate the prevalence of sequence variants in LCA5 in patients with Leber congenital amaurosis (LCA), early onset rod-cone dystrophy (EORD) and autosomal recessive retinitis pigmentosa (RP), to delineate the ocular phenotypes, and to provide an overview of all published LCA5 variants in an online database._Patients underwent standard ophthalmic evaluations after providing informed consent. In selected patients, optical coherence tomography (OCT) and fundus autofluorescence imaging was possible. DNA samples from 797 unrelated patients with LCA and 211 with the various types of RP were screened by Sanger sequence analysis of all LCA5 exons and intron/exon junctions. Some LCA patients were pre-screened by APEX technology or selected based on homozygosity mapping. In silico analyses were performed to assess the pathogenicity of the variants. Segregation analysis was performed where possible. Published and novel LCA5 variants were collected, amended for their correct nomenclature, and listed in a Leiden Open Variation Database (LOVD). Sequence analysis identified 18 new probands with 19 different LCA5 variants. Seventeen of the 19 LCA5 variants were novel. Except for two missense variants and one splice site variant, all variants were protein-truncating mutations. Most patients expressed a severe phenotype, typical of LCA. However, some LCA subjects had better vision and intact inner segment/outer segment (IS/OS) junctions on OCT imaging. In two families with LCA5 variants, the phenotype was more compatible with EORD with affected individuals displaying preserved islands of RPE. One of these milder families harbored a homozygous splice site mutation, a second family was found to have a combination of a stop mutation and a missense mutation. This is the largest LCA5 study to date. We sequenced 1008 patients (797 with LCA, 211 with arRP) and identified 18 probands with LCA5 mutations. Mutations in LCA5 are a rare cause of childhood retinal dystrophy accounting for

  1. A mutation in the rice chalcone isomerase gene causes the golden hull and internode 1 phenotype.

    PubMed

    Hong, Lilan; Qian, Qian; Tang, Ding; Wang, Kejian; Li, Ming; Cheng, Zhukuan

    2012-07-01

    The biosynthesis of flavonoids, important secondary plant metabolites, has been investigated extensively, but few mutants of genes in this pathway have been identified in rice (Oryza sativa). The rice gold hull and internode (gh) mutants exhibit a reddish-brown pigmentation in the hull and internode and their phenotype has long been used as a morphological marker trait for breeding and genetic study. Here, we characterized that the gh1 mutant was a mutant of the rice chalcone isomerase gene (OsCHI). The result showed that gh1 had a Dasheng retrotransposon inserted in the 5′ UTR of the OsCHI gene, which resulted in the complete loss of OsCHI expression. gh1 exhibited golden pigmentation in hulls and internodes once the panicles were exposed to light. The total flavonoid content in gh1 hulls was increased threefold compared to wild type. Consistent with the gh1 phenotype, OsCHI transcripts were expressed in most tissues of rice and most abundantly in internodes. It was also expressed at high levels in panicles before heading, distributed mainly in lemmas and paleae, but its expression decreased substantially after the panicles emerged from the sheath. OsCHI encodes a protein functionally and structurally conserved to chalcone isomerases in other species. Our findings demonstrated that the OsCHI gene was indispensable for flux of the flavonoid pathway in rice.

  2. RNA editing by T7 RNA polymerase bypasses InDel mutations causing unexpected phenotypic changes

    PubMed Central

    Wons, Ewa; Furmanek-Blaszk, Beata; Sektas, Marian

    2015-01-01

    DNA-dependent T7 RNA polymerase (T7 RNAP) is the most powerful tool for both gene expression and in vitro transcription. By using a Next Generation Sequencing (NGS) approach we have analyzed the polymorphism of a T7 RNAP-generated mRNA pool of the mboIIM2 gene. We find that the enzyme displays a relatively high level of template-dependent transcriptional infidelity. The nucleotide misincorporations and multiple insertions in A/T-rich tracts of homopolymers in mRNA (0.20 and 0.089%, respectively) cause epigenetic effects with significant impact on gene expression that is disproportionally high to their frequency of appearance. The sequence-dependent rescue of single and even double InDel frameshifting mutants and wild-type phenotype recovery is observed as a result. As a consequence, a heterogeneous pool of functional and non-functional proteins of almost the same molecular mass is produced where the proteins are indistinguishable from each other upon ordinary analysis. We suggest that transcriptional infidelity as a general feature of the most effective RNAPs may serve to repair and/or modify a protein function, thus increasing the repertoire of phenotypic variants, which in turn has a high evolutionary potential. PMID:25824942

  3. An emerging, recognizable facial phenotype in association with mutations in GLI-similar 3 (GLIS3).

    PubMed

    Dimitri, Paul; De Franco, Elisa; Habeb, Abdelhadi M; Gurbuz, Fatih; Moussa, Khairya; Taha, Doris; Wales, Jerry K H; Hogue, Jacob; Slavotinek, Anne; Shetty, Ambika; Balasubramanian, Meena

    2016-07-01

    Neonatal diabetes and hypothyroidism (NDH) syndrome was first described in 2003 in a consanguineous Saudi Arabian family where two out of four siblings were reported to have presented with proportionate IUGR, neonatal non-autoimmune diabetes mellitus, severe congenital hypothyroidism, cholestasis, congenital glaucoma, and polycystic kidneys. Liver disease progressed to hepatic fibrosis. The renal disease was characterized by enlarged kidneys and multiple small cysts with deficient cortico-medullary junction differentiation and normal kidney function. There was minor facial dysmorphism (depressed nasal bridge, large anterior fontanelle, long philtrum) reported but no facial photographs were published. Mutations in the transcription factor GLI-similar 3 (GLIS3) gene in the original family and two other families were subsequently reported in 2006. All affected individuals had neonatal diabetes, congenital hypothyroidism but glaucoma and liver and kidney involvement were less consistent features. Detailed descriptions of the facial dysmorphism have not been reported previously. In this report, we describe the common facial dysmorphism consisting of bilateral low-set ears, depressed nasal bridge with overhanging columella, elongated, upslanted palpebral fissures, persistent long philtrum with a thin vermilion border of the upper lip in a cohort of seven patients with GLIS3 mutations and report the emergence of a distinct, probably recognizable facial gestalt in this group which evolves with age. © 2016 Wiley Periodicals, Inc.

  4. The Mutation of Glu at Amino Acid 3838 of AtMDN1 Provokes Pleiotropic Developmental Phenotypes in Arabidopsis

    PubMed Central

    Li, Peng-Cheng; Yu, Shao-Wei; Li, Ke; Huang, Jin-Guang; Wang, Xing-Jun; Zheng, Cheng-Chao

    2016-01-01

    MDN1/Rea1, as an AAA-type ATPase, is predicted to be the largest protein involved in pre-ribosome maturation in most organisms. However, its function in plant growth and development is poorly understood. Here, we characterized a novel Arabidopsis mutant, dwarf & short root (dsr) 1, which shows pleiotropic developmental phenotypes, such as slow germination, short root, dwarf shoot, and reduced seed set under normal growth conditions. Using positional cloning, we revealed that the AtMDN1 function is impaired by a ‘glutamic acid’ to ‘lysine’ change at position 3838 of the amino acid sequence in dsr1. Multiple sequence alignment analysis revealed that the mutated Glu residue, which located in the linker domain of AtMDN1, is extremely conserved among organisms. AtMDN1 is expressed in various tissues, particularly in the shoot apex and root tip. Moreover, the results of transcript profile analyses showed that the dysfunction of AtMDN1 in dsr1 impairs the expression of genes related to plant growth and development, which is tightly associated with the pleiotropic phenotypes of dsr1. Thus, we concluded that the Glu residue plays a vital role in maintaining AtMDN1 functions, which are essential for plant growth and development. PMID:27824150

  5. The exome sequencing identified the mutation in YARS2 encoding the mitochondrial tyrosyl-tRNA synthetase as a nuclear modifier for the phenotypic manifestation of Leber's hereditary optic neuropathy-associated mitochondrial DNA mutation.

    PubMed

    Jiang, Pingping; Jin, Xiaofen; Peng, Yanyan; Wang, Meng; Liu, Hao; Liu, Xiaoling; Zhang, Zengjun; Ji, Yanchun; Zhang, Juanjuan; Liang, Min; Zhao, Fuxin; Sun, Yan-Hong; Zhang, Minglian; Zhou, Xiangtian; Chen, Ye; Mo, Jun Qin; Huang, Taosheng; Qu, Jia; Guan, Min-Xin

    2016-02-01

    Leber's hereditary optic neuropathy (LHON) is the most common mitochondrial disorder. Nuclear modifier genes are proposed to modify the phenotypic expression of LHON-associated mitochondrial DNA (mtDNA) mutations. By using an exome sequencing approach, we identified a LHON susceptibility allele (c.572G>T, p.191Gly>Val) in YARS2 gene encoding mitochondrial tyrosyl-tRNA synthetase, which interacts with m.11778G>A mutation to cause visual failure. We performed functional assays by using lymphoblastoid cell lines derived from members of Chinese families (asymptomatic individuals carrying m.11778G>A mutation, or both m.11778G>A and heterozygous p.191Gly>Val mutations and symptomatic subjects harboring m.11778G>A and homozygous p.191Gly>Val mutations) and controls lacking these mutations. The 191Gly>Val mutation reduced the YARS2 protein level in the mutant cells. The aminoacylated efficiency and steady-state level of tRNA(Tyr) were markedly decreased in the cell lines derived from patients both carrying homozygous YARS2 p.191Gly>Val and m.11778G>A mutations. The failure in tRNA(Tyr) metabolism impaired mitochondrial translation, especially for polypeptides with high content of tyrosine codon such as ND4, ND5, ND6 and COX2 in cells lines carrying homozygous YARS2 p.191Gly>Val and m.11778G>A mutations. The YARS2 p.191Gly>Val mutation worsened the respiratory phenotypes associated with m.11778G>A mutation, especially reducing activities of complexes I and IV. The respiratory deficiency altered the efficiency of mitochondrial ATP synthesis and increased the production of reactive oxygen species. Thus, mutated YARS2 aggravates mitochondrial dysfunctions associated with the m.11778G>A mutation, exceeding the threshold for the expression of blindness phenotype. Our findings provided new insights into the pathophysiology of LHON that were manifested by interaction between mtDNA mutation and mutated nuclear-modifier YARS2.

