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1

Human Immunoglobulin (Ig)M 1 IgD 1 Peripheral Blood B Cells Expressing the CD27 Cell Surface Antigen Carry Somatically Mutated Variable Region Genes: CD27 as a General Marker for Somatically Mutated (Memory) B Cells  

Microsoft Academic Search

Summary Immunoglobulin (Ig)M 1 IgD 1 B cells are generally assumed to represent antigen-inexperi- enced, naive B cells expressing variable (V) region genes without somatic mutations. We report here that human IgM 1 IgD 1 peripheral blood (PB) B cells expressing the CD27 cell surface antigen carry mutated V genes, in contrast to CD27-negative IgM 1 IgD 1 B cells.

Ulf Klein; Klaus Rajewsky; Ralf Küppers

2

Occurrence of mutations impairing sigma factor B (SigB) function upon inactivation of Listeria monocytogenes genes encoding surface proteins.  

PubMed

Bacteria of the genus Listeria contain the largest family of LPXTG surface proteins covalently anchored to the peptidoglycan. The extent to which these proteins may function or be regulated cooperatively is at present unknown. Because of their unique cellular location, we reasoned that distinct LPXTG proteins could act as elements contributing to cell wall homeostasis or influencing the stability of other surface proteins bound to peptidoglycan. To test this hypothesis, we used proteomics to analyse mutants of the intracellular pathogen Listeria monocytogenes lacking distinct LPXTG proteins implicated in pathogen-host interactions, such as InlA, InlF, InlG, InlH, InlJ, LapB and Vip. Changes in the cell wall proteome were found in inlG and vip mutants, which exhibited reduced levels of the LPXTG proteins InlH, Lmo0610, Lmo0880 and Lmo2085, all regulated by the stress-related sigma factor SigB. The ultimate basis of this alteration was uncovered by genome sequencing, which revealed that these inlG and vip mutants carried loss-of-function mutations in the rsbS, rsbU and rsbV genes encoding regulatory proteins that control SigB activity. Attempts to recapitulate this negative selection of SigB in a large series of new inlG or vip mutants constructed for this purpose were, however, unsuccessful. These results indicate that inadvertent secondary mutations affecting SigB functionality can randomly arise in L. monocytogenes when using common genetic procedures or during subculturing. Testing of SigB activity could be therefore valuable when manipulating genetically L. monocytogenes prior to any subsequent phenotypic analysis. This test may be even more justified when generating deletions affecting cell envelope components. PMID:23657685

Quereda, Juan J; Pucciarelli, M Graciela; Botello-Morte, Laura; Calvo, Enrique; Carvalho, Filipe; Bouchier, Christiane; Vieira, Ana; Mariscotti, Javier F; Chakraborty, Trinad; Cossart, Pascale; Hain, Torsten; Cabanes, Didier; García-Del Portillo, Francisco

2013-05-08

3

De Novo Sequencing of Astyanax mexicanus Surface Fish and Pach?n Cavefish Transcriptomes Reveals Enrichment of Mutations in Cavefish Putative Eye Genes  

PubMed Central

Astyanax mexicanus, a teleost species with surface dwelling (surface fish) and cave adapted (cavefish) morphs, is an important model system in evolutionary developmental biology (evodevo). Astyanax cavefish differ from surface fish in numerous traits, including the enhancement of non-visual sensory systems, and the loss of eyes and pigmentation. The genetic bases for these differences are not fully understood as genomic and transcriptomic data are lacking. We here present de novo transcriptome sequencing of embryonic and larval stages of a surface fish population and a cavefish population originating from the Pachón cave using the Sanger method. This effort represents the first large scale sequence and clone resource for the Astyanax research community. The analysis of these sequences show low levels of polymorphism in cavefish compared to surface fish, confirming previous studies on a small number of genes. A high proportion of the genes mutated in cavefish are known to be expressed in the zebrafish visual system. Such a high number of mutations in cavefish putative eye genes may be explained by relaxed selection for vision during the evolution in the absence of light. Based on these sequence differences, we provide a list of 11 genes that are potential candidates for having a role in cavefish visual system degeneration.

Hinaux, Helene; Jeffery, William R.; Casane, Didier; Retaux, Sylvie

2013-01-01

4

De novo sequencing of Astyanax mexicanus surface fish and Pachón cavefish transcriptomes reveals enrichment of mutations in cavefish putative eye genes.  

PubMed

Astyanax mexicanus, a teleost species with surface dwelling (surface fish) and cave adapted (cavefish) morphs, is an important model system in evolutionary developmental biology (evodevo). Astyanax cavefish differ from surface fish in numerous traits, including the enhancement of non-visual sensory systems, and the loss of eyes and pigmentation. The genetic bases for these differences are not fully understood as genomic and transcriptomic data are lacking. We here present de novo transcriptome sequencing of embryonic and larval stages of a surface fish population and a cavefish population originating from the Pachón cave using the Sanger method. This effort represents the first large scale sequence and clone resource for the Astyanax research community. The analysis of these sequences show low levels of polymorphism in cavefish compared to surface fish, confirming previous studies on a small number of genes. A high proportion of the genes mutated in cavefish are known to be expressed in the zebrafish visual system. Such a high number of mutations in cavefish putative eye genes may be explained by relaxed selection for vision during the evolution in the absence of light. Based on these sequence differences, we provide a list of 11 genes that are potential candidates for having a role in cavefish visual system degeneration. PMID:23326453

Hinaux, Hélčne; Poulain, Julie; Da Silva, Corinne; Noirot, Céline; Jeffery, William R; Casane, Didier; Rétaux, Sylvie

2013-01-09

5

Naturally occurring escape mutants of hepatitis B virus with various mutations in the S gene in carriers seropositive for antibody to hepatitis B surface antigen.  

PubMed Central

Hepatitis B virus (HBV) DNA was extracted from sera of six carriers with hepatitis B e antigen as well as antibody to hepatitis B surface antigen and sequenced within the pre-S regions and the S gene. HBV DNA clones from five of these carriers had point mutations in the S gene, resulting in conversion from Ile-126 or Thr-126 of the wild-type virus to Ser-126 or Asn-126 in three carriers and conversion from Gly-145 to Arg-145 in three of them; clones with Asn-126 or Arg-145 were found in one carrier. All 12 clones from the other carrier had an insertion of 24 bp encoding an additional eight amino acids between Thr-123 and Cys-124. In addition, all or at least some of the HBV DNA clones from these carriers had in-phase deletions in the 5' terminus of the pre-S2 region. These results indicate that HBV escape mutants with mutations in the S gene affecting the expression of group-specific determinants would survive in some carriers after they seroconvert to antibody against surface antigen. Carriers with HBV escape mutants may transmit HBV either by donation of blood units without detectable surface antigen or through community-acquired infection, which would hardly be prevented by current hepatitis B immuneglobulin or vaccines.

Yamamoto, K; Horikita, M; Tsuda, F; Itoh, K; Akahane, Y; Yotsumoto, S; Okamoto, H; Miyakawa, Y; Mayumi, M

1994-01-01

6

Mutations and polymorphisms in gonadotropin genes  

Microsoft Academic Search

Mutations in gonadotropin genes are extremely rare. Only one case of inactivating human luteinizing hormone (LH) ? mutation exists in the literature, a male with absence of Leydig cells, lack of spontaneous puberty and infertility. A total of four cases of inactivating mutation of the follicle-stimulating hormone ? (FSH?) gene (two female and two male) are known. The phenotype of

I. Huhtaniemi; M. Jiang; C. Nilsson; K. Pettersson

1999-01-01

7

The androgen receptor gene mutations database.  

PubMed

The androgen receptor gene mutations database is a comprehensive listing of mutations published in journals and meetings proceedings. The majority of mutations are point mutations identified in patients with androgen insensitivity syndrome. Information is included regarding the phenotype, the nature and location of the mutations, as well as the effects of the mutations on the androgen binding activity of the receptor. The current version of the database contains 149 entries, of which 114 are unique mutations. The database is available from EMBL (NetServ@EMBL-Heidelberg.DE) or as a Macintosh Filemaker file (mc33001@musica.mcgill.ca). PMID:7937057

Patterson, M N; Hughes, I A; Gottlieb, B; Pinsky, L

1994-09-01

8

A mutation in the human norepinephrine transporter gene (SLC6A2) associated with orthostatic intolerance disrupts surface expression of mutant and wild-type transporters.  

PubMed

The norepinephrine transporter (NET) mediates reuptake of norepinephrine released from neurons, and, as such, it is an important regulator of noradrenergic neurotransmission. Recently, our laboratory reported a polymorphism in the human NET (hNET) gene A457P in an individual with the autonomic disorder orthostatic intolerance (OI). The presence of the hNET-A457P allele tracked with elevated heart rates and plasma NE levels in family members. hNET-A457P lacks >98% transport activity in several heterologous expression systems. In the present work, Western blot and biotinylation analyses performed in transiently transfected COS-7 cells revealed impairment in processing of hNET-A457P to the fully glycosylated form and a decrease in surface expression to approximately 30% of hNET-wild type (hNET-wt). Because the hNET-A457P mutation is carried on a single allele in OI subjects, we examined the influence of cotransfection of hNET-wt and hNET-A457P and found that hNET-A457P exerts a dominant-negative effect on hNET-wt uptake activity. Experiments to determine oligomerization as a potential mechanism of the dominant-negative effect demonstrated that hNET-A457P coimmunoprecipitates with, and diminishes surface expression of, hNET-wt. These results reveal that hNET-A457P causes a conformational disruption that interferes with transporter biosynthetic progression and trafficking of both the mutant transporter and hNET-wt. These results elucidate a molecular mechanism for the disrupted NE homeostasis and cardiovascular function evident in OI patients with the hNET-A457P mutation. PMID:12805287

Hahn, Maureen K; Robertson, David; Blakely, Randy D

2003-06-01

9

The Human Gene Mutation Database: 2008 update  

Microsoft Academic Search

The Human Gene Mutation Database (HGMD®) is a comprehensive core collection of germline mutations in nuclear genes that underlie or are associated with human inherited\\u000a disease. Here, we summarize the history of the database and its current resources. By December 2008, the database contained\\u000a over 85,000 different lesions detected in 3,253 different genes, with new entries currently accumulating at a

Peter D Stenson; Matthew Mort; Edward V Ball; Katy Howells; Andrew D Phillips; Nick ST Thomas; David N Cooper

2009-01-01

10

Mutations in the human factor XII gene.  