  6. Phenotypic Variability from Benign Infantile Epilepsy to Ohtahara Syndrome Associated with a Novel Mutation in SCN2A

    PubMed Central

    Syrbe, Steffen; Zhorov, Boris S.; Bertsche, Astrid; Bernhard, Matthias K.; Hornemann, Frauke; Mütze, Ulrike; Hoffmann, Jessica; Hörtnagel, Konstanze; Kiess, Wieland; Hirsch, Franz W.; Lemke, Johannes R.; Merkenschlager, Andreas

    2016-01-01

    Mutations in SCN2A have been associated with benign familial neonatal-infantile seizures (BFNIS) as well as infantile-onset epileptic encephalopathy, such as Ohtahara syndrome (OS). We describe a family with 3 affected individuals carrying the novel SCN2A missense variant c.1147C>G, p.Q383E affecting a residue proximal to the highly conserved selectivity filter in the P-loop of the voltage-gated sodium channel (Nav1.2). All 3 individuals presented with seizures in early infancy. However, there were striking differences in the spectrum of clinical presentations, ranging from BFNIS to OS. A change of ion selectivity of Nav1.2 is considered to be the potential pathomechanism underlying this Nav1.2 channel dysfunction. The observation of benign and severe phenotypes due to an identical mutation within one family contradicts the hypothesis of different modes of inheritance as a mandatory feature discriminating BFNIS from SCN2A encephalopathy. PMID:27781028

  7. A new mutation in MC1R explains a coat color phenotype in 2 "old" breeds: Saluki and Afghan hound.

    PubMed

    Dreger, Dayna L; Schmutz, Sheila M

    2010-01-01

    Melanocortin 1 Receptor (MC1R) has been studied in a wide variety of domestic animals (Klungland et al. 1995; Marklund et al. 1996; Våge et al. 1997; Kijas et al. 1998; Newton et al. 2000; Våge et al. 2003), and also several wild animals (Robbins et al. 1993; Ritland et al. 2001; Eizirik et al. 2003; Nachman et al. 2003; McRobie et al. 2009) in relation to coat color variation. A variety of phenotypic changes have been reported including coat colors from pure black to pure red, as well as some phenotypes with hairs with red and black bands. One phenotype, called grizzle in Salukis and domino in Afghan Hounds, appears to be unique to these 2 old dog breeds. This pattern is characterized by a pale face with a widow's peak above the eyes. The body hairs on the dorsal surface of Salukis and Afghan Hounds have both phaeomelanin and eumelanin portions, even though they had an a(t)/a(t) genotype at ASIP. In addition, all had at least one copy of a newly identified mutation in MC1R, g.233G>T, resulting in p.Gly78Val. This new allele, that we suggest be designated as E(G), is dominant to the E and e (p.Arg306ter) alleles at MC1R but recessive to the E(M) (p.Met264Val) allele. The K(B) allele (p.Gly23del) at DEFB103 and the a(y) allele (p.Ala82Ser and p.Arg83His) of ASIP are epistatic to grizzle and domino.

  8. Human SOD1 ALS Mutations in a Drosophila Knock-In Model Cause Severe Phenotypes and Reveal Dosage-Sensitive Gain- and Loss-of-Function Components.

    PubMed

    Şahin, Aslı; Held, Aaron; Bredvik, Kirsten; Major, Paxton; Achilli, Toni-Marie; Kerson, Abigail G; Wharton, Kristi; Stilwell, Geoff; Reenan, Robert

    2017-02-01

    Amyotrophic Lateral Sclerosis (ALS) is the most common adult-onset motor neuron disease and familial forms can be caused by numerous dominant mutations of the copper-zinc superoxide dismutase 1 (SOD1) gene. Substantial efforts have been invested in studying SOD1-ALS transgenic animal models; yet, the molecular mechanisms by which ALS-mutant SOD1 protein acquires toxicity are not well understood. ALS-like phenotypes in animal models are highly dependent on transgene dosage. Thus, issues of whether the ALS-like phenotypes of these models stem from overexpression of mutant alleles or from aspects of the SOD1 mutation itself are not easily deconvolved. To address concerns about levels of mutant SOD1 in disease pathogenesis, we have genetically engineered four human ALS-causing SOD1 point mutations (G37R, H48R, H71Y, and G85R) into the endogenous locus of Drosophila SOD1 (dsod) via ends-out homologous recombination and analyzed the resulting molecular, biochemical, and behavioral phenotypes. Contrary to previous transgenic models, we have recapitulated ALS-like phenotypes without overexpression of the mutant protein. Drosophila carrying homozygous mutations rendering SOD1 protein enzymatically inactive (G85R, H48R, and H71Y) exhibited neurodegeneration, locomotor deficits, and shortened life span. The mutation retaining enzymatic activity (G37R) was phenotypically indistinguishable from controls. While the observed mutant dsod phenotypes were recessive, a gain-of-function component was uncovered through dosage studies and comparisons with age-matched dsod null animals, which failed to show severe locomotor defects or nerve degeneration. We conclude that the Drosophila knock-in model captures important aspects of human SOD1-based ALS and provides a powerful and useful tool for further genetic studies.

  9. Colorectal cancer risk variants at 8q23.3 and 11q23.1 are associated with disease phenotype in APC mutation carriers.

    PubMed

    Ghorbanoghli, Z; Nieuwenhuis, M H; Houwing-Duistermaat, J J; Jagmohan-Changur, S; Hes, F J; Tops, C M; Wagner, A; Aalfs, C M; Verhoef, S; Gómez García, E B; Sijmons, R H; Menko, F H; Letteboer, T G; Hoogerbrugge, N; van Wezel, T; Vasen, H F A; Wijnen, J T

    2016-10-01

    Familial adenomatous polyposis (FAP) is a dominantly inherited syndrome caused by germline mutations in the APC gene and characterized by the development of multiple colorectal adenomas and a high risk of developing colorectal cancer (CRC). The severity of polyposis is correlated with the site of the APC mutation. However, there is also phenotypic variability within families with the same underlying APC mutation, suggesting that additional factors influence the severity of polyposis. Genome-wide association studies identified several single nucleotide polymorphisms (SNPs) that are associated with CRC. We assessed whether these SNPs are associated with polyp multiplicity in proven APC mutation carriers. Sixteen CRC-associated SNPs were analysed in a cohort of 419 APC germline mutation carriers from 182 families. Clinical data were retrieved from the Dutch Polyposis Registry. Allele frequencies of the SNPs were compared for patients with <100 colorectal adenomas versus patients with ≥100 adenomas, using generalized estimating equations with the APC genotype as a covariate. We found a trend of association of two of the tested SNPs with the ≥100 adenoma phenotype: the C alleles of rs16892766 at 8q23.3 (OR 1.71, 95 % CI 1.05-2.76, p = 0.03, dominant model) and rs3802842 at 11q23.1 (OR 1.51, 95 % CI 1.03-2.22, p = 0.04, dominant model). We identified two risk variants that are associated with a more severe phenotype in APC mutation carriers. These risk variants may partly explain the phenotypic variability in families with the same APC gene defect. Further studies with a larger sample size are recommended to evaluate and confirm the phenotypic effect of these SNPs in FAP.

  10. A novel mutation (a886g) in exon 5 of FGFR2 in members of a family with Crouzon phenotype and plagiocephaly.

    PubMed Central

    Steinberger, D; Collmann, H; Schmalenberger, B; Müller, U

    1997-01-01

    We identified a novel mutation in members of a family with signs of Crouzon syndrome and plagiocephaly. In affected members of the family an A-->G transition was found at position 886 in exon 5 of the fibroblast growth factor receptor 2 (FGFR2) gene. The base change results in the replacement of a lysine by glutamic acid in Ig-like loop III of FGFR2. The unusual finding of plagiocephaly in these Crouzon patients may either be the result of the type of mutation or because of genetic and environmental factors that affect the phenotype in addition to the mutated FGF receptor. Images PMID:9152842

  11. Adaptor protein-2 sigma subunit mutations causing familial hypocalciuric hypercalcaemia type 3 (FHH3) demonstrate genotype–phenotype correlations, codon bias and dominant-negative effects

    PubMed Central

    Hannan, Fadil M.; Howles, Sarah A.; Rogers, Angela; Cranston, Treena; Gorvin, Caroline M.; Babinsky, Valerie N.; Reed, Anita A.; Thakker, Clare E.; Bockenhauer, Detlef; Brown, Rosalind S.; Connell, John M.; Cook, Jacqueline; Darzy, Ken; Ehtisham, Sarah; Graham, Una; Hulse, Tony; Hunter, Steven J.; Izatt, Louise; Kumar, Dhavendra; McKenna, Malachi J.; McKnight, John A.; Morrison, Patrick J.; Mughal, M. Zulf; O'Halloran, Domhnall; Pearce, Simon H.; Porteous, Mary E.; Rahman, Mushtaqur; Richardson, Tristan; Robinson, Robert; Scheers, Isabelle; Siddique, Haroon; van't Hoff, William G.; Wang, Timothy; Whyte, Michael P.; Nesbit, M. Andrew; Thakker, Rajesh V.

    2015-01-01

    The adaptor protein-2 sigma subunit (AP2σ2) is pivotal for clathrin-mediated endocytosis of plasma membrane constituents such as the calcium-sensing receptor (CaSR). Mutations of the AP2σ2 Arg15 residue result in familial hypocalciuric hypercalcaemia type 3 (FHH3), a disorder of extracellular calcium (Ca2+o) homeostasis. To elucidate the role of AP2σ2 in Ca2+o regulation, we investigated 65 FHH probands, without other FHH-associated mutations, for AP2σ2 mutations, characterized their functional consequences and investigated the genetic mechanisms leading to FHH3. AP2σ2 mutations were identified in 17 probands, comprising 5 Arg15Cys, 4 Arg15His and 8 Arg15Leu mutations. A genotype–phenotype correlation was observed with the Arg15Leu mutation leading to marked hypercalcaemia. FHH3 probands harboured additional phenotypes such as cognitive dysfunction. All three FHH3-causing AP2σ2 mutations impaired CaSR signal transduction in a dominant-negative manner. Mutational bias was observed at the AP2σ2 Arg15 residue as other predicted missense substitutions (Arg15Gly, Arg15Pro and Arg15Ser), which also caused CaSR loss-of-function, were not detected in FHH probands, and these mutations were found to reduce the numbers of CaSR-expressing cells. FHH3 probands had significantly greater serum calcium (sCa) and magnesium (sMg) concentrations with reduced urinary calcium to creatinine clearance ratios (CCCR) in comparison with FHH1 probands with CaSR mutations, and a calculated index of sCa × sMg/100 × CCCR, which was ≥ 5.0, had a diagnostic sensitivity and specificity of 83 and 86%, respectively, for FHH3. Thus, our studies demonstrate AP2σ2 mutations to result in a more severe FHH phenotype with genotype–phenotype correlations, and a dominant-negative mechanism of action with mutational bias at the Arg15 residue. PMID:26082470

  12. Mutations in fibroblast growth factor receptors: Phenotypic consequences during eukaryotic development

    SciTech Connect

    Park, W.J.; Bellus, G.A.; Jabs, E.W.

    1995-10-01

    Recently, a tremendous amount of excitement and interest has been generated by the rapid succession of discoveries in the human fibroblast growth factor receptor (FGFR) field. In less than a year, mutations in three FGFRs (FGFR1-FGFR3) have been associated with three skeletal dysplasias and four craniosynostotic syndromes. FGFRs are members of the receptor tyrosine kinase family that bind fibroblast growth factors (FGFs). The FGF family consists of structurally related polypeptides that play a key role in numerous aspects of embryogenesis, growth, and homeostasis. FGFs have a potent growth stimulatory and/or differentiation-inducing effect on cells such as those derived from the early-embryonic mesoderm or ectoderm. In addition to mitogenesis and differentiation, FGFs also stimulate chemotaxis, cell survival, and angiogenesis. FGFs mediate cellular responses on binding to and activation of FGFRs. 45 refs., 2 figs., 1 tab.

  13. Phenotypic characterization of a patient homozygous for the D558N LDL receptor gene mutation.

    PubMed

    Jensen, H K; Jensen, L G; Heath, F; Melsen, F; Hansen, P S; Meinertz, H; Bolund, L; Gregersen, N; Faergeman, O

    1996-11-01

    We describe the clinical, biochemical, and genetic features of a patient with true homozygous familial hypercholesterolemia due to the D558N low-density lipoprotein receptor gene mutation, previously designated FH Cincinnati-4. Functional flow-cytometric analysis of the LDL receptorR protein on upregulated EBV-transformed lymphocytes indicated reduction of the number of receptors on the cell surface by 87% and reduction of receptor activity by 89% compared to control cells. With drugs and a portacaval shunt operation, performed when the patient was 15 years old, serum cholesterol was reduced from about 28 to about 15 mmol/l. He died at the age of 32 of a myocardial infarction. The autopsy showed generalized atherosclerosis, especially in the coronary arteries, which were severely stenosed proximally. A rare finding was a large intracranial xanthoma that apparently had been asymptomatic.

  14. Identification of two different point mutations associated with the fluoride-resistant phenotype for human butyrylcholinesterase

    SciTech Connect

    Nogueira, C.P.; McGuire, M.C.; Adkins, S.; Van Der Spek, A.F.L.; La Du, B.N. ); Bartels, C.F.; Lockridge, O. Eppley Institute, Univ. of Nebraska Medical Center, Omaha, NE ); Lubrano, T.; Rubinstein, H.M. Loyola Univ. Stritch School of Medicine, Maywood, IL ); Lightstone, H. )

    1992-10-01

    The fluoride variant of human butyrylcholinesterase owes its name to the observation that it is resistant to inhibition by 0.050 mM sodium fluoride in the in vitro assay. Individuals who are heterozygous for the fluoride and atypical alleles experience about 30 min of apnea, rather than the usual 3-5 min, after receiving succinyldicholine. Earlier the authors reported that the atypical variant has a nucleotide substitution which changes Asp 70 to Gly. In the present work they have identified two different point mutations associated with the fluoride-resistant phentotype. Fluoride-1 has a nucleotide substitution which changes Thr 243 to Met (ACG to ATG). Fluoride-2 has a substitution which changes Gly 390 to Val (GGT to GTT). These results were obtained by DNA sequence analysis of the butyrylcholinesterase gene after amplification by PCR. The subjects for these analyses were 4 patients and 21 family members. 36 refs., 8 figs.

  15. Heterozygous STAT1 gain-of-function mutations underlie an unexpectedly broad clinical phenotype

    PubMed Central

    Toubiana, Julie; Okada, Satoshi; Hiller, Julia; Oleastro, Matias; Lagos Gomez, Macarena; Aldave Becerra, Juan Carlos; Ouachée-Chardin, Marie; Fouyssac, Fanny; Girisha, Katta Mohan; Etzioni, Amos; Van Montfrans, Joris; Camcioglu, Yildiz; Kerns, Leigh Ann; Belohradsky, Bernd; Blanche, Stéphane; Bousfiha, Aziz; Rodriguez-Gallego, Carlos; Meyts, Isabelle; Kisand, Kai; Reichenbach, Janine; Renner, Ellen D.; Rosenzweig, Sergio; Grimbacher, Bodo; van de Veerdonk, Frank L.; Traidl-Hoffmann, Claudia; Picard, Capucine; Marodi, Laszlo; Morio, Tomohiro; Kobayashi, Masao; Lilic, Desa; Milner, Joshua D.; Holland, Steven; Casanova, Jean-Laurent

    2016-01-01

    Since their discovery in patients with autosomal dominant (AD) chronic mucocutaneous candidiasis (CMC) in 2011, heterozygous STAT1 gain-of-function (GOF) mutations have increasingly been identified worldwide. The clinical spectrum associated with them needed to be delineated. We enrolled 274 patients from 167 kindreds originating from 40 countries from 5 continents. Demographic data, clinical features, immunological parameters, treatment, and outcome were recorded. The median age of the 274 patients was 22 years (range, 1-71 years); 98% of them had CMC, with a median age at onset of 1 year (range, 0-24 years). Patients often displayed bacterial (74%) infections, mostly because of Staphylococcus aureus (36%), including the respiratory tract and the skin in 47% and 28% of patients, respectively, and viral (38%) infections, mostly because of Herpesviridae (83%) and affecting the skin in 32% of patients. Invasive fungal infections (10%), mostly caused by Candida spp. (29%), and mycobacterial disease (6%) caused by Mycobacterium tuberculosis, environmental mycobacteria, or Bacille Calmette-Guérin vaccines were less common. Many patients had autoimmune manifestations (37%), including hypothyroidism (22%), type 1 diabetes (4%), blood cytopenia (4%), and systemic lupus erythematosus (2%). Invasive infections (25%), cerebral aneurysms (6%), and cancers (6%) were the strongest predictors of poor outcome. CMC persisted in 39% of the 202 patients receiving prolonged antifungal treatment. Circulating interleukin-17A–producing T-cell count was low for most (82%) but not all of the patients tested. STAT1 GOF mutations underlie AD CMC, as well as an unexpectedly wide range of other clinical features, including not only a variety of infectious and autoimmune diseases, but also cerebral aneurysms and carcinomas that confer a poor prognosis. PMID:27114460

  16. Suppression of the abnormal phenotype of Salmonella typhimurium rfaH mutants by mutations in the gene for transcription termination factor Rho.

    PubMed Central

    Farewell, A; Brazas, R; Davie, E; Mason, J; Rothfield, L I

    1991-01-01

    Mutations in the rfaH gene have previously been shown to cause premature termination of transcription of the traYZ operon of the F factor and also to prevent expression of the rfaGBIJ gene cluster of Salmonella typhimurium. In the present study, mutants were selected for their ability to restore the normal pattern of rfaGBIJ function. On the basis of this initial section, several classes of extragenic suppressor mutants were isolated that completely or partially corrected the Tra- and Rfa- phenotypes of the prototype rfaH mutant. The suppressor mutations included mutations in rho and mutations that mapped in or close to rpoBC. Other suppressor mutations were located elsewhere on the chromosome, presumably identifying other genes that play a role in the RfaH-mediated transcriptional regulation. PMID:1860828

  17. FGFR2 mutation in a patient without typical features of Pfeiffer syndrome--The emerging role of combined NGS and phenotype based strategies.

    PubMed

    Flöttmann, Ricarda; Knaus, Alexej; Zemojtel, Tomasz; Robinson, Peter N; Mundlos, Stefan; Horn, Denise; Spielmann, Malte

    2015-08-01

    Pfeiffer syndrome (MIM: #101600) is a rare autosomal dominant disorder classically characterized by limb and craniofacial anomalies. It is caused by heterozygous mutations in the fibroblast growth factor receptors types 1 and 2 (FGFR1 and FGFR2). We applied a next generation sequencing (NGS) panel approach comprising all 2877 genes currently known to be causative for one or more Mendelian diseases combined with the phenotype based computational tool PhenIX (Phenotypic Interpretation of eXomes). We report on a patient presenting with multiple anomalies of hands and feet including brachydactyly and symphalangism. No clinical diagnosis could be established based on the clinical findings and testing of several genes associated with brachydactyly and symphalangism failed to identify mutations. Via next generation sequencing (NGS) panel approach we then identified a novel de novo missense FGFR2 mutation affecting an amino acid reported to be mutated in Pfeiffer syndrome. Since our patient shows typical radiological findings of Pfeiffer syndrome in hands and feet but at the same time lacks several characteristic features such as clinical signs of craniosynostosis and prominent eyes we suggest introducing the term "FGFR2 associated phenotypes" for similar cases. Our results highlight the emerging role of combined NGS and phenotype based bioinformatics strategies to establish clinical diagnoses.

  18. Mutation survey and genotype-phenotype analysis of COL2A1 and COL11A1 genes in 16 Chinese patients with Stickler syndrome

    PubMed Central

    Wang, Xun; Jia, Xiaoyun; Xiao, Xueshan; Li, Shiqiang; Li, Jie; Li, Yadi; Wei, Yantao; Liang, Xiaoling

    2016-01-01

    Purpose To identify mutations in COL2A1 and COL11A1 genes and to examine the genotype-phenotype correlation in a cohort of Chinese patients with Stickler syndrome. Methods A total of 16 Chinese probands with Stickler syndrome were recruited, including nine with a family history of an autosomal dominant pattern and seven sporadic cases. All patients underwent full ocular and systemic examinations. Sanger sequencing was used to analyze all coding and adjacent regions of the COL2A1 and COL11A1 genes. Multiplex ligation-dependent probe amplification was performed to detect the gross indels of COL2A1 and COL11A1. Bioinformatics analysis was performed to evaluate the pathogenicity of the variants. Results Five mutations in COL2A1 were identified in six of 16 probands, including three novel (c.85C>T, c.3356delG, c.3401delG) mutations and two known mutations (c.1693C>T, c.2710C>T). Of the five mutations, three were truncated mutations, and the other two were missense mutations. Putative pathogenic mutations of the COL11A1 gene were absent in this cohort of patients. Gross indels were not found in COL2A1 or COL11A1 in any of the probands. High myopia was the most frequent initial ocular phenotype of Stickler syndrome. In this study, 12 Chinese probands lacked obvious systemic phenotypes. Conclusions In this study, three novel and two known mutations in the COL2A1 gene were identified in six of 16 Chinese patients with Stickler syndrome. This is the first study in a cohort of Chinese patients with Stickler syndrome, and the results expand the mutation spectrum of the COL2A1 gene. Analysis of the genotype-phenotype correlation showed that the early onset of high myopia with vitreous abnormalities may serve as a key indicator of Stickler syndrome, while the existence of mandibular protrusion in pediatric patients may be an efficient indicator for the absence of mutations in COL2A1 and COL11A1. PMID:27390512

  19. Limited phenotypic variation of hypocalcified amelogenesis imperfecta in a Danish five-generation family with a novel FAM83H nonsense mutation.

    PubMed

    Haubek, Dorte; Gjørup, Hans; Jensen, Lillian G; Juncker, Inger; Nyegaard, Mette; Børglum, Anders D; Poulsen, Sven; Hertz, Jens M

    2011-11-01

    BACKGROUND.  Autosomal dominant hypocalcified amelogenesis imperfecta (ADHCAI) is a disease with severe dental manifestations. OBJECTIVES.  The aims were by means of a genome-wide linkage scan to search for the gene underlying the ADHCAI phenotype in a Danish five-generation family and to study the phenotypic variation of the enamel in affected family members. RESULTS.  Significant linkage was found to a locus at chromosome 8q24.3 comprising the gene FAM83H identified to be responsible for ADHCAI in other families. Subsequent sequencing of FAM83H in affected family members revealed a novel nonsense mutation, p.Y302X. Limited phenotypic variation was found among affected family members with loss of translucency and discoloration of the enamel. Extensive posteruptive loss of enamel was found in all teeth of affected subjects. The tip of the cusps on the premolars and molars and a zone along the gingival margin seemed resistant to posteruptive loss of enamel. We have screened FAM83H in another five unrelated Danish patients with a phenotype of ADHCAI similar to that in the five-generation family, and identified a de novo FAM83H nonsense mutation, p.Q452X in one of these patients. CONCLUSION.  We have identified a FAM83H mutation in two of six unrelated families with ADHCAI and found limited phenotypic variation of the enamel in these patients.

  20. The rem mutations in the ATP-binding groove of the Rad3/XPD helicase lead to Xeroderma pigmentosum-Cockayne syndrome-like phenotypes.

    PubMed

    Herrera-Moyano, Emilia; Moriel-Carretero, María; Montelone, Beth A; Aguilera, Andrés

    2014-12-01

    The eukaryotic TFIIH complex is involved in Nucleotide Excision Repair and transcription initiation. We analyzed three yeast mutations of the Rad3/XPD helicase of TFIIH known as rem (recombination and mutation phenotypes). We found that, in these mutants, incomplete NER reactions lead to replication fork breaking and the subsequent engagement of the homologous recombination machinery to restore them. Nevertheless, the penetrance varies among mutants, giving rise to a phenotype gradient. Interestingly, the mutations analyzed reside at the ATP-binding groove of Rad3 and in vivo experiments reveal a gain of DNA affinity upon damage of the mutant Rad3 proteins. Since mutations at the ATP-binding groove of XPD in humans are present in the Xeroderma pigmentosum-Cockayne Syndrome (XP-CS), we recreated rem mutations in human cells, and found that these are XP-CS-like. We propose that the balance between the loss of helicase activity and the gain of DNA affinity controls the capacity of TFIIH to open DNA during NER, and its persistence at both DNA lesions and promoters. This conditions NER efficiency and transcription resumption after damage, which in human cells would explain the XP-CS phenotype, opening new perspectives to understand the molecular basis of the role of XPD in human disease.