PubMed

The factor XII gene from 31 unrelated factor XII-deficient patients from Germany, Switzerland, and Austria was screened for mutations at the genomic level. Several novel mutations were detected and their absence in a control group of 74 healthy unrelated individuals was checked. Most changes are in the serine protease domain affecting the catalytic triad His-393-Asp-442-Ser-544; two missense mutations, R398Q (arginine 398 to glutamine; gene bank accession no. U71276) and L395M (leucine 395 to methionine; gene bank accession no. U71277), are close to the active site histidine at position 393. Another mutation detected in a cross-reacting material (CRM)-positive female with a history of three abortions affects the active site aspartic acid by changing it to asparagine (D442N; gene bank accession no. U71275). The novel mutation G570R (glycine 570 to arginine; gene bank accession no. U71274) giving rise to a CRM-positive phenotype is located next to Cys571, which forms a vital disulfide bridge. Two mutations are causing reading frame shifts: one single basepair deletion in exon 12 [exon 12: 10590(DelC); gene bank accession no. U71278] and one acceptor splice site mutation [exon 14: 11397(G --> A); gene bank accession no. L43615]. The putative regulatory mutation exon 1:-8 (g --> c) in the upstream region of the gene is associated with an aberrant Taq I restriction site allele in intron B of the gene (gene bank accession no. X80393). PMID:9354665

Schloesser, M; Zeerleder, S; Lutze, G; Halbmayer, W M; Hofferbert, S; Hinney, B; Koestering, H; Lämmle, B; Pindur, G; Thies, K; Köhler, M; Engel, W

1997-11-15

11

Tyrosinase Gene Mutations Causing Oculocutaneous Albinisms  

Microsoft Academic Search

Since the first report of a mutation in the tyrosinase gene that causes tyrosinase-negative oculocutaneous albinism (OCA), more than 25 alleles with a different mutation in patients with three types of OCA, i.e., tyrosinase-negative OCA (type IA), yellow-mutant OCA (type IB), and temperature sensitive OCA (type ITS), have been found in several laboratories. The mutated alleles are presently classified into

Yasushi Tomita

1993-01-01

12

A microarray approach for identifying mutated genes  

Microsoft Academic Search

This study was performed to evaluate if microarray technology can identify genes using their transcriptionally defective mutant alleles. Three barley (Hordeum vulgare L.) mutant strains, xantha-h57, xantha-f27 and xantha-g28, with mutations in the genes encoding the three subunits of the chlorophyll biosynthetic enzyme magnesium chelatase, were used in a reconstruction experiment. The mutation xantha-h57 prevents transcription of Xantha-h mRNA. Microarrays

Shakhira Zakhrabekova; C. Gamini Kannangara; Diter von Wettstein; Mats Hansson

2002-01-01

13

Mutation update for the PORCN gene.  

PubMed

Mutations in the PORCN gene were first identified in Goltz-Gorlin syndrome patients in 2007. Since then, several reports have been published describing a large variety of genetic defects resulting in the Goltz-Gorlin syndrome, and mutations or deletions were also reported in angioma serpiginosum, the pentalogy of Cantrell and Limb-Body Wall Complex. Here we present a review of the published mutations in the PORCN gene to date and report on seven new mutations together with the corresponding clinical data. Based on the review we have created a Web-based locus-specific database that lists all identified variants and allows the inclusion of future reports. The database is based on the Leiden Open (source) Variation Database (LOVD) software, and is accessible online at http://www.lovd.nl/porcn. At present, the database contains 106 variants, representing 68 different mutations, scattered along the whole coding sequence of the PORCN gene, and 12 large gene rearrangements, which brings up to 80 the number of unique mutations identified in Goltz-Gorlin syndrome patients. PMID:21472892

Lombardi, Maria Paola; Bulk, Saskia; Celli, Jacopo; Lampe, Anne; Gabbett, Michael T; Ousager, Lillian Bomme; van der Smagt, Jasper J; Soller, Maria; Stattin, Eva-Lena; Mannens, Marcel A M M; Smigiel, Robert; Hennekam, Raoul C

2011-06-21

14

The androgen receptor gene mutations database.  

PubMed

The current version of the androgen receptor (AR) gene mutations database is described. We have added (if available) data on the androgen binding phenotype of the mutant AR, the clinical phenotype of the affected persons, the family history and whether the pathogenicity of a mutation has been proven. Exonic mutations are now listed in 5'-->3' sequence regardless of type and single base pair changes are presented in codon context. Splice site and intronic mutations are listed separately. The database has allowed us to substantiate and amplify the observation of mutational hot spots within exons encoding the AR androgen binding domain. The database is available from EML (ftp://www.ebi.ac.uk/pub/databases/androgen) or as a Macintosh Filemaker file (MC33@musica.mcgill.ca). PMID:8594566

Gottlieb, B; Trifiro, M; Lumbroso, R; Vasiliou, D M; Pinsky, L

1996-01-01

15

Haemochromatosis gene mutations in idiopathic dilated cardiomyopathy  

Microsoft Academic Search

BACKGROUNDTwo common mutations of the haemochromatosis associated gene (HFE) (cys282tyr (C282Y) and his63asp (H63D)) have been implicated in haemochromatosis and as modulators in cardiovascular disease.OBJECTIVETo investigate the role of these mutations in the pathogenesis of idiopathic dilated cardiomyopathy.DESIGN AND SETTINGCase–control and prospective cohort study of patients attending a cardiomyopathy unit in a tertiary referral cardiac centre.METHODS207 unrelated white patients with

N G Mahon; A S Coonar; S Jeffery; F Coccolo; J Akiyu; B Zal; R Houlston; G E Levin; C Baboonian; W J McKenna

2000-01-01

16

Mutational robustness of gene regulatory networks.  

PubMed

Mutational robustness of gene regulatory networks refers to their ability to generate constant biological output upon mutations that change network structure. Such networks contain regulatory interactions (transcription factor-target gene interactions) but often also protein-protein interactions between transcription factors. Using computational modeling, we study factors that influence robustness and we infer several network properties governing it. These include the type of mutation, i.e. whether a regulatory interaction or a protein-protein interaction is mutated, and in the case of mutation of a regulatory interaction, the sign of the interaction (activating vs. repressive). In addition, we analyze the effect of combinations of mutations and we compare networks containing monomeric with those containing dimeric transcription factors. Our results are consistent with available data on biological networks, for example based on evolutionary conservation of network features. As a novel and remarkable property, we predict that networks are more robust against mutations in monomer than in dimer transcription factors, a prediction for which analysis of conservation of DNA binding residues in monomeric vs. dimeric transcription factors provides indirect evidence. PMID:22295094

van Dijk, Aalt D J; van Mourik, Simon; van Ham, Roeland C H J

2012-01-25

17

Classification of Missense Mutations of Disease Genes  

PubMed Central

Clinical management of individuals found to harbor a mutation at a known disease-susceptibility gene depends on accurate assessment of mutation-specific disease risk. For missense mutations (MMs)—mutations that lead to a single amino acid change in the protein coded by the gene—this poses a particularly challenging problem. Because it is not possible to predict the structural and functional changes to the protein product for a given amino acid substitution, and because functional assays are often not available, disease association must be inferred from data on individuals with the mutation. Inference is complicated by small sample sizes and by sampling mechanisms that bias toward individuals at high familial risk of disease. We propose a Bayesian hierarchical model to classify the disease association of MMs given pedigree data collected in the high-risk setting. The model’s structure allows simultaneous characterization of multiple MMs. It uses a group of pedigrees identified through probands tested positive for known disease associated mutations and a group of test-negative pedigrees, both obtained from the same clinic, to calibrate classification and control for potential ascertainment bias. We apply this model to study MMs of breast-ovarian susceptibility genes BRCA1 and BRCA2, using data collected at the Duke University Medical Center in Durham, North Carolina.

Zhou, Xi; Iversen, Edwin S.; Parmigiani, Giovanni

2008-01-01

18

Fas and Fas ligand gene mutations in Hashimoto's thyroiditis.  

PubMed

To clarify whether Fas and Fas ligand (FasL) mutations are involved in the pathogenesis of Hashimoto's thyroiditis (HT), we examined the open reading frame of Fas and FasL in 21 cases. Mutations of Fas and FasL genes were detected in 8 (38.1%) and 1 (4.8%) of 21 cases, respectively. All but one of the Fas mutations were frameshift mutations, which affect the cytoplasmic region (death domain) known to be involved in apoptotic signal transduction and thus could be loss-of-function mutations. FasL mutation in one case was a 46-bp deletion from nucleotide 349 to 394, which corresponded to exon 2. Lack of exon 2 results in a frameshift, which generates a stop codon at residue 128. This mutant encodes the protein that contains only a part of the intracellular domain, thus the abnormal protein might not be expressed on the cell surface. The cells with Fas mutations were confined to the mantle zone and the germinal center, as determined by microdissection methods. These findings suggest that the cells with Fas mutations might accumulate in those areas and might be involved in the pathogenesis of Hashimoto's thyroiditis. PMID:12480911

Dong, Zhiming; Takakuwa, Tetsuya; Takayama, Hitoshi; Luo, Wen-Juan; Takano, Toru; Amino, Nobuyuki; Matsuzuka, Fumio; Aozasa, Katsuyuki

2002-12-01

19

The androgen receptor gene mutations database.  

PubMed

The current version of the androgen receptor (AR) gene mutations database is described. The total number of reported mutations has risen from 212 to 272. We have expanded the database: (i) by adding a large amount of new data on somatic mutations in prostatic cancer tissue; (ii) by defining a new constitutional phenotype, mild androgen insensitivity (MAI); (iii) by placing additional relevant information on an internet site (http://www.mcgill.ca/androgendb/ ). The database has allowed us to examine the contribution of CpG sites to the multiplicity of reports of the same mutation in different families. The database is also available from EMBL (ftp.ebi.ac.uk/pub/databases/androgen) or as a Macintosh Filemaker Pro or Word file (MC33@musica,mcgill.ca) PMID:9016528

Gottlieb, B; Trifiro, M; Lumbroso, R; Pinsky, L

1997-01-01

20

The Neurological Presentation of Ceruloplasmin Gene Mutations  

Microsoft Academic Search

Aceruloplasminemia is an autosomal recessive disorder of iron metabolism resulting from mutations of the ceruloplasmin gene. To better define the neurological phenotype of aceruloplasminemia we reviewed reports of published cases and sought details of unpublished ones. We identified 32 published reports and 1 unpublished case. The age at diagnosis ranged from 16 to 71 years with a mean of 51.

Alisdair McNeill; Massimo Pandolfo; Jens Kuhn; Huifang Shang; Hiroaki Miyajima

2008-01-01

21

Candidate gene strategy reveals ENAM mutations.  

PubMed

Amelogenesis imperfecta (AI) is a genetically and phenotypically heterogeneous genetic disorder affecting tooth enamel without other non-oral syndromic conditions. Based on a review of the literature, the authors constructed a candidate-gene-based mutational analysis strategy. To test the strategy, they identified two Turkish families with hypoplastic enamel without any other non-oral syndromic phenotype. The authors analyzed all exons and exon/intron boundaries of the enamelin (ENAM) gene for family 1 and the DLX3 and ENAM genes for family 2, to identify the underlying genetic etiology. The analysis revealed 2 ENAM mutations (autosomal-dominant g.14917delT and autosomal-recessive g.13185-13186insAG mutations). A single T deletion in exon 10 is a novel deletional mutation (g.14917delT, c.2991delT), which is predicted to result in a frameshift with a premature termination codon (p.L998fsX1062). This result supports the use of a candidate-gene-based strategy to study the genetic basis for AI. PMID:19329462

Kang, H-Y; Seymen, F; Lee, S-K; Yildirim, M; Tuna, E Bahar; Patir, A; Lee, K-E; Kim, J-W

2009-03-01

22

From Gene Mutation to Protein Characterization  

ERIC Educational Resources Information Center

|A seven-week "gene to protein" laboratory sequence is described for an undergraduate biochemistry laboratory course. Student pairs were given the task of introducing a point mutation of their choosing into the well studied protein, enhanced green fluorescent protein (EGFP). After conducting literature searches, each student group chose the…

Moffet, David A.

2009-01-01

23

Multicentric origin of hemochromatosis gene (HFE) mutations.  

PubMed Central

Genetic hemochromatosis (GH) is believed to be a disease restricted to those of European ancestry. In northwestern Europe, >80% of GH patients are homozygous for one mutation, the substitution of tyrosine for cysteine at position 282 (C282Y) in the unprocessed protein. In a proportion of GH patients, two mutations are present, C282Y and H63D. The clinical significance of this second mutation is such that it appears to predispose 1%-2% of compound heterozygotes to expression of the disease. The distribution of the two mutations differ, C282Y being limited to those of northwestern European ancestry and H63D being found at allele frequencies>5%, in Europe, in countries bordering the Mediterranean, in the Middle East, and in the Indian subcontinent. The C282Y mutation occurs on a haplotype that extends mutation has arisen during the past 2,000 years. The H63D mutation is older and does not occur on such a large extended haplotype, the haplotype in this case extending mutations on new haplotypes. In Sri Lanka we have found H63D on three new haplotypes and have found C282Y on one new haplotype, demonstrating that these mutations have arisen independently on this island. These results suggest that the HFE gene has been the subject of selection pressure. These selection pressures could be due to infectious diseases, environmental conditions, or other genetic disorders such as anemia.