  1. The rem Mutations in the ATP-Binding Groove of the Rad3/XPD Helicase Lead to Xeroderma pigmentosum-Cockayne Syndrome-Like Phenotypes

    PubMed Central

    Montelone, Beth A.; Aguilera, Andrés

    2014-01-01

    The eukaryotic TFIIH complex is involved in Nucleotide Excision Repair and transcription initiation. We analyzed three yeast mutations of the Rad3/XPD helicase of TFIIH known as rem (recombination and mutation phenotypes). We found that, in these mutants, incomplete NER reactions lead to replication fork breaking and the subsequent engagement of the homologous recombination machinery to restore them. Nevertheless, the penetrance varies among mutants, giving rise to a phenotype gradient. Interestingly, the mutations analyzed reside at the ATP-binding groove of Rad3 and in vivo experiments reveal a gain of DNA affinity upon damage of the mutant Rad3 proteins. Since mutations at the ATP-binding groove of XPD in humans are present in the Xeroderma pigmentosum-Cockayne Syndrome (XP-CS), we recreated rem mutations in human cells, and found that these are XP-CS-like. We propose that the balance between the loss of helicase activity and the gain of DNA affinity controls the capacity of TFIIH to open DNA during NER, and its persistence at both DNA lesions and promoters. This conditions NER efficiency and transcription resumption after damage, which in human cells would explain the XP-CS phenotype, opening new perspectives to understand the molecular basis of the role of XPD in human disease. PMID:25500814

  2. A Mutation in the β3 Subunit of the Cardiac Sodium Channel Associated with Brugada ECG Phenotype

    PubMed Central

    Hu, Dan; Barajas-Martinez, Hector; Burashnikov, Elena; Springer, Michael; Wu, Yuesheng; Varro, Andras; Pfeiffer, Ryan; Koopmann, Tamara T.; Cordeiro, Jonathan M.; Guerchicoff, Alejandra; Pollevick, Guido D.; Antzelevitch, Charles

    2009-01-01

    Background Brugada Syndrome (BrS), characterized by ST segment elevation in the right precordial ECG leads and the development of life-threatening ventricular arrhythmias, has been associated with mutations in six different genes. Here, we identify and characterize a mutation in a new gene. Methods and Results A 64-year-old Caucasian male displayed a Type-1 ST segment elevation in V1 and V2 during procainamide challenge. Polymerase chain reaction (PCR)-based direct sequencing was performed using a candidate gene approach. A missense mutation (L10P) was detected in exon 1 of SCN3B, the β3 subunit of the cardiac sodium channel, but not in any other gene known to be associated with BrS or in 296 controls. Wild type (WT) and mutant genes were expressed in TSA201 cells and studied using whole-cell patch-clamp techniques. Co-expression of SCN5A/WT+SCN1B/WT+SCN3B/L10P resulted in an 82.6% decrease in peak sodium current density, accelerated inactivation, slowed reactivation and a -9.6 mV shift of half-inactivation voltage compared to SCN5A/WT+SCN1B/WT+SCN3B/WT. Confocal microscopy revealed that SCN5A/WT channels tagged with green fluorescent protein (GFP) are localized to the cell surface when co-expressed with WT SCN1B and SCN3B, but remain trapped in intracellular organelles when co-expressed with SCN1B/WT and SCN3B/L10P. Western blot analysis confirmed the presence of NaVβ3 in human ventricular myocardium. Conclusions Our results provide support for the hypothesis that mutations in SCN3B can lead to loss of transport and functional expression of the hNav1.5 protein, leading to reduction in sodium channel current and clinical manifestation of a Brugada phenotype. PMID:20031595

  3. Novel compound heterozygous mutations in DYNC2H1 in a patient with severe short-rib polydactyly syndrome type III phenotype.

    PubMed

    Okamoto, Toshio; Nagaya, Ken; Kawata, Yumi; Asai, Hiroko; Tsuchida, Etsushi; Nohara, Fumikatsu; Okajima, Kazuki; Azuma, Hiroshi

    2015-08-01

    Short-rib polydactyly syndrome type III is an autosomal recessive lethal skeletal ciliopathy, which is phenotypically similar to nonlethal asphyxiating thoracic dystrophy. Mutations in DYNC2H1 have been identified in both of these disorders, indicating that they are variants of a single disorder. However, short-rib polydactyly syndrome type III is the more severe variant. Here, we report novel compound heterozygous mutations in DYNC2H1 (p.E1894fsX10 and p.R3004C) in a patient with typical short-rib polydactyly syndrome type III phenotype. R3004 is located within the microtubule-binding domain of DYNC2H1, and its substitution is predicted to disrupt the interaction with microtubules. Considering the severe phenotype of our patient, our findings suggest that R3004 may be a key residue for the microtubule-binding affinity of dynein.

  4. A Mutation in the Mouse Chd2 Chromatin Remodeling Enzyme Results in a Complex Renal Phenotype

    PubMed Central

    Marfella, Concetta G.A.; Henninger, Nils; LeBlanc, Scott E.; Krishnan, Namrata; Garlick, David S.; Holzman, Lawrence B.; Imbalzano, Anthony N.

    2009-01-01

    Background and Aims Glomerular diseases are the third leading cause of kidney failure worldwide, behind only diabetes and hypertension. The molecular mechanisms underlying the cause of glomerular diseases are still largely unknown. The identification and characterization of new molecules associated with glomerular function should provide new insights into understanding the diverse group of glomerular diseases. The Chd2 protein belongs to a family of enzymes involved in ATP-dependent chromatin remodeling, suggesting that it likely functions as an epigenetic regulator of gene expression via the modification of chromatin structure. Methods In this study, we present a detailed histomorphologic characterization of mice containing a mutation in the chromodomain helicase DNA-binding protein 2 (Chd2). Results We show that Chd2-mutant mice present with glomerulopathy, proteinuria, and significantly impaired kidney function. Additionally, serum analysis revealed decreased hemoglobin and hematocrit levels in Chd2-mutant mice, suggesting that the glomerulopathy observed in these mice is associated with anemia. Conclusion Collectively, the data suggest a role for the Chd2 protein in the maintenance of kidney function. PMID:19142019

  5. Molecular pathogenesis of Wilson and Menkes disease: correlation of mutations with molecular defects and disease phenotypes

    PubMed Central

    de Bie, P; Muller, P; Wijmenga, C; Klomp, L W J

    2007-01-01

    The trace metal copper is essential for a variety of biological processes, but extremely toxic when present in excessive amounts. Therefore, concentrations of this metal in the body are kept under tight control. Central regulators of cellular copper metabolism are the copper‐transporting P‐type ATPases ATP7A and ATP7B. Mutations in ATP7A or ATP7B disrupt the homeostatic copper balance, resulting in copper deficiency (Menkes disease) or copper overload (Wilson disease), respectively. ATP7A and ATP7B exert their functions in copper transport through a variety of interdependent mechanisms and regulatory events, including their catalytic ATPase activity, copper‐induced trafficking, post‐translational modifications and protein–protein interactions. This paper reviews the extensive efforts that have been undertaken over the past few years to dissect and characterise these mechanisms, and how these are affected in Menkes and Wilson disease. As both disorders are characterised by an extensive clinical heterogeneity, we will discus how the underlying genetic defects correlate with the molecular functions of ATP7A and ATP7B and with the clinical expression of these disorders. PMID:17717039

  6. Mutations in alternative carbon utilization pathways in Candida albicans attenuate virulence and confer pleiotropic phenotypes.

    PubMed

    Ramírez, Melissa A; Lorenz, Michael C

    2007-02-01

    The interaction between Candida albicans and cells of the innate immune system is a key determinant of disease progression. Transcriptional profiling has revealed that C. albicans has a complex response to phagocytosis, much of which is similar to carbon starvation. This suggests that nutrient limitation is a significant stress in vivo, and we have shown that glyoxylate cycle mutants are less virulent in mice. To examine whether other aspects of carbon metabolism are important in vivo during an infection, we have constructed strains lacking FOX2 and FBP1, which encode key components of fatty acid beta-oxidation and gluconeogenesis, respectively. As expected, fox2Delta mutants failed to utilize several fatty acids as carbon sources. Surprisingly, however, these mutants also failed to grow in the presence of several other carbon sources, whose assimilation is independent of beta-oxidation, including ethanol and citric acid. Mutants lacking the glyoxylate enzyme ICL1 also had more severe carbon utilization phenotypes than were expected. These results suggest that the regulation of alternative carbon metabolism in C. albicans is significantly different from that in other fungi. In vivo, fox2Delta mutants show a moderate but significant reduction in virulence in a mouse model of disseminated candidiasis, while disruption of the glyoxylate cycle or gluconeogenesis confers a severe attenuation in this model. These data indicate that C. albicans often encounters carbon-poor conditions during growth in the host and that the ability to efficiently utilize multiple nonfermentable carbon sources is a virulence determinant. Consistent with this in vivo requirement, C. albicans uniquely regulates carbon metabolism in a more integrated manner than in Saccharomyces cerevisiae, such that defects in one part of the machinery have wider impacts than expected. These aspects of alternative carbon metabolism may then be useful as targets for therapeutic intervention.

  7. Tracing the pathway between mutation and phenotype in osteogenesis imperfecta: Isolation of mineralization-specific genes

    SciTech Connect

    Culbert, A.A.; Wallis, G.A.; Kadler, K.E.

    1996-05-03

    The brittleness of bone in people with lethal (type II) osteogenesis imperfecta, a heritable disorder caused by mutations in the type I collagen genes, arises from the deposition of abnormal collagen in the bone matrix. The inability of the abnormal collagen to participate in mineralization may be caused by its failure to interact with other bone proteins. Here, we have designed a strategy to isolate the genes important for mineralization of collagen during bone formation. Cells isolated from 16-day embryonic chick calvaria and seeded post-confluence in culture deposited a mineralized matrix over a period of 2 weeks. Chick skin fibroblasts seeded and cultured under the same conditions did not mineralize. Using RT-PCR, we prepared short cDNAs ({approximately}300 bp) corresponding to the 3{prime} ends of mRNA from fibroblasts and separately from the mineralizing calvarial cells. Subtractive cDNA hybridization generated a pool of cDNAs that were specific to mineralizing calvarial cells but not to fibroblasts. Screening of 100,000 plaques of a chick bone ZAP Express cDNA library with this pool of mineralizing-specific cDNAs identified ten clones which comprised full-length cDNAs for the bone proteins osteopontin (eight of the ten positives), bone sialoprotein II (one of the ten positives), and cystatin (one of the ten positives). cDNAs for type I collagen, fibronectin, alkaline phosphatase, house-keeping genes, and other genes expressed in fibroblasts were not identified in this preliminary screen. The pool of short cDNAs is likely to comprise cDNAs for further bone-specific genes and will be used to screen the entire bone cDNA library of 4.2 million clones. 30 refs., 4 figs.