Rochette, J; Pointon, J J; Fisher, C A; Perera, G; Arambepola, M; Arichchi, D S; De Silva, S; Vandwalle, J L; Monti, J P; Old, J M; Merryweather-Clarke, A T; Weatherall, D J; Robson, K J

1999-01-01

24

The Wilson disease gene: Haplotypes and mutations  

SciTech Connect

Wilson disease (WND) is an autosomal recessive defect of copper transport. The gene involved in WND, located on chromosome 13, has recently been shown to be a putative copper transporting P-type ATPase, designated ATP7B. The gene is highly similar to ATP7A, located on the X chromosome, which is defective in Menkes disease, another disorder of copper transport. We have available for study WND families from Canada (34 families), the United Kingdom (32 families), Japan (4 families), Iceland (3 families) and Hong Kong (2 families). We have utilized four highly polymorphic CA repeat markers (D13S296, D13S301, D13S314 and D13S316) surrounding the ATP7B locus to construct haplotypes in these families. Analysis indicates that there are many unique WND haplotypes not present on normal chromosomes and that there may be a large number of different WND mutations. We have screened the WND patients for mutations in the ATP7B gene. Fifty six patients, representing all of the identified haplotypes, have been screened using single strand conformational polymorphism (SSCP), followed by selective sequencing. To date, 19 mutations and 12 polymorphisms have been identified. All of the changes are nucleotide substitutions or small insertions/deletions and there is no evidence for larger deletions as seen in the similar gene on the X chromosome, ATP7A. Haplotypes of close markers and the ability to detect some of the mutations present in the gene allow for more reliable molecular diagnosis of presymptomatic sibs of WND patients. A reassessment of individuals previously diagnosed in the presymptomatic phase is now required, as we have have identified some heterozygotes who are biochemically indistinguishable from affected homozygotes. The identification of specific mutations will soon allow direct diagnosis of WND patients with a high level of certainty.

Thomas, G.R.; Roberts, E.A.; Cox, D.W. [Hospital for Sick Children, Toronto (Canada); Walshe, J.M. [Middlesex Hospital, London (United Kingdom)

1994-09-01

25

LEOPARD Syndrome: Clinical Features and Gene Mutations  

PubMed Central

The RAS/MAPK pathway proteins with germline mutations in their respective genes are associated with some disorders such as Noonan, LEOPARD (LS), neurofibromatosis type 1, Costello and cardio-facio-cutaneous syndromes. LEOPARD is an acronym, mnemonic for the major manifestations of this disorder, characterized by multiple lentigines, electrocardiographic abnormalities, ocular hypertelorism, pulmonic stenosis, abnormal genitalia, retardation of growth, and sensorineural deafness. Though it is not included in the acronym, hypertrophic cardiomyopathy is the most frequent cardiac anomaly observed, representing a potentially life-threatening problem in these patients. PTPN11, RAF1 and BRAF are the genes known to be associated with LS, identifying molecular genetic testing of the 3 gene mutations in about 95% of affected individuals. PTPN11 mutations are the most frequently found. Eleven different missense PTPN11 mutations (Tyr279Cys/Ser, Ala461Thr, Gly464Ala, Thr468Met/Pro, Arg498Trp/Leu, Gln506Pro, and Gln510Glu/Pro) have been reported so far in LS, 2 of which (Tyr279Cys and Thr468Met) occur in about 65% of the cases. Here, we provide an overview of clinical aspects of this disorder, the molecular mechanisms underlying pathogenesis and major genotype-phenotype correlations.

Martinez-Quintana, E.; Rodriguez-Gonzalez, F.

2012-01-01

26

LEOPARD Syndrome: Clinical Features and Gene Mutations.  

PubMed

The RAS/MAPK pathway proteins with germline mutations in their respective genes are associated with some disorders such as Noonan, LEOPARD (LS), neurofibromatosis type 1, Costello and cardio-facio-cutaneous syndromes. LEOPARD is an acronym, mnemonic for the major manifestations of this disorder, characterized by multiple lentigines, electrocardiographic abnormalities, ocular hypertelorism, pulmonic stenosis, abnormal genitalia, retardation of growth, and sensorineural deafness. Though it is not included in the acronym, hypertrophic cardiomyopathy is the most frequent cardiac anomaly observed, representing a potentially life-threatening problem in these patients. PTPN11, RAF1 and BRAF are the genes known to be associated with LS, identifying molecular genetic testing of the 3 gene mutations in about 95% of affected individuals. PTPN11 mutations are the most frequently found. Eleven different missense PTPN11 mutations (Tyr279Cys/Ser, Ala461Thr, Gly464Ala, Thr468Met/Pro, Arg498Trp/Leu, Gln506Pro, and Gln510Glu/Pro) have been reported so far in LS, 2 of which (Tyr279Cys and Thr468Met) occur in about 65% of the cases. Here, we provide an overview of clinical aspects of this disorder, the molecular mechanisms underlying pathogenesis and major genotype-phenotype correlations. PMID:23239957

Martínez-Quintana, E; Rodríguez-González, F

2012-08-29

27

Frequent Mutations of Fas Gene in Thyroid Lymphoma1  

Microsoft Academic Search

Fas (Apo-1\\/CD95) is a cell-surface receptor involved in cell death signaling through binding of Fas ligand. Mutation of the Fas gene results in accumulation of lymphoid cells and thus might contribute to lym- phomagenesis. Thyroid lymphoma (TL) is supposed to arise from active lymphoid cells formed in the preceding autoimmune chronic lymphocytic thyroiditis (CLTH). We examined the open reading frame

Tetsuya Takakuwa; Zhiming Dong; Hitoshi Takayama; Fumio Matsuzuka; Shigekazu Nagata; Katsuyuki Aozasa

2001-01-01

28

Mutation scanning of peach floral genes  

PubMed Central

Background Mutation scanning technology has been used to develop crop species with improved traits. Modifications that improve screening throughput and sensitivity would facilitate the targeted mutation breeding of crops. Technical innovations for high-resolution melting (HRM) analysis are enabling the clinic-based screening for human disease gene polymorphism. We examined the application of two HRM modifications, COLD-PCR and QMC-PCR, to the mutation scanning of genes in peach, Prunus persica. The targeted genes were the putative floral regulators PpAGAMOUS and PpTERMINAL FLOWER I. Results HRM analysis of PpAG and PpTFL1 coding regions in 36 peach cultivars found one polymorphic site in each gene. PpTFL1 and PpAG SNPs were used to examine approaches to increase HRM throughput. Cultivars with SNPs could be reliably detected in pools of twelve genotypes. COLD-PCR was found to increase the sensitivity of HRM analysis of pooled samples, but worked best with small amplicons. Examination of QMC-PCR demonstrated that primary PCR products for further analysis could be produced from variable levels of genomic DNA. Conclusions Natural SNPs in exons of target peach genes were discovered by HRM analysis of cultivars from a southeastern US breeding program. For detecting natural or induced SNPs in larger populations, HRM efficiency can be improved by increasing sample pooling and template production through approaches such as COLD-PCR and QMC-PCR. Technical advances developed to improve clinical diagnostics can play a role in the targeted mutation breeding of crops.

2011-01-01

29

Tyrosinase gene mutations causing oculocutaneous albinisms.  

PubMed

Since the first report of a mutation in the tyrosinase gene that causes tyrosinase-negative oculocutaneous albinism (OCA), more than 25 alleles with a different mutation in patients with three types of OCA, i.e., tyrosinase-negative OCA (type IA), yellow-mutant OCA (type IB), and temperature sensitive OCA (type ITS), have been found in several laboratories. The mutated alleles are presently classified into three types. The first and the second group of alleles, termed t- and y, produce tyrosinases with no enzyme activity and with very low activity, respectively. The third, termed ts, produces temperature-sensitive tyrosinase with very low activity at 35 degrees C, but with no activity at temperatures greater than 35 degrees C. Various combinations of these alleles result in tyrosinase-negative (t-/t-), yellow mutant (y/y, y/t-, y/ts), or temperature-sensitive (ts/t-, ts/ts) OCA. PMID:8433007

Tomita, Y

1993-02-01

30

Identifying Mutations in Duplicated Functions in Saccharomyces cererrisiae: Recessive Mutations in HMGCoA Reductase Genes  

Microsoft Academic Search

The two yeast genes for 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, HMGl and HMG2, each encode a functional isozyme. Although cells bearing null mutations in both genes are inviable, cells bearing a null mutation in either gene are viable. This paper describes a method of screening for recessive mutations in the HMGl gene, the gene encoding the majority of HMG-CoA reductase activity

Michael E. Basson; Robert L. Moore; Jules O'Rear; Jasper Rine

31

Mutations of the Prion Protein Gene  

Microsoft Academic Search

.   Prion diseases are inherited in 5–15 % of cases. They are classified according to changes in the prion protein gene (PRNP) or conventionally according to phenotype as Gerstmann-Sträussler-Scheinker disease (GSS), fatal familial insomnia (FFI),\\u000a or familial Creutzfeldt-Jakob disease (fCJD). Point mutations and insertions within PRNP form the genetic background. We report the results of a systematic analysis of over

Gábor G. Kovács; Gianriccardo Trabattoni; Johannes A. Hainfellner; James W. Ironside; Richard S. G. Knight; Herbert Budka

2002-01-01

32

RNA Gene Finding with Biased Mutation Operators  

Microsoft Academic Search

The use of genetic algorithms for non-coding RNA gene finding has previously been investigated and found to be a potentially viable method for accelerating covariance-model-based database search relative to full dynamic-programming methods. The mutation operators in previous work chose new alignment insertion and deletion locations uniformly over the length of the model consensus sequence. Since the covariance models are estimated

Scott F. Smith

2007-01-01

33

Adaptive evolution by mutations in the FLO11 gene  

PubMed Central

In nature, Saccharomyces yeasts manifest a number of adaptive responses to overcome adverse environments such as filamentation, invasive growth, flocculation and adherence to solid surfaces. Certain Saccharomyces wild yeasts, namely “flor yeasts,” have also acquired the ability to form a buoyant biofilm at the broth surface. Here we report that mutations in a single gene, identified as FLO11, separate these “floating” yeasts from their nonfloating relatives. We have determined that the capability to form a self-supporting biofilm at the liquid surface is largely dependent on two changes in the FLO11 gene. First, we identified a 111-nt deletion within a repression region of the FLO11 promoter that significantly increases FLO11 gene expression. Secondly, we found rearrangements within the central tandem repeat domain of the coding region that yield a more hydrophobic Flo11p variant. Together, these mutations result in dramatic increase in cell surface hydrophobicity, which in turn confers these yeasts the ability to float by surface tension, an adaptive mechanism to gain direct access to oxygen within oxygen-poor liquid environments.