  8. Eight Novel Mutations Confirm the Role of AAGAB in Punctate Palmoplantar Keratoderma Type 1 (Buschke-Fischer-Brauer) and Show Broad Phenotypic Variability.

    PubMed

    Giehl, Kathrin A; Herzinger, Thomas; Wolff, Hans; Sárdy, Miklós; von Braunmühl, Tanja; Dekeuleneer, Valérie; Sznajer, Yves; Tennstedt, Dominique; Boes, Pascaline; Rapprich, Stefan; Wagner, Nicola; Betz, Regina C; Braun-Falco, Markus; Strom, Tim; Ruzicka, Thomas; Eckstein, Gertrud N

    2016-05-01

    Punctate palmoplantar keratoderma (PPKP1; Buschke-Fischer-Brauer) is a rare autosomal dominant inherited skin disease characterized by multiple hyperkeratotic papules involving the palms and soles. Mutations have been found at 2 loci, on chromosomes 15q22-15q24 and 8q24.13-8q24.21. We recently identified mutations in 3 families, in the AAGAB gene on 15q, which encodes the alpha- and gamma-adaptin-binding protein p34. The current study examined 14 additional families, comprising a total of 26 affected individuals and identified 8 novel mutations in 9 families. In one family a mutation that was present only in the affected individuals was found, and in 4 other families, previously reported mutations were found (1, 2). These results confirm the role of AAGAB in PPKP1. Our findings suggest that there is no correlation with age, but with mechanical factors. No additional obvious genotype-phenotype correlation was observed, even when comparing different types of mutations. Rather, identical genotypes presented a very broad interfamilial and intrafamilial variability of phenotypes.

  9. The clustered regularly interspaced short palindromic repeats/associated proteins system for the induction of gene mutations and phenotypic changes in Bombyx mori.

    PubMed

    Song, Jia; Che, Jiaqian; You, Zhengying; Ye, Xiaogang; Li, Jisheng; Ye, Lupeng; Zhang, Yuyu; Qian, Qiujie; Zhong, Boxiong

    2016-12-01

    To probe the general phenomena of gene mutations, Bombyx mori, the lepidopterous model organism, was chosen as the experimental model. To easily detect phenotypic variations, the piggyBac system was utilized to introduce two marker genes into the silkworm, and 23.4% transposition efficiency aided in easily breeding a new strain for the entire experiment. Then, the clustered regularly interspaced short palindromic repeats/an associated protein (Cas9) system was utilized. The results showed that the Cas9 system can induce efficient gene mutations and the base changes could be detected since the G0 individuals in B. mori; and that the mutation rates on different target sites were diverse. Next, the gRNA2-targeted site that generated higher mutation rate was chosen, and the experimental results were enumerated. First, the mutation proportion in G1 generation was 30.1%, and some gene mutations were not inherited from the G0 generation; second, occasionally, base substitutions did not lead to variation in the amino-acid sequence, which decreased the efficiency of phenotypic changes compared with that of genotypic changes. These results laid the foundation for better use of the Cas9 system in silkworm gene editing.

  10. A novel mutation in DNAJB6, p.(Phe91Leu), in childhood-onset LGMD1D with a severe phenotype.

    PubMed

    Nam, Tai-Seung; Li, Wenting; Heo, Suk-Hee; Lee, Kyung-Hwa; Cho, Anna; Shin, Jin-Hong; Kim, Young Ok; Chae, Jong-Hee; Kim, Dae-Seong; Kim, Myeong-Kyu; Choi, Seok-Yong

    2015-11-01

    To identify and characterize genetic mutation in a Korean family with limb-girdle muscular dystrophy 1 (LGMD1), we analyzed in the affected family members clinical features, DNAJB6 by Sanger sequencing, muscle structures by magnetic resonance imaging (MRI), and functional consequences of the identified mutation using a zebrafish model. The clinical phenotypes along with identification of a novel c.271T > C (p.(Phe91Leu)) mutation in DNAJB6 led to the diagnosis of LGMD1D in the affected family members. This mutation presents unique clinical and radiological features compared with other DNAJB6 mutants. All affected members examined showed reduced pulmonary function, and had nasal voice and dysphagia except the two members who were thirteen and twelve years of age at the time of examination. Muscle phenotypes developed between 8 and 11 years of age and were more severe as compared to previously reported LGMD1D patients with mutant DNAJB6. Patients' MRI scans exhibited early involvement of the lateral head of gastrocnemius, in contrast to its late involvement in reported LGMD1D cases. Functional study using zebrafish embryos demonstrated that p.Phe91Leu elicits more severe muscle defects than the reported p.Phe93Leu and p.Pro96Arg mutations. We conclude that a novel p.(Phe91Leu) mutation in DNAJB6 is associated with severe childhood-onset LGMD1D.

  11. The roles of two novel FBN1 gene mutations in the genotype-phenotype correlations of Marfan syndrome and ectopia lentis patients with marfanoid habitus.

    PubMed

    Li, Dan; Yu, Jie; Gu, Feng; Pang, Xiuqin; Ma, Xixin; Li, Rong; Liu, Ningpu; Ma, Xu

    2008-06-01

    Mutations in the fibrillin-1 (FBN1) gene have been identified in patients with Marfan syndrome (MFS) and Marfan-like connective tissue disorders. In this study, two Chinese families were recruited. The patients in family 1 were well characterized with MFS, while those in family 2 displayed Marfan-like disorders such as ectopia lentis (EL) and marfanoid habitus, but did not develop cardiovascular diseases. We aimed to analyze the pathogenic mutations and their relationships with phenotypes in these two Chinese families. All participants underwent complete physical, ophthalmic, and cardiovascular examinations. The 65 exons and flanking intronic sequences of FBN1 were amplified by polymerase chain reaction, and screened for mutations by denaturing high-performance liquid chromatography and sequencing. One hundred and fifteen unrelated controls were analyzed using the same methods to confirm the mutations. In family 1, we identified the mutation p.C499S in the calcium-binding epidermal growth factor (cbEGF)-like domain 3 of FBN1. In family 2, the mutation p.C908Y was identified in an interdomain region of the hybrid motif 2 linked to the cbEGF-like domain 10. It can be concluded that FBN1 mutations involving cysteine substitutions are usually associated with MFS and EL with some MFS features. Moreover, pathology seemed more serious when the mutations disrupted the three disulfide bridges in the cbEGF-like domains, which was more likely to cause typical MFS than if the mutations occurred in the hybrid motifs. Our data preliminarily establish a genotype-phenotype correlation in the diagnostic process of MFS and predominant EL with Marfan-like features.

  12. Mutations in UDP-Glucose:sterol glucosyltransferase in Arabidopsis cause transparent testa phenotype and suberization defect in seeds.

    PubMed

    DeBolt, Seth; Scheible, Wolf-Rüdiger; Schrick, Kathrin; Auer, Manfred; Beisson, Fred; Bischoff, Volker; Bouvier-Navé, Pierrette; Carroll, Andrew; Hematy, Kian; Li, Yonghua; Milne, Jennifer; Nair, Meera; Schaller, Hubert; Zemla, Marcin; Somerville, Chris

    2009-09-01

    In higher plants, the most abundant sterol derivatives are steryl glycosides (SGs) and acyl SGs. Arabidopsis (Arabidopsis thaliana) contains two genes, UGT80A2 and UGT80B1, that encode UDP-Glc:sterol glycosyltransferases, enzymes that catalyze the synthesis of SGs. Lines having mutations in UGT80A2, UGT80B1, or both UGT80A2 and UGT8B1 were identified and characterized. The ugt80A2 lines were viable and exhibited relatively minor effects on plant growth. Conversely, ugt80B1 mutants displayed an array of phenotypes that were pronounced in the embryo and seed. Most notable was the finding that ugt80B1 was allelic to transparent testa15 and displayed a transparent testa phenotype and a reduction in seed size. In addition to the role of UGT80B1 in the deposition of flavanoids, a loss of suberization of the seed was apparent in ugt80B1 by the lack of autofluorescence at the hilum region. Moreover, in ugt80B1, scanning and transmission electron microscopy reveals that the outer integument of the seed coat lost the electron-dense cuticle layer at its surface and displayed altered cell morphology. Gas chromatography coupled with mass spectrometry of lipid polyester monomers confirmed a drastic decrease in aliphatic suberin and cutin-like polymers that was associated with an inability to limit tetrazolium salt uptake. The findings suggest a membrane function for SGs and acyl SGs in trafficking of lipid polyester precursors. An ancillary observation was that cellulose biosynthesis was unaffected in the double mutant, inconsistent with a predicted role for SGs in priming cellulose synthesis.

  13. EGFR-activating mutations correlate with a Fanconi anemia-like cellular phenotype that includes PARP inhibitor sensitivity.

    PubMed

    Pfäffle, Heike N; Wang, Meng; Gheorghiu, Liliana; Ferraiolo, Natalie; Greninger, Patricia; Borgmann, Kerstin; Settleman, Jeffrey; Benes, Cyril H; Sequist, Lecia V; Zou, Lee; Willers, Henning

    2013-10-15

    In patients with lung cancer whose tumors harbor activating mutations in the EGF receptor (EGFR), increased responses to platinum-based chemotherapies are seen compared with wild-type cancers. However, the mechanisms underlying this association have remained elusive. Here, we describe a cellular phenotype of cross-linker sensitivity in a subset of EGFR-mutant lung cancer cell lines that is reminiscent of the defects seen in cells impaired in the Fanconi anemia pathway, including a pronounced G2-M cell-cycle arrest and chromosomal radial formation. We identified a defect downstream of FANCD2 at the level of recruitment of FAN1 nuclease and DNA interstrand cross-link (ICL) unhooking. The effect of EGFR mutation was epistatic with FANCD2. Consistent with the known role of FANCD2 in promoting RAD51 foci formation and homologous recombination repair (HRR), EGFR-mutant cells also exhibited an impaired RAD51 foci response to ICLs, but not to DNA double-strand breaks. EGFR kinase inhibition affected RAD51 foci formation neither in EGFR-mutant nor wild-type cells. In contrast, EGFR depletion or overexpression of mutant EGFR in wild-type cells suppressed RAD51 foci, suggesting an EGFR kinase-independent regulation of DNA repair. Interestingly, EGFR-mutant cells treated with the PARP inhibitor olaparib also displayed decreased FAN1 foci induction, coupled with a putative block in a late HRR step. As a result, EGFR-mutant lung cancer cells exhibited olaparib sensitivity in vitro and in vivo. Our findings provide insight into the mechanisms of cisplatin and PARP inhibitor sensitivity of EGFR-mutant cells, yielding potential therapeutic opportunities for further treatment individualization in this genetically defined subset of lung cancer.

  14. Intragenic telSMN mutations: frequency, distribution, evidence of a founder effect, and modification of the spinal muscular atrophy phenotype by cenSMN copy number.

    PubMed Central

    Parsons, D W; McAndrew, P E; Iannaccone, S T; Mendell, J R; Burghes, A H; Prior, T W

    1998-01-01

    The autosomal recessive neuromuscular disorder proximal spinal muscular atrophy (SMA) is caused by the loss or mutation of the survival motor neuron (SMN) gene, which exists in two nearly identical copies, telomeric SMN (telSMN) and centromeric SMN (cenSMN). Exon 7 of the telSMN gene is homozygously absent in approximately 95% of SMA patients, whereas loss of cenSMN does not cause SMA. We searched for other telSMN mutations among 23 SMA compound heterozygotes, using heteroduplex analysis. We identified telSMN mutations in 11 of these unrelated SMA-like individuals who carry a single copy of telSMN: these include two frameshift mutations (800ins11 and 542delGT) and three missense mutations (A2G, S262I, and T274I). The telSMN mutations identified to date cluster at the 3' end, in a region containing sites for SMN oligomerization and binding of Sm proteins. Interestingly, the novel A2G missense mutation occurs outside this conserved carboxy-terminal domain, closely upstream of an SIP1 (SMN-interacting protein 1) binding site. In three patients, the A2G mutation was found to be on the same allele as a rare polymorphism in the 5' UTR, providing evidence for a founder chromosome; Ag1-CA marker data also support evidence of an ancestral origin for the 800ins11 and 542delGT mutations. We note that telSMN missense mutations are associated with milder disease in our patients and that the severe type I SMA phenotype caused by frameshift mutations can be ameliorated by an increase in cenSMN gene copy number. PMID:9837824

  15. A mutation in the neurofibromatosis type 2 tumor-suppressor gene, giving rise to widely different clinical phenotypes in two unrelated individuals

    SciTech Connect

    Bourn, D.; Carter, S.A.; Goodship, J.; Strachan, T. ); Evans, G.R.; Coakham, H.

    1994-07-01

    The authors have sought mutations in the recently identified neurofibromatosis type 2 (NF2) tumor-suppressor gene in a large panel of NF2 patients, using PCR-based SSCP and heteroduplex analysis, followed by cloning and sequencing of appropriate PCR products. Two unrelated NF2 patients were found to have identical nonsense mutations caused by a C-to-T transition in a CpG dinucleotide that is a potential mutational hot spot in the NF2 tumor-suppressor gene. Unexpectedly, the two individuals had widely different clinical phenotypes, representing the severe Wishart and mild Gardner clinical subtypes. Analysis of DNA samples from different tissues of the mildly affected patient suggests that he is a somatic mosaic for the mutation. 26 refs., 3 figs.

  16. Severe craniosynostosis with Noonan syndrome phenotype associated with SHOC2 mutation: clinical evidence of crosslink between FGFR and RAS signaling pathways.

    PubMed

    Takenouchi, Toshiki; Sakamoto, Yoshiaki; Miwa, Tomoru; Torii, Chiharu; Kosaki, Rika; Kishi, Kazuo; Takahashi, Takao; Kosaki, Kenjiro

    2014-11-01

    Dysregulation in the RAS signaling cascade results in a family of malformation syndromes called RASopathies. Meanwhile, alterations in FGFR signaling cascade are responsible for various syndromic forms of craniosynostosis. In general, the phenotypic spectra of RASopathies and craniosynostosis syndromes do not overlap. Recently, however, mutations in ERF, a downstream molecule of the RAS signaling cascade, have been identified as a cause of complex craniosynostosis, suggesting that the RAS and FGFR signaling pathways can interact in the pathogenesis of malformation syndromes. Here, we document a boy with short stature, developmental delay, and severe craniosynostosis involving right coronal, bilateral lambdoid, and sagittal sutures with a de novo mutation in exon1 of SHOC2 (c.4A>G p.Ser2Gly). This observation further supports the existence of a crosslink between the RAS signaling cascade and craniosynostosis. In retrospect, the propositus had physical features suggestive of a dysregulated RAS signaling cascade, such as fetal pleural effusion, fetal hydrops, and atrial tachycardia. In addition to an abnormal cranial shape, which has been reported for this specific mutation, craniosynostosis might be a novel associated phenotype. In conclusion, the phenotypic combination of severe craniosynostosis and RASopathy features observed in the propositus suggests an interaction between the RAS and FGFR signaling cascades. Patients with craniosynostosis in combination with any RASopathy feature may require mutation screening for molecules in the FGFR-RAS signaling cascade.

  17. Structural and Dynamic Characterization of the C313Y Mutation in Myostatin Dimeric Protein, Responsible for the “Double Muscle” Phenotype in Piedmontese Cattle

    PubMed Central

    Bongiorni, Silvia; Valentini, Alessio; Chillemi, Giovanni

    2016-01-01

    The knowledge of the molecular effects of the C313Y mutation, responsible for the “double muscle” phenotype in Piedmontese cattle, can help understanding the actual mechanism of phenotype determination and paves the route for a better modulation of the positive effects of this economic important phenotype in the beef industry, while minimizing the negative side effects, now inevitably intersected. The structure and dynamic behavior of the active dimeric form of Myostatin in cattle was analyzed by means of three state-of-the-art Molecular Dynamics simulations, 200-ns long, of wild-type and C313Y mutants. Our results highlight a role for the conserved Arg333 in establishing a network of short and long range interactions between the two monomers in the wild-type protein that is destroyed upon the C313Y mutation even in a single monomer. Furthermore, the native protein shows an asymmetry in residue fluctuation that is absent in the double monomer mutant. Time window analysis on further 200-ns of simulation demonstrates that this is a characteristic behavior of the protein, likely dependent on long range communications between monomers. The same behavior, in fact, has already been observed in other mutated dimers. Finally, the mutation does not produce alterations in the secondary structure elements that compose the characteristic TGF-β cystine-knot motif. PMID:26904102

  18. Two novel heterozygous mutations of EVC2 cause a mild phenotype of Ellis-van Creveld syndrome in a Chinese family.

    PubMed

    Shen, Wenjing; Han, Dong; Zhang, Jin; Zhao, Hongshan; Feng, Hailan

    2011-09-01

    Ellis-van Creveld syndrome (EvC, chondroectodermal dysplasia; OMIM 225500) is an autosomal recessive skeletal dysplasia with associated multisystem involvement. The syndrome is characterized by short limbs, short ribs, postaxial polydactyly, dysplastic nails, and abnormal teeth. Congenital heart defects occur in 50-60% of cases. In this study, we report EvC in a 6-year-old Chinese girl with hypodontia and polydactyly, mild short stature, and abnormalities of the knee joints. No signs of short ribs, narrow thorax, or congenital heart defects were found in this patient. The EvC phenotype shares some similarity with Weyers acrofacial dysostosis (Weyer; OMIM 193530), an autosomal dominant disorder clinically characterized by mild short stature, postaxial polydactyly, nail dystrophy, and dysplastic teeth. Mutations in EVC or EVC2 are associated with both EvC syndrome and Weyers acrodental dysostosis, but the two conditions differ in the severity of the phenotype and their pattern of inheritance. In this study, two novel heterozygous EVC2 mutations, IVS5-2A > G and c.2653C > T (Arg885X), were identified in the patient. The IVS5-2A > G mutation was inherited from the patient's mother and the c.2653C > T from her father. Her parents have no phenotypic symptoms similar to those of the patient. These findings extend the mutation spectrum of this malformation syndrome and provide the possibility of prenatal diagnosis for future offspring in this family.

  19. N-acetylglutamate synthase deficiency: Novel mutation associated with neonatal presentation and literature review of molecular and phenotypic spectra.

    PubMed

    Al Kaabi, Eiman H; El-Hattab, Ayman W

    2016-09-01

    The urea cycle is the main pathway for the disposal of excess nitrogen. Carbamoylphosphate synthetase 1 (CPS1), the first and rate-limiting enzyme of urea cycle, is activated by N-acetylglutamate (NAG), and thus N-acetylglutamate synthase (NAGS) is an essential part of the urea cycle. Although NAGS deficiency is the rarest urea cycle disorder, it is the only one that can be specifically and effectively treated by a drug, N-carbamylglutamate, a stable structural analogous of NAG that activates CPS1. Here we report an infant with NAGS deficiency who presented with neonatal hyperammonemia. She was found to have a novel homozygous splice-site mutation, c.1097-2A>T, in the NAGS gene. We describe the clinical course of this infant, who had rapid response to N-carbamylglutamate treatment. In addition, we reviewed the clinical and molecular spectra of previously reported individuals with NAGS deficiency, which presents in most cases with neonatal hyperammonemia, and in some cases the presentation is later, with a broad spectrum of ages and manifestations. With this broad later-onset phenotypic spectrum, maintaining a high index of suspicion is needed for the early diagnosis of this treatable disease.

  20. G1 cell cycle arrest and apoptosis induction by nuclear Smad4/Dpc4: Phenotypes reversed by a tumorigenic mutation

    PubMed Central

    Dai, Jia Le; Bansal, Ravi K.; Kern, Scott E.

    1999-01-01

    The tumor suppressor Smad4/Dpc4 is a transcription activator that binds specific DNA sequences and whose nuclear localization is induced after exposure to type β transforming growth factor-like cytokines. We explored an inducible system in which Smad4 protein is activated by translocation to the nucleus when cell lines that stably express wild-type or mutant Smad4 proteins fused to a murine estrogen receptor domain are treated with 4-hydroxytamoxifen. This induced Smad4-mediated transcriptional activation and a decrease in growth rate, attributable to a cell cycle arrest at the G1 phase and an induction of apoptosis. A tumor-derived mutation (Arg-100 → Thr) affecting a residue critical for DNA-binding demonstrated an “oncogenic” phenotype, having decreases in both the G1 fraction and apoptosis and, consequently, an augmentation of population growth. This model should be useful in the exploration and control of components that lie further downstream in the Smad4 tumor-suppressor pathway. PMID:9990040

  1. Cyclic adenosine monophosphate metabolism in synaptic growth, strength, and precision: neural and behavioral phenotype-specific counterbalancing effects between dnc phosphodiesterase and rut adenylyl cyclase mutations.

    PubMed

    Ueda, Atsushi; Wu, Chun-Fang

    2012-03-01

    Two classic learning mutants in Drosophila, rutabaga (rut) and dunce (dnc), are defective in cyclic adenosine monophosphate (cAMP) synthesis and degradation, respectively, exhibiting a variety of neuronal and behavioral defects. We ask how the opposing effects of these mutations on cAMP levels modify subsets of phenotypes, and whether any specific phenotypes could be ameliorated by biochemical counter balancing effects in dnc rut double mutants. Our study at larval neuromuscular junctions (NMJs) demonstrates that dnc mutations caused severe defects in nerve terminal morphology, characterized by unusually large synaptic boutons and aberrant innervation patterns. Interestingly, a counterbalancing effect led to rescue of the aberrant innervation patterns but the enlarged boutons in dnc rut double mutant remained as extreme as those in dnc. In contrast to dnc, rut mutations strongly affect synaptic transmission. Focal loose-patch recording data accumulated over 4 years suggest that synaptic currents in rut boutons were characterized by unusually large temporal dispersion and a seasonal variation in the amount of transmitter release, with diminished synaptic currents in summer months. Experiments with different rearing temperatures revealed that high temperature (29-30°C) decreased synaptic transmission in rut, but did not alter dnc and wild-type (WT). Importantly, the large temporal dispersion and abnormal temperature dependence of synaptic transmission, characteristic of rut, still persisted in dnc rut double mutants. To interpret these results in a proper perspective, we reviewed previously documented differential effects of dnc and rut mutations and their genetic interactions in double mutants on a variety of physiological and behavioral phenotypes. The cases of rescue in double mutants are associated with gradual developmental and maintenance processes whereas many behavioral and physiological manifestations on faster time scales could not be rescued. We discuss

  2. Loss-of-function HDAC8 mutations cause a phenotypic spectrum of Cornelia de Lange syndrome-like features, ocular hypertelorism, large fontanelle and X-linked inheritance