Fidalgo, Manuel; Barrales, Ramon R.; Ibeas, Jose I.; Jimenez, Juan

2006-01-01

34

Towards linked open gene mutations data  

PubMed Central

Background With the advent of high-throughput technologies, a great wealth of variation data is being produced. Such information may constitute the basis for correlation analyses between genotypes and phenotypes and, in the future, for personalized medicine. Several databases on gene variation exist, but this kind of information is still scarce in the Semantic Web framework. In this paper, we discuss issues related to the integration of mutation data in the Linked Open Data infrastructure, part of the Semantic Web framework. We present the development of a mapping from the IARC TP53 Mutation database to RDF and the implementation of servers publishing this data. Methods A version of the IARC TP53 Mutation database implemented in a relational database was used as first test set. Automatic mappings to RDF were first created by using D2RQ and later manually refined by introducing concepts and properties from domain vocabularies and ontologies, as well as links to Linked Open Data implementations of various systems of biomedical interest. Since D2RQ query performances are lower than those that can be achieved by using an RDF archive, generated data was also loaded into a dedicated system based on tools from the Jena software suite. Results We have implemented a D2RQ Server for TP53 mutation data, providing data on a subset of the IARC database, including gene variations, somatic mutations, and bibliographic references. The server allows to browse the RDF graph by using links both between classes and to external systems. An alternative interface offers improved performances for SPARQL queries. The resulting data can be explored by using any Semantic Web browser or application. Conclusions This has been the first case of a mutation database exposed as Linked Data. A revised version of our prototype, including further concepts and IARC TP53 Mutation database data sets, is under development. The publication of variation information as Linked Data opens new perspectives: the exploitation of SPARQL searches on mutation data and other biological databases may support data retrieval which is presently not possible. Moreover, reasoning on integrated variation data may support discoveries towards personalized medicine.

2012-01-01

35

Basal core promoter T1762/A1764 and precore A1896 gene mutations in hepatitis B surface antigen-positive hepatocellular carcinoma: a comparison with chronic carriers  

PubMed Central

Background Chronic hepatitis B virus (HBV) infection is associated with hepatocellular carcinoma (HCC), and specific viral factors have been identified that may increase the risk for HCC development. However, the differences in these viral factors in chronic carriers who seldom develop HCC compared with HCC patients have not been adequately evaluated. Methods From 1989 to 2005, 101 hepatitis B surface antigen-positive patients presented to our clinic with HCC. Baseline basal core promoter (BCP) T1762/A1764 mutants, precore (PC) A1896 mutants, HBV genotypes and HBV DNA in HCC patients were compared with 67 chronic carriers who had been followed for a mean of 112.1±77.7 standard deviation months. Results At baseline, HCC patients had lower levels of serum albumin, but higher values of alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, bilirubin and ?-foetoprotein than those of chronic carriers (P < 0.001 for all comparisons). The presence of genotype C, higher frequencies of PC A1896 mutants, BCP T1762/A1764 mutants and higher circulating levels of HBV DNA were more frequently detected in HCC patients than that in chronic carriers (P < 0.001 for all observations). Logistic regression analysis revealed that BCP T1762/A1764 mutants [odds ratio (OR) 11.14, 95% confidence interval (CI) 3.05–40.72; P < 0.001] and PC A1896 mutants (OR 3.75, 95% CI 1.14–12.34; P < 0.05) were significantly associated with HCC development. Conclusion Our results indicate that the presence of BCP and PC mutations significantly increases the risk for HCC in chronic hepatitis B patients. These mutations were less often detected in chronic carriers who seldom develop HCC.

Tong, Myron J; Blatt, Lawrence M; Kao, Jia-Horng; Cheng, Jason Tzuying; Corey, William G

2007-01-01

36

PRKAR1A gene mutation in patients with cardiac myxoma  

Microsoft Academic Search

BackgroundPRKAR1A gene encodes the type 1A regulatory subunit of protein kinase A. The mutation of this gene causes Carney complex which is an autosomal dominant multiple neoplasia syndrome characterized by spotty pigmentations, endocrine overactivity and cardiac myxoma. We hypothesized that cardiac myxoma may be associated with PRKAR1A gene mutation and determined whether mutation in the PRKAR1A gene is the cause

T. Mabuchi; M. Shimizu; H. Ino; M. Yamguchi; H. Terai; N. Fujino; M. Nagata; K. Sakata; M. Inoue; T. Yoneda; H. Mabuchi

2005-01-01

37

Mutational analysis of the human MAOA gene.  

PubMed

The monoamine oxidases (MAO-A and MAO-B) are the enzymes primarily responsible for the degradation of amine neurotransmitters, such as dopamine, norepinephrine, and serotonin. Wide variations in activity of these isozymes have been reported in control humans. The MAOA and MAOB genes are located next to each other in the p11.3-11.4 region of the human X chromosome. Our recent documentation of an MAO-A-deficiency state, apparently associated with impulsive aggressive behavior in males, has focused attention of genetic variations in the MAOA gene. In the present study variations in the coding sequence of the MAOA gene were evaluated by RT-PCR, SSCP, and sequencing a mRNA or genomic DNA in 40 control males with > 100-fold variations of MAO-A activity, as measured in cultured skin fibroblasts. Remarkable conservation of the coding sequence was found with only 5 polymorphisms observed. All but one of these were in the third codon position and thus did not alter the deduced amino acid sequence. The one amino acid alteration observed, lys --> arg, was neutral and should not affect the structure of the protein. This study demonstrates high conservation of coding sequence in the human MAOA gene in control males, and provides primer sets which can be used to search genomic DNA for mutations in this gene in males with neuropsychiatric conditions. PMID:8678123

Tivol, E A; Shalish, C; Schuback, D E; Hsu, Y P; Breakefield, X O

1996-02-16

38

Mutational analysis of the human MAOA gene  

SciTech Connect

The monoamine oxidases (MAO-A and MAO-B) are the enzymes primarily responsible for the degradation of amine neurotransmitters, such as dopamine, norepinephrine, and serotonin. Wide variations in activity of these isozymes have been reported in control humans. The MAOA and MAOB genes are located next to each other in the p11.3-11.4 region of the human X chromosome. Our recent documentation of an MAO-A-deficiency state, apparently associated with impulsive aggressive behavior in males, has focused attention on genetic variations in the MAOA gene. In the present study, variations in the coding sequence of the MAOA gene were evaluated by RT-PCR, SSCP, and sequencing of mRNA or genomic DNA in 40 control males with >100-fold variations in MAOA activity, as measured in cultured skin fibroblasts. Remarkable conservation of the coding sequence was found, with only 5 polymorphisms observed. All but one of these were in the third codon position and thus did not alter the deduced amino acid sequence. The one amino acid alteration observed, lys{r_arrow}arg, was neutral and should not affect the structure of the protein. This study demonstrates high conservation of coding sequence in the human MAOA gene in control males, and provides primer sets which can be used to search genomic DNA for mutations in this gene in males with neuropsychiatric conditions. 47 refs., 1 fig., 2 tabs.

Tivol, E.A.; Shalish, C.; Schuback, D.E.; Breakefield, X.O. [Harvard Medical School, Boston, MA (United States); Hsu, Yun-Pung [VA Medical Center, West Roxbury, MA (United States)

1996-02-16

39

Combinatorial patterns of somatic gene mutations in cancer  

Microsoft Academic Search

Cancer is a complex process in which the abnormalities of many genes appear to be involved. The combinatorial patterns of gene mutations may reveal the functional relations between genes and path- ways in tumorigenesis as well as identify targets for treatment. We examined the patterns of somatic muta- tions of cancers from Catalog of Somatic Mutations in Cancer (COSMIC), a

Chen-Hsiang Yeang; Frank McCormick; Arnold Levine

2008-01-01

40

Ankyrin gene mutations in japanese patients with hereditary spherocytosis.  

PubMed

We studied mutations of the ankyrin-1 (ANK-1) gene of genomic DNA from Japanese patients with hereditary spherocytosis (HS). Forty-nine patients from 46 unrelated families were included in this study. Of these patients, 19 cases from 16 unrelated families had HS of autosomal-dominant inheritance, and 30 patients had non-autosomal-dominant HS. Fifteen mutations of the ANK-1 gene pathognomonic for HS were identified: 4 nonsense mutations, 7 frameshift mutations, and 4 abnormal splicing mutations. These 15 mutations have not been previously reported. The frameshift mutations were found from exon 1 to exon 26, corresponding particularly to the band 3-binding domain of ankyrin. The nonsense mutations, on the contrary, were present mostly at the 3'-terminal side, especially in the spectrin-binding domain and the regulatory domain. The patients with ankyrin gene mutations tended to be more anemic with a higher level of reticulocytosis than those without these mutations. Fifteen silent mutations of the ANK-1 gene, most of which have previously been detected in HS patients in Western populations, were also found. The allele frequency of these silent mutations in the HS patients was nearly identical to that in normal subjects. There was no difference between the Japanese and Western populations in the allele frequency of these gene polymorphisms in healthy subjects or HS patients. PMID:11372755

Nakanishi, H; Kanzaki, A; Yawata, A; Yamada, O; Yawata, Y

2001-01-01

41

NOTCH3 gene mutations in subjects clinically suspected of CADASIL  

Microsoft Academic Search

BackgroundCerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited cerebrovascular disease due to mutations involving loss or gain of a cysteine residue in the NOTCH3 gene. A cluster of mutations around exons 3 and 4 was originally reported. Identification of pathogenic mutation is important for diagnostic confirmation of the disease, however genetic counselling and testing of

Lorena Mosca; Raffaella Marazzi; Alfonso Ciccone; Ignazio Santilli; Anna Bersano; Valeria Sansone; Enrico Grosso; Giorgia Mandrile; Daniela Francesca Giachino; Laura Adobbati; Elisabetta Corengia; Elio Agostoni; Anna Fiumani; Salvatore Gallone; Elio Scarpini; Mario Guidotti; Roberto Sterzi; Clara Ajmone; Alessandro Marocchi; Silvana Penco

2011-01-01

42

Mutation analysis of the gene involved in adrenoleukodystrophy  

SciTech Connect

A gene responsible for the X-linked genetic disorder adrenoleukodystrophy (ALD) that is characterized by demyelination of the nervous system and adrenocortical insufficiency has been identified by positional cloning. The gene encodes an ATP-binding transporter which is located in the peroxisomal membrane. Deficiency of the gene leads to accumulation of unsaturated very long chain fatty acids due to impaired peroxisomal {beta}-oxidation. A systematic analysis of the open reading frame of the ALD gene unraveled the mutations in 28 different families using reverse transcriptase-PCR followed by direct sequencing. No entire gene deletions or drastic promoter mutations have been detected. Only in one family did the mutation involved multiple exons. The remaining mutations were subtle alterations leading to missense (about 50%) or nonsense mutations, frameshifts or splice acceptor site defects. In one patient a single codon was missing. Mutations affecting a single amino acid were concentrated in the region between the third and fourth putative membrane spanning fragments and in the ATP-binding domain. This overview of mutations aids in the determination of structural and functional important regions and facilitates the screening for mutations in other ALD patients. The detection of mutations in virtually all ALD families tested indicates that the isolated gene is the only gene responsible for ALD located in Xq28.

Oost, B.A. van; Ligtenberg, M.J.L. [Univ. Hospital Nijmegen (Netherlands); Kemp, S.; Bolhuis, P.A. [Academic Medical Center, Amsterdam (Netherlands)

1994-09-01

43

Clonal diversity of recurrently mutated genes in myelodysplastic syndromes  

PubMed Central

Recent studies suggest that most cases of myelodysplastic syndrome (MDS) are clonally heterogeneous, with a founding clone and multiple subclones. It is not known whether specific gene mutations typically occur in founding clones or subclones. We screened a panel of 94 candidate genes in a cohort of 157 patients with MDS or secondary acute myeloid leukemia (sAML). This included 150 cases with samples obtained at MDS diagnosis and 15 cases with samples obtained at sAML transformation (8 were also analyzed at the MDS stage). We performed whole-genome sequencing (WGS) to define the clonal architecture in eight sAML genomes and identified the range of variant allele frequencies (VAFs) for founding clone mutations. At least one mutation or cytogenetic abnormality was detected in 83% of the 150 MDS patients and 17 genes were significantly mutated (false discovery rate ?0.05). Individual genes and patient samples displayed a wide range of VAFs for recurrently mutated genes, indicating that no single gene is exclusively mutated in the founding clone. The VAFs of recurrently mutated genes did not fully recapitulate the clonal architecture defined by WGS, suggesting that comprehensive sequencing may be required to accurately assess the clonal status of recurrently mutated genes in MDS.

Walter, MJ; Shen, D; Shao, J; Ding, L; White, BS; Kandoth, C; Miller, CA; Niu, B; McLellan, MD; Dees, ND; Fulton, R; Elliot, K; Heath, S; Grillot, M; Westervelt, P; Link, DC; DiPersio, JF; Mardis, E; Ley, TJ; Wilson, RK; Graubert, TA

2013-01-01

44

PTEN gene mutations in colorectal cancers displaying microsatellite instability  

Microsoft Academic Search

To determine the relationship between the mutation of the PTEN gene and genomic instability in human colorectal cancer, we screened the PTEN gene in 32 colorectal cancers (eight cell lines and 24 tissues) displaying microsatellite instability (MSI) and 32 colorectal cancers (six cell lines and 26 tissues) displaying microsatellite stability (MSS). Of 64 samples, six frameshift mutations were identified in

Ki-Hyuk Shin; Young Jin Park; Jae-Gahb Park

2001-01-01

45

Conditional Lethal Amber Mutations in Essential Escherichia coli Genes  

Microsoft Academic Search

The essential genes of microorganisms encode biological functions important for survival and thus tend to be of high scientific interest. Drugs that interfere with essential functions are likely to be interesting candidates for antimicrobials. However, these genes are hard to study genetically because knockout mutations in them are by definition inviable. We recently described a conditional mutation system in Escherichia

Christopher D. Herring; Frederick R. Blattner

2004-01-01

46

Gene Mutations in Adult Japanese Patients With Dilated Cardiomyopathy  

Microsoft Academic Search

Background Some patients with dilated cardiomyopathy (DCM) have mutations of the genes that encode sarcomeric or cytoskeletal proteins of cardiomyocytes, but the prevalence of these mutations in Japan remains unclear. Methods and Results A group of 99 unrelated adult patients with DCM (familial n=27, sporadic n=72) were screened for the following genes: cardiac -myosin heavy chain, cardiac myosin-binding protein C

Masami Shimizu; Hidekazu Ino; Toshihiko Yasuda; Noboru Fujino; Katsuharu Uchiyama; Tomohito Mabuchi; Tetsuo Konno; Tomoya Kaneda; Takashi Fujita; Eiichi Masuta; Masahiro Katoh; Akira Funada; Hiroshi Mabuchi

2005-01-01

47

Mutations of the HFE gene among Turkish hereditary hemochromatosis patients  

Microsoft Academic Search

Since the discovery of the HFE gene, C282Y and H63D mutations have been reported as significantly correlated with clinically manifested hereditary hemochromatosis (HH). As the other genes involved in iron metabolism have been described, non-HFE cases of HH have been identified. Since in the general Turkish population, the C282Y mutation is not found and the H63D mutation is of high

Halis Simsek; Yasemin H. Balaban; Engin Yilmaz; Hale Sumer; Yahya Buyukasik; Cem Cengiz; Osman Ozcebe; Gulsen Hascelik; Gonca Tatar

2005-01-01

48

Hepatoblastoma and APC gene mutation in familial adenomatous polyposis.  

PubMed Central

BACKGROUND: Hepatoblastoma is a rare, rapidly progressive, usually fatal childhood malignancy, which if confined to the liver can be cured by radical surgical resection. An association between hepatoblastoma and familial adenomatous polyposis (FAP), which is due to germline mutation of the APC (adenomatous polyposis coli) gene, has been confirmed, but correlation with site of APC mutation has not been studied. AIM: To analyse the APC mutational spectrum in FAP families with hepatoblastoma as a possible basis to select kindreds for surveillance. PATIENTS: Eight patients with hepatoblastoma in seven FAP kindreds were compared with 97 families with identified APC gene mutation in a large Registry. METHODS: APC gene mutation was evaluated by RNase protection assay or in vitro synthesis protein assay. The chi 2 test and correlation were used for data analysis. RESULTS: APC gene mutation was identified in all seven FAP kindreds in which an at risk member developed hepatoblastoma. A male predominance was noted (six of eight), similar to literature cases (18 of 25, p < 0.01. Mutations were restricted to codons 141 to 1230, but no significant difference in site of mutation between pedigrees with and without hepatoblastoma was identified. CONCLUSIONS: Hepatoblastoma occurs primarily in boys in FAP kindreds and is associated with germline APC mutation in the 5' end of the gene. However, the site of APC mutation cannot be used to predict occurrence of this extracolonic cancer in FAP pedigrees.

Giardiello, F M; Petersen, G M; Brensinger, J D; Luce, M C; Cayouette, M C; Bacon, J; Booker, S V; Hamilton, S R

1996-01-01

49

Mutations in Putative Mutator Genes of Mycobacterium tuberculosis Strains of the W-Beijing Family  

Microsoft Academic Search

Alterations in genes involved in the repair of DNA mutations (mut genes) result in an increased mutation fre- quency and better adaptability of the bacterium to stressful conditions. W-Beijing genotype strains displayed unique missense alterations in three putative mut genes, including two of the mutT type (Rv3908 and mutT2) and ogt. These polymorphisms were found to be characteristic and unique

Mina Ebrahimi Rad; Pablo Bifani; Carlos Martin; Kristin Kremer; Sofia Samper; Jean Rauzier; Barry Kreiswirth; Jesus Blazquez; Marc Jouan; Dick van Soolingen; Brigitte Gicquel

2003-01-01

50

DRUMS: a human disease related unique gene mutation search engine.  

PubMed

With the completion of the human genome project and the development of new methods for gene variant detection, the integration of mutation data and its phenotypic consequences has become more important than ever. Among all available resources, locus-specific databases (LSDBs) curate one or more specific genes' mutation data along with high-quality phenotypes. Although some genotype-phenotype data from LSDB have been integrated into central databases little effort has been made to integrate all these data by a search engine approach. In this work, we have developed disease related unique gene mutation search engine (DRUMS), a search engine for human disease related unique gene mutation as a convenient tool for biologists or physicians to retrieve gene variant and related phenotype information. Gene variant and phenotype information were stored in a gene-centred relational database. Moreover, the relationships between mutations and diseases were indexed by the uniform resource identifier from LSDB, or another central database. By querying DRUMS, users can access the most popular mutation databases under one interface. DRUMS could be treated as a domain specific search engine. By using web crawling, indexing, and searching technologies, it provides a competitively efficient interface for searching and retrieving mutation data and their relationships to diseases. The present system is freely accessible at http://www.scbit.org/glif/new/drums/index.html. PMID:21913285

Li, Zuofeng; Liu, Xingnan; Wen, Jingran; Xu, Ye; Zhao, Xin; Li, Xuan; Liu, Lei; Zhang, Xiaoyan

2011-10-01

51

G protein gene mutations in patients with multiple endocrinopathies.  

PubMed

Point mutations of G protein genes that result in the constitutive activation of G proteins have been described. Such mutations have been shown to occur in a number of endocrine diseases. We have examined tissues from patients having more than one organ affected by an endocrine disorder and patients having separate distinct endocrine diseases for G protein gene mutations. G protein genes encoding for Gs alpha and Gi2 alpha were examined for activating mutations at codons 201 and 227 (Gs alpha) and codons 179 and 205 (Gi2 alpha) using site-directed oligonucleotide hybridization and direct sequencing of tissue DNA amplified by polymerase chain reaction. Tissues from six patients were examined. The only mutation that was identified was at codon 201 of Gs alpha (gsp), which encoded a change from arginine to cysteine. Patient 1 had the mutation in a corticotroph adenoma, a chemodectoma, and a nodular hyperplastic adrenal gland. patient 2 had the mutation in an extraadrenal pheochromocytoma, but an adrenal gland with medullary hyperplasia was wild-type. Patient 3 had an aggressive corticotroph adenoma and developed Nelson's syndrome after bilateral adrenalectomy. The corticotroph adenoma was wild-type, but both hyperplastic adrenal glands had the mutation. Patient 4 had the mutation in a parathyroid adenoma and in two hyperplastic parathyroid glands. Patient 5 had the mutation in both a primary and a metastatic pheochromocytoma. Patient 6 had the mutation in a parathyroid adenoma and also in histologically normal thyroid and parathyroid tissue. Leukocyte DNA was examined from five patients and was found to be wild-type in all cases. We conclude that G protein gene mutations occur in a wider range of endocrine conditions than has been recognized hereto. In addition, the presence of gsp mutations in different endocrine disorders in the same patient is suggestive of a common underlying etiology. PMID:7745022

Williamson, E A; Johnson, S J; Foster, S; Kendall-Taylor, P; Harris, P E

1995-05-01

52

Crystallin gene mutations in Indian families with inherited pediatric cataract  

PubMed Central

Purpose Pediatric cataract is the most common form of treatable childhood blindness and is both clinically and genetically heterogeneous. Autosomal dominant and recessive forms of cataract have been reported to be caused by mutations in 22 different genes so far. Of the cataract mutations reported to date, about half the mutations occur in crystallins, a quarter of the mutations in connexins, and the remainder is evenly divided between intrinsic membrane proteins, intermediate filament proteins, and transcription factors. This study is aimed at identification of the spectrum and frequency of crystallin gene mutations in cataractous patients in an Indian population. Methods Genetic analysis was extended to screen the entire coding region of the CRYAA, CRYAB, CRYBA1, CRYBA4, CRYBB1, CRYBB2, CRYBB3, CRYGC, CRYGD, and CRYGS genes using single stranded conformational polymorphism (SSCP) analysis as a screening technique followed by direct sequencing of all subjects that displayed an electrophoretic shift. Results This report describes the first simultaneous mutation analysis of 10 crystallin genes in the same population, represented by 60 south Indian families. The analysis allowed the identification of causative mutations in 10 of the families (three novel and six reported). This includes six missense mutations (CRYAA-R12C, R21W, R54C, CRYAB- A171T, CRYGC-R168W, CRYGS- S39C), two nonsense mutations (CRYBB2- Q155X, CRYGD- R140X), and one splice mutation, which was identified in two families (CRYBA1-IVS3+1G>A). Conclusions Crystallin mutations are responsible for 16.6% of the inherited pediatric cataract in this population. As causative mutations have not been found in many of the families analyzed, this study suggests the presence of further novel genes or sequence elements involved in the pathogenesis of cataract in these families.

Devi, Ramachandran Ramya; Yao, Wenliang; Vijayalakshmi, Perumalsamy; Sergeev, Yuri V.; Sundaresan, Periasamy

2008-01-01

53

Clinical implications for BRCA gene mutation in breast cancer.  