    PubMed Central

    Kaiser, Frank J.; Ansari, Morad; Braunholz, Diana; Concepción Gil-Rodríguez, María; Decroos, Christophe; Wilde, Jonathan J.; Fincher, Christopher T.; Kaur, Maninder; Bando, Masashige; Amor, David J.; Atwal, Paldeep S.; Bahlo, Melanie; Bowman, Christine M.; Bradley, Jacquelyn J.; Brunner, Han G.; Clark, Dinah; Del Campo, Miguel; Di Donato, Nataliya; Diakumis, Peter; Dubbs, Holly; Dyment, David A.; Eckhold, Juliane; Ernst, Sarah; Ferreira, Jose C.; Francey, Lauren J.; Gehlken, Ulrike; Guillén-Navarro, Encarna; Gyftodimou, Yolanda; Hall, Bryan D.; Hennekam, Raoul; Hudgins, Louanne; Hullings, Melanie; Hunter, Jennifer M.; Yntema, Helger; Innes, A. Micheil; Kline, Antonie D.; Krumina, Zita; Lee, Hane; Leppig, Kathleen; Lynch, Sally Ann; Mallozzi, Mark B.; Mannini, Linda; Mckee, Shane; Mehta, Sarju G.; Micule, Ieva; Mohammed, Shehla; Moran, Ellen; Mortier, Geert R.; Moser, Joe-Ann S.; Noon, Sarah E.; Nozaki, Naohito; Nunes, Luis; Pappas, John G.; Penney, Lynette S.; Pérez-Aytés, Antonio; Petersen, Michael B.; Puisac, Beatriz; Revencu, Nicole; Roeder, Elizabeth; Saitta, Sulagna; Scheuerle, Angela E.; Schindeler, Karen L.; Siu, Victoria M.; Stark, Zornitza; Strom, Samuel P.; Thiese, Heidi; Vater, Inga; Willems, Patrick; Williamson, Kathleen; Wilson, Louise C.; Hakonarson, Hakon; Quintero-Rivera, Fabiola; Wierzba, Jolanta; Musio, Antonio; Gillessen-Kaesbach, Gabriele; Ramos, Feliciano J.; Jackson, Laird G.; Shirahige, Katsuhiko; Pié, Juan; Christianson, David W.; Krantz, Ian D.; Fitzpatrick, David R.; Deardorff, Matthew A.

    2014-01-01

    Cornelia de Lange syndrome (CdLS) is a multisystem genetic disorder with distinct facies, growth failure, intellectual disability, distal limb anomalies, gastrointestinal and neurological disease. Mutations in NIPBL, encoding a cohesin regulatory protein, account for >80% of cases with typical facies. Mutations in the core cohesin complex proteins, encoded by the SMC1A, SMC3 and RAD21 genes, together account for ∼5% of subjects, often with atypical CdLS features. Recently, we identified mutations in the X-linked gene HDAC8 as the cause of a small number of CdLS cases. Here, we report a cohort of 38 individuals with an emerging spectrum of features caused by HDAC8 mutations. For several individuals, the diagnosis of CdLS was not considered prior to genomic testing. Most mutations identified are missense and de novo. Many cases are heterozygous females, each with marked skewing of X-inactivation in peripheral blood DNA. We also identified eight hemizygous males who are more severely affected. The craniofacial appearance caused by HDAC8 mutations overlaps that of typical CdLS but often displays delayed anterior fontanelle closure, ocular hypertelorism, hooding of the eyelids, a broader nose and dental anomalies, which may be useful discriminating features. HDAC8 encodes the lysine deacetylase for the cohesin subunit SMC3 and analysis of the functional consequences of the missense mutations indicates that all cause a loss of enzymatic function. These data demonstrate that loss-of-function mutations in HDAC8 cause a range of overlapping human developmental phenotypes, including a phenotypically distinct subgroup of CdLS. PMID:24403048

  3. Genotype-phenotype dilemma in a case of sudden cardiac death with the E1053K mutation and a deletion in the SCN5A gene.

    PubMed

    Jenewein, T; Beckmann, B M; Rose, S; Osterhues, H H; Schmidt, U; Wolpert, C; Miny, P; Marschall, C; Alders, M; Bezzina, C R; Wilde, A A M; Kääb, S; Kauferstein, S

    2017-03-20

    Mutations in the cardiac sodium channel gene SCN5A may result in various arrhythmia syndromes such as long QT syndrome type 3 (LQTS), Brugada syndrome (BrS), sick sinus syndrome (SSS), cardiac conduction diseases (CCD) and possibly dilated cardiomyopathy (DCM). In most of these inherited cardiac arrhythmia syndromes the phenotypical expression may range from asymptomatic phenotypes to sudden cardiac death (SCD). A 16-year-old female died during sleep. Autopsy did not reveal any explanation for her death and a genetic analysis was performed. A variant in the SCN5A gene (E1053K) that was previously described as disease causing was detected. Family members are carriers of the same E1053K variant, some even in a homozygous state, but surprisingly did not exhibit any pathological cardiac phenotype. Due to the lack of genotype-phenotype correlation further genetic studies were performed. A novel deletion in the promoter region of SCN5A was identified in the sudden death victim but was absent in other family members. These findings demonstrate the difficulties in interpreting the results of a family-based genetic screening and underline the phenotypic variability of SCN5A mutations.

  4. Brief Report: VAX1 mutation associated with microphthalmia, corpus callosum agenesis and orofacial clefting – the first description of a VAX1 phenotype in humans

    PubMed Central

    Slavotinek, Anne M.; Chao, Ryan; Vacik, Tomas; Yahyavi, Mani; Abouzeid, Hana; Bardakjian, Tanya; Schneider, Adele; Shaw, Gary; Sherr, Elliott H.; Lemke, Greg; Youssef, Mohammed; Schorderet, Daniel F.

    2011-01-01

    Vax1 and Vax2 have been implicated in eye development and the closure of the choroid fissure in mice and zebrafish. We sequenced the coding exons of VAX1 and VAX2 in 70 patients with anophthalmia/microphthalmia. In VAX1, we observed homozygosity for two successive nucleotide substitutions c.453G>A and c.454C>A, predicting p.Arg152Ser, in a proband of Egyptian origin with microphthalmia, small optic nerves, cleft lip/palate and corpus callosum agenesis. This mutation affects an invariant residue in the homeodomain of VAX1 and was absent from 96 Egyptian controls. It is likely that the mutation results in a loss of function, as the mutation results in a phenotype similar to the Vax1 homozygous null mouse. We did not identify any mutations in VAX2. This is the first description of a phenotype associated with a VAX1 mutation in humans and establishes VAX1 as a new causative gene for anophthalmia/microphthalmia. PMID:22095910

  5. Homozygosity for the V377I mutation in mevalonate kinase causes distinct clinical phenotypes in two sibs with hyperimmunoglobulinaemia D and periodic fever syndrome (HIDS)

    PubMed Central

    Messer, Laurent; Alsaleh, Ghada; Georgel, Philippe; Carapito, Raphael; Waterham, Hans R; Dali-Youcef, Nassim; Bahram, Siamak; Sibilia, Jean

    2016-01-01

    Objective Mevalonate kinase (MVK) deficiency is a rare autosomal recessive auto-inflammatory disorder characterised by recurring episodes of fever associated with multiple non-specific inflammatory symptoms and caused by mutations in the MVK gene. The phenotypic spectrum is wide and depends mostly on the nature of the mutations. Hyperimmunoglobulinaemia D and periodic fever syndrome (HIDS) is a relatively mild presentation and predominantly associated with a c.1129G>A (p.V377I) mutation in the MVK gene. We report cases of two sisters homozygous for this mutation but exhibiting distinct (symptomatic vs asymptomatic) phenotypes. Methods Patient history was obtained; physical and clinical examination and laboratory tests were performed; lipopolysaccharide (LPS) response of peripheral blood mononuclear cells was quantified. Results Low MVK enzymatic activity is not necessarily associated with inflammatory symptoms. Increased inflammatory cytokine secretion in response to LPS is associated with symptomatic MVK deficiency. Conclusions Individuals who are homozygous for the common p.V377I mutation in the MVK gene may not display the characteristic inflammatory episodes diagnostic of MKD and thus may be lost for correct and timely diagnosis. PMID:26977311

  6. Hyper-IgD and periodic fever syndrome: a new MVK mutation (p.R277G) associated with a severe phenotype.

    PubMed

    Santos, Joana A; Aróstegui, Juan I; Brito, Maria J; Neves, Conceição; Conde, Marta

    2014-06-01

    Hyperimmunoglobulinemia D and periodic fever syndrome (HIDS; MIM# 260920) is a rare recessively-inherited autoinflammatory condition caused by mutations in the MVK gene, which encodes for mevalonate kinase, an essential enzyme in the isoprenoid pathway. HIDS is clinically characterized by recurrent episodes of fever and inflammation. Here we report on the case of a 2 year-old Portuguese boy with recurrent episodes of fever, malaise, massive cervical lymphadenopathy and hepatosplenomegaly since the age of 12 months. Rash, arthralgia, abdominal pain and diarrhea were also seen occasionally. During attacks a vigorous acute-phase response was detected, including elevated erythrocyte sedimentation rate, C-reactive protein, serum amyloid A and leukocytosis. Clinical and laboratory improvement was seen between attacks. Despite normal serum IgD level, HIDS was clinically suspected. Mutational MVK analysis revealed the homozygous genotype with the novel p.Arg277Gly (p.R277G) mutation, while the healthy non-consanguineous parents were heterozygous. Short nonsteroidal anti-inflammatory drugs and corticosteroid courses were given during attacks with poor benefits, whereas anakinra showed positive responses only at high doses. The p.R277G mutation here described is a novel missense MVK mutation, and it has been detected in this case with a severe HIDS phenotype. Further studies are needed to evaluate a co-relation genotype, enzyme activity and phenotype, and to define the best therapeutic strategies.

  7. Congenital encephalomyopathy and adult-onset myopathy and diabetes mellitus: Different phenotypic associations of a new heteroplasmic mtDNA tRNA glutamic acid mutation

    SciTech Connect

    Hanna, M.G.; Nelson, I.; Sweeney, M.G.; Cooper, J.M.; Watkins, P.J.; Morgan-Hughes, J.A.; Harding, A.E.

    1995-05-01

    We report the clinical, biochemical, and molecular genetic findings in a family with an unusual mitochondrial disease phenotype harboring a novel mtDNA tRNA glutamic acid mutation at position 14709. The proband and his sister presented with congenital myopathy and mental retardation and subsequently developed cerebellar ataxia. Other family members had either adult-onset diabetes mellitus with muscle weakness or adult-onset diabetes mellitus alone. Ragged-red and cytochrome c oxidase (COX)-negative fibers were present in muscle biopsies. Biochemical studies of muscle mitochondria showed reduced complex I and IV activities. The mtDNA mutation was heteroplasmic in blood and muscle in all matrilineal relatives analyzed. Primary myoblast, but not fibroblast, cultures containing high proportions of mutant mtDNA exhibited impaired mitochondrial translation. These observations indicate that mtDNA tRNA point mutations should be considered in the differential diagnosis of congenital myopathy. In addition they illustrate the diversity of phenotypes associated with this mutation in the same family and further highlight the association between mtDNA mutations and diabetes mellitus. 43 refs., 4 figs., 1 tab.

  8. A novel mutation in NF1 is associated with diverse intra-familial phenotypic variation and astrocytoma in a Chinese family.

    PubMed

    Banerjee, Santasree; Dai, Yi; Liang, Shengran; Chen, Huishuang; Wang, Yanyan; Tang, Lihui; Wu, Jing; Huang, Hui

    2016-09-01

    Neurofibromatosis type 1 (NF1) is a dysregulated neurocutaneous disorder, characterized by neurofibromas and café-au-lait spots. NF1 is caused by mutations in the NF1 gene, encoding neurofibromin. Here, we present a clinical molecular study of a three-generation Chinese family with NF1. The proband was a male patient who showed café-au-lait spots and multiple subcutaneous neurofibromas over the whole body, but his siblings only had regional lesions. The man's daughter presented with severe headache and vomiting. Neurological examination revealed an intracranial space occupying lesion. Surgery was undertaken and the histopathological examination showed a grade I-II astrocytoma. Next-Generation sequencing (Illumina HiSeq2500 Analyzers; Illumina, San Diego, CA, USA) and Sanger sequencing (ABI PRISM 3730 automated sequencer; Applied Biosystems, Foster City, CA, USA) identified the c.227delA mutation in the NF1 gene in the man. The mutation is co-segregated with the disease phenotypes among the affected members of this family and was absent in 100 healthy controls. This novel mutation results in a frameshift (p.Asn78IlefsX7) as well as truncation of neurofibromin by formation of a premature stop codon. Our results not only extended the mutational and phenotypic spectra of the gene and the disease, but also highlight the importance of the other genetic or environmental factors in the development and severity of the disease.

  9. Screening in ALS and FTD patients reveals 3 novel UBQLN2 mutations outside the PXX domain and a pure FTD phenotype.

    PubMed

    Synofzik, Matthis; Maetzler, Walter; Grehl, Torsten; Prudlo, Johannes; Vom Hagen, Jennifer Müller; Haack, Tobias; Rebassoo, Piret; Munz, Marita; Schöls, Ludger; Biskup, Saskia

    2012-12-01

    Mutations in UBQLN2 have recently been shown to cause dominant X-linked amyotrophic lateral sclerosis (ALS) and ALS plus frontotemporal dementia (FTD). Information on their frequency in different populations is still rare, and a pure FTD phenotype has not yet been reported. Moreover, the mutational spectrum of known UBQLN2 mutations is still limited to its PXX repeat region. Based on a screening of 206 ALS and FTD patients, we here report 3 novel UBQLN2 mutations, accounting for 1.2% (2/161) ALS and 2.2% (1/45) FTD patients, including a patient with pure FTD. All mutations were located in highly conserved domains outside the PXX repeat region and not observed in 1450 ethnically matched control X-chromosomes. All affected patients presented with apparently sporadic disease. UBQLN2 mutations are rare in Central European ALS and FTD patients, but contribute significantly to patients with seemingly sporadic disease. UBQLN2 is able to cause any disease on the ALS-FTD continuum, including pure FTD. Because the pathogenic mechanism of UBQLN2 mutations is not limited to its PXX region, UBQLN2 screening in neurodegenerative patients should not be limited to this region.

  10. IL36RN Mutations Affect Protein Expression and Function: A Basis for Genotype-Phenotype Correlation in Pustular Diseases.

    PubMed

    Tauber, Marie; Bal, Elodie; Pei, Xue-Yuan; Madrange, Marine; Khelil, Amel; Sahel, Houria; Zenati, Akila; Makrelouf, Mohamed; Boubridaa, Khaled; Chiali, Amel; Smahi, Naima; Otsmane, Farida; Bouajar, Bakar; Marrakchi, Slaheddine; Turki, Hamida; Bourrat, Emmanuelle; Viguier, Manuelle; Hamel, Yamina; Bachelez, Hervé; Smahi, Asma

    2016-09-01

    Homozygous or compound heterozygous IL36RN gene mutations underlie the pathogenesis of psoriasis-related pustular eruptions including generalized pustular psoriasis, palmoplantar pustular psoriasis, acrodermatitis continua of Hallopeau, and acute generalized exanthematous pustular eruption. We identified two unreported IL36RN homozygous mutations (c.41C>A/p.Ser14X and c.420_426del/p.Gly141MetfsX29) in patients with familial generalized pustular psoriasis. We analyzed the impact of a spectrum of IL36RN mutations on IL-36 receptor antagonist protein by using site-directed mutagenesis and expression in HEK293T cells. This enabled us to differentiate null mutations with complete absence of IL-36 receptor antagonist (the two previously unreported mutations, c.80T>C/p.Leu27Pro, c.28C>T/p.Arg10X, c.280G>T/p.Glu94X, c.368C>G/p.Thr123Arg, c.368C>T/p.Thr123Met, and c.227C>T/p.Pro76Leu) from mutations with decreased (c.95A>G/p.His32Arg, c.142C>T/p.Arg48Trp, and c.308C>T/p.Ser113Leu) or unchanged (c.304C>T/p.Arg102Trp and c.104A>G/p.Lys35Arg) protein expression. Functional assays measuring the impact of mutations on the capacity to repress IL-36-dependent activation of the NF-κB pathway showed complete functional impairment for null mutations, whereas partial or no impairment was observed for other mutations considered as hypomorphic. Finally, null mutations were associated with severe clinical phenotypes (generalized pustular psoriasis, acute generalized exanthematous pustular eruption), whereas hypomorphic mutations were identified in both localized (palmoplantar pustular psoriasis, acrodermatitis continua of Hallopeau) and generalized variants. These results provide a preliminary basis for genotype-phenotype correlation in patients with deficiency of the IL-36Ra (DITRA), and suggest the involvement of other factors in the modulation of clinical expression.

  11. Expansion of the spectrum of TUBB4A-related disorders: a new phenotype associated with a novel mutation in the TUBB4A gene.

    PubMed

    Blumkin, Lubov; Halevy, Ayelet; Ben-Ami-Raichman, Dominique; Dahari, Dvir; Haviv, Ami; Sarit, Cohen; Lev, Dorit; van der Knaap, Marjo S; Lerman-Sagie, Tally; Leshinsky-Silver, Esther

    2014-05-01

    Mutations in the TUBB4A gene have been identified so far in two neurodegenerative disorders with extremely different clinical features and course: whispering dysphonia, also known as dystonia type 4 (DYT4), and hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC). We describe a patient with slowly progressive spastic paraparesis, segmental dystonia, intellectual disability, behavioral problems, and evidence of permanent, incomplete myelination associated with progressive cerebellar atrophy. Whole exome sequencing revealed a novel E410K de novo heterozygous mutation in the TUBB4A gene. The clinical and radiological picture of our patient is different from the classic phenotype; thus, it expands the phenotypic variation of TUBB4A-gene-related disorders.

  12. Phenotypic expression and origin of the rare beta-thalassemia splice site mutation HBB:c.315 + 1G>T.

    PubMed

    Broquere, Cédrick; Brudey, Karine; Harteveld, Cornelis L; Saint-Martin, Christian; Elion, Jacques; Giordano, Piero C; Romana, Marc

    2010-06-01

    We present the hematological characteristics of five patients from Surinam and the bordering French Guyana, who are carriers of the rare beta-thalassemia (beta-thal) mutation HBB:c.315+1G>T. Analysis of the phenotype/genotype relationship shows that this allele is a beta(0)-thal variant and illustrates the modulating effect of the alpha-globin gene status on the beta-thal phenotype. The ethnic origin of the five probands, belonging to the so-called Bush Negroes Maroons of Surinam and French Guyana, strongly suggests that this beta-thal mutation has a West African origin and spread in this ethnic group because of a founder effect and/or genetic drift.

  13. The recurrent PPP1CB mutation p.Pro49Arg in an additional Noonan-like syndrome individual: Broadening the clinical phenotype.

    PubMed

    Bertola, Débora; Yamamoto, Guilherme; Buscarilli, Michelle; Jorge, Alexander; Passos-Bueno, Maria Rita; Kim, Chong

    2017-03-01

    We report on a 12-year-old Brazilian boy with the p.Pro49Arg mutation in PPP1CB, a novel gene associated with RASopathies. This is the fifth individual described, and the fourth presenting the same variant, suggesting a mutational hotspot. Phenotypically, he also showed the same hair pattern-sparse, thin, and with slow growing-, similar to the typical ectodermal finding observed in Noonan syndrome-like disorder with loose anagen hair. Additionally, he presented craniosynostosis, a rare clinical finding in RASopathies. This report gives further support that this novel RASopathy-PPP1CB-related Noonan syndrome with loose anagen hair-shares great similarity to Noonan syndrome-like disorder with loose anagen hair, and expands the phenotypic spectrum by adding the cranial vault abnormality. © 2017 Wiley Periodicals, Inc.

  14. Gain-of-function mutation in PIK3R1 in a patient with a narrow clinical phenotype of respiratory infections.

    PubMed

    Martínez-Saavedra, María Teresa; García-Gomez, Sonia; Domínguez Acosta, Ana; Mendoza Quintana, Juan Jesús; Páez, Jesús Poch; García-Reino, Eduardo J; Camps, Gracián; Martinez-Barricarte, Rubén; Itan, Yuval; Boisson, Bertrand; Sánchez-Ramón, Silvia; Regueiro, José Ramón; Casanova, Jean-Laurent; Rodríguez-Gallego, Carlos; Pérez de Diego, Rebeca

    2016-12-01

    Antibody deficiencies can be caused by a variety of defects that interfere with B-cell development, maturation, and/or function. Using whole-exome sequencing we found a PIK3R1 mutation in a patient with hypogammaglobulinemia and a narrow clinical phenotype of respiratory infections. Early diagnosis is crucial; careful analysis of B and T-cells followed by genetic analyses may help to distinguish activated PI3K-delta syndrome (APDS) from other, less severe, predominantly antibody deficiencies.

  15. Junctophilin 3 (JPH3) expansion mutations causing Huntington disease like 2 (HDL2) are common in South African patients with African ancestry and a Huntington disease phenotype.

    PubMed

    Krause, Amanda; Mitchell, Claire; Essop, Fahmida; Tager, Susan; Temlett, James; Stevanin, Giovanni; Ross, Christopher; Rudnicki, Dobrila; Margolis, Russell

    2015-10-01

    Huntington disease (HD) is a progressive autosomal dominant neurodegenerative disorder, characterized by abnormal movements, cognitive decline, and psychiatric symptoms, caused by a CAG repeat expansion in the huntingtin (HTT) gene on chromosome 4p. A CAG/CTG repeat expansion in the junctophilin-3 (JPH3) gene on chromosome 16q24.2 causes a Huntington disease-like phenotype (HDL2). All patients to date with HDL2 have some African ancestry. The present study aimed to characterize the genetic basis of the Huntington disease phenotype in South Africans and to investigate the possible origin of the JPH3 mutation. In a sample of unrelated South African individuals referred for diagnostic HD testing, 62% (106/171) of white patients compared to only 36% (47/130) of black patients had an expansion in HTT. However, 15% (20/130) of black South African patients and no white patients (0/171) had an expansion in JPH3, confirming the diagnosis of Huntington disease like 2 (HDL2). Individuals with HDL2 share many clinical features with individuals with HD and are clinically indistinguishable in many cases, although the average age of onset and diagnosis in HDL2 is 5 years later than HD and individual clinical features may be more prominent. HDL2 mutations contribute significantly to the HD phenotype in South Africans with African ancestry. JPH3 haplotype studies in 31 families, mainly from South Africa and North America, provide evidence for a founder mutation and support a common African origin for all HDL2 patients. Molecular testing in individuals with an HD phenotype and African ancestry should include testing routinely for JPH3 mutations.

  16. JUNCTOPHILIN 3 (JPH3) EXPANSION MUTATIONS CAUSING HUNTINGTON DISEASE LIKE 2 (HDL2) ARE COMMON IN SOUTH AFRICAN PATIENTS WITH AFRICAN ANCESTRY AND A HUNTINGTON DISEASE PHENOTYPE

    PubMed Central

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