PubMed

To investigate the mutations of BRCA1 and BRCA2 and determine whether clinic-pathological factors related to BRCA gene mutation. Mastectomy specimens from 360 breast cancers were enrolled and examined in the study. The relationship between BRCA gene mutation and clinic-pathological factors was evaluated. Overall, 280 patients were BRCA negative and 80 got BRCA gene mutation. Triple-negative breast cancers--i.e., breast cancers that do not express estrogen receptors (ER), progesterone receptors (PR) or human epidermal growth factor receptor 2 (HER2/neu)--was observed in 53.85% of the BRCA1 mutation patients, in 28.57% of the BRCA2 mutation cases, while 14.29% of BRCA negative patients. BRCA1 mutation patients got a heavy lymph node metastasis and higher nuclear grade tumors than the others (P = 0.004, 0.007). Furthermore, BRCA mutation was also found to be significantly related to ER, PR and HER2/neu status (P < 0.05). BRCA1 expression was not associated with breast cancer-specific survival in the triple-negative breast cancers (P = 0.742). After Cox regression, BRCA1 mutation was not shown to be an independent prognostic factor for breast cancer. These findings substantiated the possibility of tumors associated with BRCA1 mutations divided into two distinct groups, triple-negative and non-triple-negative groups requires further investigation. PMID:21691706

Xu, Jin; Wang, Baosheng; Zhang, Yanjun; Li, Ruihui; Wang, Yuehua; Zhang, Shaokun

2011-06-21

54

CFTR gene mutations in isolated chronic obstructive pulmonary disease  

SciTech Connect

In order to identify a possible hereditary predisposition to the development of chronic obstructive pulmonary disease (COPD), we have looked for the presence of cystic fibrosis transmembrane regulator (CFTR) gene DNA sequence modifications in 28 unrelated patients with no signs of cystic fibrosis. The known mutations in Italian CF patients, as well as the most frequent worldwide CF mutations, were investigated. In addition, a denaturing gradient gel electrophoresis analysis of about half of the coding sequence of the gene in 56 chromosomes from the patients and in 102 chromosomes from control individuals affected by other pulmonary diseases and from normal controls was performed. Nine different CFTR gene mutations and polymorphisms were found in seven patients, a highly significant increase over controls. Two of the patients were compound heterozygotes. Two frequent CF mutations were detected: deletion F508 and R117H; two rare CF mutations: R1066C and 3667ins4; and five CF sequence variants: R75Q (which was also described as a disease-causing mutation in male sterility cases due to the absence of the vasa deferentia), G576A, 2736 A{r_arrow}G, L997F, and 3271+18C{r_arrow}T. Seven (78%) of the mutations are localized in transmembrane domains. Six (86%) of the patients with defined mutations and polymorphisms had bronchiectasis. These results indicate that CFTR gene mutations and sequence alterations may be involved in the etiopathogenesis of some cases of COPD.

Pignatti, P.F.; Bombien, C.; Marigo, C. [and others

1994-09-01

55

Common Familial Mediterranean Fever gene mutations in a Turkish cohort.  

PubMed

Familial Mediterranean Fever (FMF) is an autosomal recessive autoinflammatory disorder with the responsible gene of MEFV which primarily affects Jewish, Armenian, Turkish and Arab populations. The FMF gene (MEFV) has recently been cloned to chromosome 16 p, which encodes pyrin. In the present study, we enrolled 2,067 unrelated patients with the suspicion of FMF in Middle Anatolia between the years 2006-2009 and identified the 12 MEFV mutations. DNA was amplified by PCR and subjected to reverse hybridization for the detection of MEFV gene mutations. Among the 2,067 patients, 866 (41.9%) were males and 1,201 (58.1%) were females. The mutations were homozygous in 176 (16.85%) patients, compound heterozygous in 314 (30.1%) patients, heterozygous in 546 (52.25%) patients and the other forms of mutations were found in 8 patients (0.76%). No mutation was detected in 1,023 (49.5%) patients. The most frequent mutations were M694V, M680I (G/C), E148Q and V726A. We could not find any significant differences between the two common mutations according to the gender. The high incidence of MEFV gene mutations in the Turkish population indicated that newborn screening may be discussed in the future. Because of the ethnic origin of Anatolia, larger serial analyses are necessary to investigate the rate and coexistence of these mutations. PMID:21153919

Dundar, Munis; Emirogullari, Elif Funda; Kiraz, Aslihan; Taheri, Serpil; Baskol, Mevlut

2010-12-14

56

Analysis of mutations in the SCH gene in schwannomas.  

PubMed

Schwannomas are benign tumors of cranial, spinal, and other nerve sheaths that develop sporadically or are inherited as part of neurofibromatosis type 2 (NF2). The NF2 gene (SCH) on chromosome 22 has recently been identified and shown to be inactivated by mutation and allele loss in some schwannomas. However, only limited regions in the SCH coding region were examined for mutations. We have extended these studies by screening virtually all coding sequences of the SCH gene (95% coverage) and adjacent splice site sequences for the presence of mutations in 48 schwannomas. All tumors (34 vestibular schwannomas and 14 schwannomas of other locations) were additionally characterized for allele loss on chromosome 22. By PCR-DGGE screening of the 16 known exons of the SCH gene, 22 mutations were found. Most of these give rise to a premature stop codon and are expected to result in the synthesis of a truncated gene product (schwannomin). Although there was no apparent hotspot for mutations, 16 of the 22 mutations occurred in the first eight exons or adjacent splice site sequences of the SCH gene. In several vestibular as well as other schwannomas loss of one SCH allele and mutational inactivation of the second allele were identified in the same tumor. Our data indicate that the SCH gene is implicated in the development of schwannomas of all locations in the nervous system. PMID:7529050

Bijlsma, E K; Merel, P; Bosch, D A; Westerveld, A; Delattre, O; Thomas, G; Hulsebos, T J

1994-09-01

57

KIT gene mutation analysis in solid tumours: biology, clincial applications and trends in diagnostic reporting.  

PubMed

Gain-of-function mutations involving c-kit protein, a cell-surface transmembrane receptor for stem cell factor, have been identified as a key oncogenic driver in a variety of solid tumours. Coupled with the development of tyrosine kinase inhibitors such as imatinib, c-kit has emerged as a viable drug target in what seems to be a validated therapeutic concept. This review will focus on gastrointestinal stromal tumours and melanomas, two types of solid tumours most closely associated with KIT gene mutations. The biology of KIT mutations in both conditions, as well as the value of KIT mutation testing in predicting disease and treatment outcomes are discussed. Since initial response to imatinib is largely influenced by mutation status, genotyping these tumours serves to facilitate personalised oncology. We also summarise our experience with diagnostic reporting of KIT mutation analysis over a period of 3 years, and briefly survey future developments in treatment, which indeed look very promising. PMID:23277171

Tay, Clifton Ming; Ong, Chee Wee; Lee, Victor Kwan Min; Pang, Brendan

2013-02-01

58

Prevalence of Hemochromatosis Gene (HFE) Mutations in Greece  

Microsoft Academic Search

The frequencies of the hereditary hemochromatosis gene (HFE) mutations C282Y and H63D vary between different populations. There are a limited number of reports regarding the frequency of these mutations in populations of southeastern Europe. Two hundred and sixty-four adult individuals of Greek origin were examined for the C282Y and H63D mutations to determine the allele and genotype frequencies. The HFE

Dimitrios Papazoglou; Triada Exiara; Matthaios Speletas; Ioannis Panagopoulos; Efstratios Maltezos

2003-01-01

59

Diverse growth hormone receptor gene mutations in Laron syndrome  

SciTech Connect

To better understand the molecular genetic basis and genetic epidemiology of Laron syndrome (growth-hormone insensitivity syndrome), the authors analysed the growth-hormone receptor (GHR) genes of seven unrelated affected individuals from the United States, South America, Europe, and Africa. They amplified all nine GHR gene exons and splice junctions from these individuals by PCR and screened the products for mutations by using denaturing gradient gel electrophoresis (DGGE). They identified a single GHR gene fragment with abnormal DGGE results for each affected individual, sequenced this fragment, and, in each case, identified a mutation likely to cause Laron syndrome, including two nonsense mutations (R43X and R217X), two splice-junction mutations, (189-1 G to T and 71+1 G to A), and two frameshift mutations (46 del TT and 230 del TA or AT). Only one of these mutations, R43X, has been previously reported. Using haplotype analysis, they determined that this mutation, which involves a CpG dinucleotide hot spot, likely arose as a separate event in this case, relative to the two prior reports of R43X. Aside from R43X, the mutations identified are unique to patients from particular geographic regions. Ten GHR gene mutations have now been described in this disorder. The authors conclude that Laron syndrome is caused by diverse GHR gene mutations, including deletions, RNA processing defects, translational stop codons, and missense codons. All the identified mutations involve the extracellular domain of the receptor, and most are unique to particular families or geographic areas. 35 refs., 3 figs., 1 tab.

Berg, M.A.; Francke, U. (Stanford Univ. School of Medicine, CA (United States)); Gracia, R.; Rosenbloom, A.; Toledo, S.P.A. (Univ. Autonoma, Madrid (Spain)); Chernausek, S. (Children's Hospital Medical Center, Cincinnati, OH (United States)); Guevara-Aguirre, J. (Institute of Endocrinology, Metabolism, and Reproduction, Quito (Ecuador)); Hopp, M. (Univ. of Witwatersrand, Johannesburg (South Africa)); Rosenbloom, A.; Argente, J. (Univ. of Florida, Gainesville (United States)); Toledo, S.P.A. (Univ. of Sao Paulo (Brazil))

1993-05-01

60

Gene Mutation May Help Predict Lung Cancer Survival in Nonsmokers  

MedlinePLUS

... please enable JavaScript. Gene Mutation May Help Predict Lung Cancer Survival in Nonsmokers Finding might offer doctors a ' ... 2013 Related MedlinePlus Pages Genes and Gene Therapy Lung Cancer THURSDAY, Sept. 12 (HealthDay News) -- Researchers say they' ...

61

Mutator phenotypes of yeast strains heterozygous for mutations in the MSH2 gene  

PubMed Central

Heterozygosity for germ-line mutations in the DNA mismatch repair gene MSH2 predisposes humans to cancer. Here we use a highly sensitive reporter to describe a spontaneous mutator phenotype in diploid yeast cells containing a deletion of only one MSH2 allele. We also identify five MSH2 missense mutations that have dominant mutator effects in heterozygous cells when expressed at normal levels from the natural MSH2 promoter. For example, a 230-fold mutator effect is observed in an MSH2/msh2 diploid strain in which Gly693, which is invariant in MutS homologs and involved in ATP hydrolysis, is changed to alanine. DNA binding data suggest that mismatch repair is suppressed by binding of a mutant Msh2–Msh6 heterodimer to a mismatch with subsequent inability to dissociate from the mismatch in the presence of ATP. A dominant mutator effect also is observed in yeast when Gly693 is changed to serine. An early onset colorectal tumor is heterozygous for the analogous Gly ? Ser mutation in hMSH2, and a second hMSH2 mutation was not found, suggesting that this missense mutation may predispose to cancer via a dominant mutator effect. The mutator effects of the deletion mutant and the Gly ? Ala missense mutant in yeast MSH2 are enhanced by heterozygosity for a missense mutation in DNA polymerase ? that reduces its proofreading activity but is not a mutator in the heterozygous state. The synergistic effects of heterozygosity for mutations in two different genes that act in series to correct replication errors may be relevant to cancer predisposition.

Drotschmann, Karin; Clark, Alan B.; Tran, Hiep T.; Resnick, Michael A.; Gordenin, Dmitry A.; Kunkel, Thomas A.

1999-01-01

62

EGF receptor gene mutations are common in lung cancers from  

Microsoft Academic Search

Somatic mutations in the tyrosine kinase (TK) domain of the epidermal growth factor receptor (EGFR) gene are reportedly associated with sensitivity of lung cancers to gefitinib (Iressa), kinase inhibitor. In-frame deletions occur in exon 19, whereas point mutations occur frequently in codon 858 (exon 21). We found from sequencing the EGFR TK domain that 7 of 10 gefitinib-sensitive tumors had

William Pao; Vincent Miller; Maureen Zakowski; Jennifer Doherty; Katerina Politi; Inderpal Sarkaria; Bhuvanesh Singh; Robert Heelan; Valerie Rusch; Lucinda Fulton; Elaine Mardis; Doris Kupfer; Richard Wilson; Mark Kris; Harold Varmus

2004-01-01

63

Mutations including the promoter region of myocilin\\/TIGR gene  

Microsoft Academic Search

Mutations in the MYOC\\/TIGR gene are responsible for autosomal dominant primary open angle glaucoma (POAG). Almost all mutations responsible for POAG have been detected in the coding region (in particular at exon 3). By using the techniques of PCR, SSCP, automated sequencing and restriction analysis, we have studied 79 patients suffering from glaucoma. We have found five patients with sequence

Maria Saura; Montse Cabana; Carmen Ayuso; Diana Valverde

2005-01-01

64

Phenotypic Involvement in Females with the FMR1 Gene Mutation.  

ERIC Educational Resources Information Center

|A study investigated phenotypic effects seen in 114 females with premutation and 41 females (ages 18-58) with full Fragile X mental retardation gene mutation. Those with the full mutation had a greater incidence of hand-flapping, eye contact problems, special education help for reading and math, and grade retention. (Author/CR)|

Riddle, J. E.; Cheema, A.; Sobesky, W. E.; Gardner, S. C.; Taylor, A. K.; Pennington, B. F.; Hagerman, R. J.

1998-01-01

65

MAMMALIAN CELL GENE MUTATION ASSAYS WORKING GROUP REPORT  

EPA Science Inventory

Mammalian cell gene mutation assays have been used for many years and the diversity of the available systems attests to the varied methods found to grow mammalian dells and detect mutations. s part of the International Workshop on Standardization of Genotoxicity Test Procedures, ...

66

Ankyrin gene mutations in japanese patients with hereditary spherocytosis  

Microsoft Academic Search

We studied mutations of theankyrin-1 (ANK-1) gene of genomic DNA from Japanese patients with hereditary spherocytosis (HS). Forty-nine patients from 46 unrelated families\\u000a were included in this study. Of these patients, 19 cases from 16 unrelated families had HS of autosomal-dominant inheritance,\\u000a and 30 patients had non-autosomal-dominant HS. Fifteen mutations of theANK-1 gene pathognomonic for HS were identified: 4 nonsense

Hidekazu Nakanishi; Akio Kanzaki; Ayumi Yawata; Osamu Yamada; Yoshihito Yawata

2001-01-01

67

New approaches to understanding p53 gene tumor mutation spectra  

Microsoft Academic Search

The first p53 gene mutation arising in a human tumor was described a decade ago by Baker et al. [S.J. Baker, E.R. Fearon, J.M. Nigro, S.R. Hamilton, A.C. Preisinger, J.M. Jessup, P. van Tuinen, D.H. Ledbetter, D.F. Barker, Y. Nakamura, R. White, B. Vogelstein, Chromosome 17 deletions and p53 gene mutations in colorectal carcinomas, Science 244 (1989) 217–221]. There are

Monica Hollstein; Manfred Hergenhahn; Qin Yang; Helmut Bartsch; Zhao-Qi Wang; Pierre Hainaut

1999-01-01

68

HFE gene mutations an Apulian population: Allele frequencies  

Microsoft Academic Search

Hereditary hemochromatosis (HH) is an autosomal recessive trait regarding iron metabolism frequently found in Caucasian populations. The C282Y mutation of the HFE gene, held responsible for HH, has been identified as the major genetic basis for the phenotypic expression of HH whereas two additional mutations of the HFE H63D and S65C gene appear to be associated with a milder form

A. Pietrapertosa; A. Vitucci; D. Campanale; A. Palma; R. Renni; G. Delios; N. Tannoia

2003-01-01

69

Microarray-based mutation detection in the dystrophin gene.  

PubMed

Duchenne and Becker muscular dystrophies (DMD and BMD) are X-linked recessive neuromuscular disorders caused by mutations in the dystrophin gene affecting approximately 1 in 3,500 males. The human dystrophin gene spans>2,200 kb, or roughly 0.1% of the genome, and is composed of 79 exons. The mutational spectrum of disease-causing alleles, including exonic copy number variations (CNVs), is complex. Deletions account for approximately 65% of DMD mutations and 85% of BMD mutations. Duplications occur in approximately 6 to 10% of males with either DMD or BMD. The remaining 30 to 35% of mutations consist of small deletions, insertions, point mutations, or splicing mutations, most of which introduce a premature stop codon. Laboratory analysis of dystrophin can be used to confirm a clinical diagnosis of DMD, characterize the type of dystrophin mutation, and perform prenatal testing and carrier testing for females. Current dystrophin diagnostic assays involve a variety of methodologies, including multiplex PCR, Southern blot analysis, multiplex ligation-dependent probe amplification (MLPA), detection of virtually all mutations-SSCP (DOVAM-S), and single condition amplification/internal primer sequencing (SCAIP); however, these methods are time-consuming, laborious, and do not accurately detect duplication mutations in the dystrophin gene. Furthermore, carrier testing in females is often difficult when a related affected male is unavailable. Here we describe the development, design, validation, and implementation of a high-resolution comparative genomic hybridization (CGH) microarray-based approach capable of accurately detecting both deletions and duplications in the dystrophin gene. This assay can be readily adopted by clinical molecular testing laboratories and represents a rapid, cost-effective approach for screening a large gene, such as dystrophin. PMID:18663755

Hegde, Madhuri R; Chin, Ephrem L H; Mulle, Jennifer G; Okou, David T; Warren, Stephen T; Zwick, Michael E

2008-09-01

70

Convergence in pigmentation at multiple levels: mutations, genes and function.  

PubMed

Convergence--the independent evolution of the same trait by two or more taxa--has long been of interest to evolutionary biologists, but only recently has the molecular basis of phenotypic convergence been identified. Here, we highlight studies of rapid evolution of cryptic coloration in vertebrates to demonstrate that phenotypic convergence can occur at multiple levels: mutations, genes and gene function. We first show that different genes can be responsible for convergent phenotypes even among closely related populations, for example, in the pale beach mice inhabiting Florida's Gulf and Atlantic coasts. By contrast, the exact same mutation can create similar phenotypes in distantly related species such as mice and mammoths. Next, we show that different mutations in the same gene need not be functionally equivalent to produce similar phenotypes. For example, separate mutations produce divergent protein function but convergent pale coloration in two lizard species. Similarly, mutations that alter the expression of a gene in different ways can, nevertheless, result in similar phenotypes, as demonstrated by sister species of deer mice. Together these studies underscore the importance of identifying not only the genes, but also the precise mutations and their effects on protein function, that contribute to adaptation and highlight how convergence can occur at different genetic levels. PMID:20643733

Manceau, Marie; Domingues, Vera S; Linnen, Catherine R; Rosenblum, Erica Bree; Hoekstra, Hopi E

2010-08-27

71

Convergence in pigmentation at multiple levels: mutations, genes and function  

PubMed Central

Convergence—the independent evolution of the same trait by two or more taxa—has long been of interest to evolutionary biologists, but only recently has the molecular basis of phenotypic convergence been identified. Here, we highlight studies of rapid evolution of cryptic coloration in vertebrates to demonstrate that phenotypic convergence can occur at multiple levels: mutations, genes and gene function. We first show that different genes can be responsible for convergent phenotypes even among closely related populations, for example, in the pale beach mice inhabiting Florida's Gulf and Atlantic coasts. By contrast, the exact same mutation can create similar phenotypes in distantly related species such as mice and mammoths. Next, we show that different mutations in the same gene need not be functionally equivalent to produce similar phenotypes. For example, separate mutations produce divergent protein function but convergent pale coloration in two lizard species. Similarly, mutations that alter the expression of a gene in different ways can, nevertheless, result in similar phenotypes, as demonstrated by sister species of deer mice. Together these studies underscore the importance of identifying not only the genes, but also the precise mutations and their effects on protein function, that contribute to adaptation and highlight how convergence can occur at different genetic levels.

Manceau, Marie; Domingues, Vera S.; Linnen, Catherine R.; Rosenblum, Erica Bree; Hoekstra, Hopi E.

2010-01-01

72

Mutations in putative mutator genes of Mycobacterium tuberculosis strains of the W-Beijing family.  

PubMed

Alterations in genes involved in the repair of DNA mutations (mut genes) result in an increased mutation frequency and better adaptability of the bacterium to stressful conditions. W-Beijing genotype strains displayed unique missense alterations in three putative mut genes, including two of the mutT type (Rv3908 and mutT2) and ogt. These polymorphisms were found to be characteristic and unique to W-Beijing phylogenetic lineage. Analysis of the mut genes in 55 representative W-Beijing isolates suggests a sequential acquisition of the mutations, elucidating a plausible pathway of the molecular evolution of this clonal family. The acquisition of mut genes may explain in part the ability of the isolates of W-Beijing type to rapidly adapt to their environment. PMID:12890325

Ebrahimi-Rad, Mina; Bifani, Pablo; Martin, Carlos; Kremer, Kristin; Samper, Sofia; Rauzier, Jean; Kreiswirth, Barry; Blazquez, Jesus; Jouan, Marc; van Soolingen, Dick; Gicquel, Brigitte

2003-07-01

73

Mutations in Putative Mutator Genes of Mycobacterium tuberculosis Strains of the W-Beijing Family  

PubMed Central

Alterations in genes involved in the repair of DNA mutations (mut genes) result in an increased mutation frequency and better adaptability of the bacterium to stressful conditions. W-Beijing genotype strains displayed unique missense alterations in three putative mut genes, including two of the mutT type (Rv3908 and mutT2) and ogt. These polymorphisms were found to be characteristic and unique to W-Beijing phylogenetic lineage. Analysis of the mut genes in 55 representative W-Beijing isolates suggests a sequential acquisition of the mutations, elucidating a plausible pathway of the molecular evolution of this clonal family. The acquisition of mut genes may explain in part the ability of the isolates of W-Beijing type to rapidly adapt to their environment.

Rad, Mina Ebrahimi; Bifani, Pablo; Martin, Carlos; Kremer, Kristin; Samper, Sofia; Rauzier, Jean; Kreiswirth, Barry; Blazquez, Jesus; Jouan, Marc; van Soolingen, Dick

2003-01-01

74

Pancreatic adenocarcinomas frequently show p53 gene mutations.  

PubMed Central

Thirty-four pancreatic adenocarcinomas were studied for the presence of p53 gene mutations by the single-strand conformation polymorphism method and by direct sequencing of PCR-amplified fragments. p53 protein expression was immunohistochemically evaluated using monoclonal PAb1801 and polyclonal CM1 antibodies. Mutations were detected in 14 cases. The transitions were six G to A and two A to G; the transversions were one C to G and two A to C; the remaining three were frameshift mutations. Immunostaining results were identical with both antibodies. Nuclear immunohistochemical p53-positive cells were found in nine p53 mutated cases and in 12 cases in which no mutation was detected. In most of these latter cases only a minority of cancer cells showed immunohistochemical positivity. Twenty-nine cases, including all p53 mutated cancers, were known to contain codon 12 Ki-ras gene mutations. Also in the light of the demonstrated cooperation of ras and p53 gene alterations in the transformation of cultured cells, our data suggest that p53 mutation is one of the genetic defects that may have a role in the pathogenesis of a proportion of pancreatic cancers. Images Figure 1 Figure 2 Figure 3 Figure 4

Scarpa, A.; Capelli, P.; Mukai, K.; Zamboni, G.; Oda, T.; Iacono, C.; Hirohashi, S.

1993-01-01

75

Preservation of duplicate genes by complementary, degenerative mutations.  

PubMed Central

The origin of organismal complexity is generally thought to be tightly coupled to the evolution of new gene functions arising subsequent to gene duplication. Under the classical model for the evolution of duplicate genes, one member of the duplicated pair usually degenerates within a few million years by accumulating deleterious mutations, while the other duplicate retains the original function. This model further predicts that on rare occasions, one duplicate may acquire a new adaptive function, resulting in the preservation of both members of the pair, one with the new function and the other retaining the old. However, empirical data suggest that a much greater proportion of gene duplicates is preserved than predicted by the classical model. Here we present a new conceptual framework for understanding the evolution of duplicate genes that may help explain this conundrum. Focusing on the regulatory complexity of eukaryotic genes, we show how complementary degenerative mutations in different regulatory elements of duplicated genes can facilitate the preservation of both duplicates, thereby increasing long-term opportunities for the evolution of new gene functions. The duplication-degeneration-complementation (DDC) model predicts that (1) degenerative mutations in regulatory elements can increase rather than reduce the probability of duplicate gene preservation and (2) the usual mechanism of duplicate gene preservation is the partitioning of ancestral functions rather than the evolution of new functions. We present several examples (including analysis of a new engrailed gene in zebrafish) that appear to be consistent with the DDC model, and we suggest several analytical and experimental approaches for determining whether the complementary loss of gene subfunctions or the acquisition of novel functions are likely to be the primary mechanisms for the preservation of gene duplicates. For a newly duplicated paralog, survival depends on the outcome of the race between entropic decay and chance acquisition of an advantageous regulatory mutation.Sidow 1996(p. 717) On one hand, it may fix an advantageous allele giving it a slightly different, and selectable, function from its original copy. This initial fixation provides substantial protection against future fixation of null mutations, allowing additional mutations to accumulate that refine functional differentiation. Alternatively, a duplicate locus can instead first fix a null allele, becoming a pseudogene.Walsh 1995 (p. 426) Duplicated genes persist only if mutations create new and essential protein functions, an event that is predicted to occur rarely.Nadeau and Sankoff 1997 (p. 1259) Thus overall, with complex metazoans, the major mechanism for retention of ancient gene duplicates would appear to have been the acquisition of novel expression sites for developmental genes, with its accompanying opportunity for new gene roles underlying the progressive extension of development itself.Cooke et al. 1997 (p. 362)

Force, A; Lynch, M; Pickett, F B; Amores, A; Yan, Y L; Postlethwait, J

1999-01-01

76

Mendelian and non-mendelian mutations affecting surface antigen expression in Paramecium tetraurelia  

SciTech Connect

A screening procedure was devised for the isolation of X-ray-induced mutations affecting the expression of the A immobilization antigen (i-antigen) in Paramecium tetraurelia. Two of the mutations isolated by this procedure proved to be in modifier genes. The two genes are unlinked to each other and unlinked to the structural A i-antigen gene. These are the first modifier genes identified in a Paramecium sp. that affect surface antigen expression. Another mutation was found to be a deletion of sequences just downstream from the A i-antigen gene. In cells carrying this mutation, the A i-antigen gene lies in close proximity to the end of a macronuclear chromosome. The expression of the A i-antigen is not affected in these cells, demonstrating that downstream sequences are not important for the regulation and expression of the A i-antigen gene. A stable cell line was also recovered which shows non-Mendelian inheritance of a macronuclear deletion of the A i-antigen gene. This mutant does not contain the gene in its macronucleus, but contains a complete copy of the gene in its micronucleus. In the cytoplasm of wild-type animals, the micronuclear gene is included in the developing macronucleus; in the cytoplasm of the mutant, the incorporation of the A i-antigen gene into the macronucleus is inhibited. This is the first evidence that a mechanism is available in ciliates to control the expression of a gene by regulating its incorporation into developing macronuclei.

Epstein, L.M.; Forney, J.D.

1984-08-01

77

Mutational and Phylogenetic Analyses of the Mycobacterial mbt Gene Cluster ?§  

PubMed Central

The mycobactin siderophore system is present in many Mycobacterium species, including M. tuberculosis and other clinically relevant mycobacteria. This siderophore system is believed to be utilized by both pathogenic and nonpathogenic mycobacteria for iron acquisition in both in vivo and ex vivo iron-limiting environments, respectively. Several M. tuberculosis genes located in a so-called mbt gene cluster have been predicted to be required for the biosynthesis of the core scaffold of mycobactin based on sequence analysis. A systematic and controlled mutational analysis probing the hypothesized essential nature of each of these genes for mycobactin production has been lacking. The degree of conservation of mbt gene cluster orthologs remains to be investigated as well. In this study, we sought to conclusively establish whether each of nine mbt genes was required for mycobactin production and to examine the conservation of gene clusters orthologous to the M. tuberculosis mbt gene cluster in other bacteria. We report a systematic mutational analysis of the mbt gene cluster ortholog found in Mycobacterium smegmatis. This mutational analysis demonstrates that eight of the nine mbt genes investigated are essential for mycobactin production. Our genome mining and phylogenetic analyses reveal the presence of orthologous mbt gene clusters in several bacterial species. These gene clusters display significant organizational differences originating from an intricate evolutionary path that might have included horizontal gene transfers. Altogether, the findings reported herein advance our understanding of the genetic requirements for the biosynthesis of an important mycobacterial secondary metabolite with relevance to virulence.

Chavadi, Sivagami Sundaram; Stirrett, Karen L.; Edupuganti, Uthamaphani R.; Vergnolle, Olivia; Sadhanandan, Gigani; Marchiano, Emily; Martin, Che; Qiu, Wei-Gang; Soll, Clifford E.; Quadri, Luis E. N.

2011-01-01

78

Spectrum of ABCR gene mutations in autosomal recessive macular dystrophies  

Microsoft Academic Search

Stargardt disease (STGD) and late-onset fundus flavimaculatus (FFM) are autosomal recessive conditions leading to macular degenerations in childhood and adulthood, respectively. Recently, mutations of the photoreceptor cell-specific ATP binding transporter gene (ABCR) have been reported in Stargardt disease. Here, we report on the screening of the whole coding sequence of the ABCR gene in 40 unrelated STGD and 15 FFM

Jean-Michel Rozet; Sylvie Gerber; Eric Souied; Isabelle Perrault; Sophie Châtelin; Imad Ghazi; Corinne Leowski; Jean-Louis Dufier; Arnold Munnich; Josseline Kaplan; J-M Rozet

1998-01-01

79

Mutations in the AGXT2L2 gene cause phosphohydroxylysinuria.  

PubMed

Phosphohydroxylysinuria has been described in two patients with neurological symptoms, but the deficient enzyme or mutated gene has never been identified. In the present work, we tested the hypothesis that this condition is due to mutations in the AGXT2L2 gene, recently shown to encode phosphohydroxylysine phospholyase. DNA analysis from a third patient, without neurological symptoms, but with an extreme hyperlaxicity of the joints, shows the existence of two mutations, p. Gly240Arg and p.Glu437Val, both in the heterozygous state. Sequencing of cDNA clones derived from fibroblasts mRNA indicated that the two mutations were allelic. Both mutations replace conserved residues. The mutated proteins were produced as recombinant proteins in Escherichia coli and HEK293T cells and shown to be very largely insoluble, whereas the wild-type one was produced as a soluble and active protein. We conclude that phosphohydroxylysinuria is due to mutations in the AGXT2L2 gene and the resulting lack of activity of phosphohydroxylysine phospholyase in vivo. The finding that the nul alleles of p.Gly240Arg and p.Glu437Val are present at low frequencies in the European and/or North American population suggests that this condition is more common than previously thought. The diversity of the clinical symptoms described in three patients with phosphohydroxylysinuria indicates that this is most likely not a neurometabolic disease. PMID:23242558

Veiga-da-Cunha, Maria; Verhoeven-Duif, Nanda M; de Koning, Tom J; Duran, Marinus; Dorland, Bert; Van Schaftingen, Emile

2012-12-14

80

From minisatellites and genes: When do germinal mutations occur  

SciTech Connect

Utilization of molecular techniques has provided insight into the molecular techniques has provided insight into the molecular techniques has provided insight into the molecular character and origins of spontaneous and induced germinal mutations. Review of the variants and disease loci suggests differences among loci in the frequency of nucleotide substitutions and more complex events. Mechanistic features associated with the alterations in DNA structure are observed in each variant class. The spectrum of mutations identified reflects the gene structure and the selective pressure generating disease phenotypes, and the techniques employed to screen for variation. Locus specificity in spectra has the potential to compromise estimates of increases in germinal gene mutation rates. Recent studies have identified mosaicism, rather than de novo mutation, as the explanation for the non-traditional pattern of inheritance of disease in some families. Mosaicism is a concern for studies of induced mutation rates as it reflects embryonic exposure of the parent of the proband. This is in contrast to the {open_quotes}normal expectation{close_quotes} that induced mutations result from parental exposure to genotoxins in the environment. Observations suggest that the germ cell stage sensitivity may reflect interaction of the mutagen and the loci screened. The mosaicism and germ cell stage issues, in conjunction with incomplete ascertainment of mutational events, increase the complexity of efforts to estimate induced germinal mutation rates and associated health consequences in populations exposed to genotoxic agents.

Mohrenweiser, H. [Lawrence Livermore National Lab., CA (United States)

1997-10-01

81

Activation of Developmentally Mutated Human Globin Genes by Cell Fusion  

NASA Astrophysics Data System (ADS)

Human fetal globin genes are not expressed in hybrid cells produced by the fusion of normal human lymphocytes with mouse erythroleukemia cells. In contrast, when lymphocytes from persons with globin gene developmental mutations (hereditary persistence of fetal hemoglobin) are used for these fusions, fetal globin is expressed in the hybrid cells. Thus, mutations of developmental origin can be reconstituted in vitro by fusing mutant lymphoid cells with differentiated cell lines of the proper lineage. This system can readily be used for analyses, such as globin gene methylation, that normally require large numbers of pure nucleated erythroid cells, which are difficult to obtain.

Papayannopoulou, Thalia; Enver, Tariq; Takegawa, Susumu; Anagnou, Nicholas P.; Stamatoyannopoulos, George

1988-11-01

82

Neurocognitive profiles in Duchenne muscular dystrophy and gene mutation site.  

PubMed

The presence of nonprogressive cognitive impairment is recognized as a common feature in a substantial proportion of patients with Duchenne muscular dystrophy. To investigate the possible role of mutations along the dystrophin gene affecting different brain dystrophin isoforms and specific cognitive profiles, 42 school-age children affected with Duchenne muscular dystrophy, subdivided according to sites of mutations along the dystrophin gene, underwent a battery of tests tapping a wide range of intellectual, linguistic, and neuropsychologic functions. Full-scale intelligence quotient was approximately 1 S.D. below the population average in the whole group of dystrophic children. Patients with Duchenne muscular dystrophy and mutations located in the distal portion of the dystrophin gene (involving the 140-kDa brain protein isoform, called Dp140) were generally more severely affected and expressed different patterns of strengths and impairments, compared with patients with Duchenne muscular dystrophy and mutations located in the proximal portion of the dystrophin gene (not involving Dp140). Patients with Duchenne muscular dystrophy and distal mutations demonstrated specific impairments in visuospatial functions and visual memory (which seemed intact in proximally mutated patients) and greater impairment in syntactic processing. PMID:22000308

D'Angelo, Maria Grazia; Lorusso, Maria Luisa; Civati, Federica; Comi, Giacomo Pietro; Magri, Francesca; Del Bo, Roberto; Guglieri, Michela; Molteni, Massimo; Turconi, Anna Carla; Bresolin, Nereo

2011-11-01

83

A novel mutation of the fibrillin gene causing Ectopia lentis  

SciTech Connect

Ectopia lentis (EL), a dominantly inherited connective tissue disorder, has been genetically linked to the fibrillin gene on chromosome 15 (FBN1) in earlier studies. Here, the authors report the first EL mutation in the FBN1 gene confirming that EL is caused by mutations of this gene. So far, several mutations in the FBN1 gene have been reported in patients with Marfan syndrome (MFS). EL and MFS are clinically related but distinct conditions with typical manifestations in the ocular and skeletal systems, the fundamental difference between them being the absence of cardiovascular involvement in EL. They report a point mutation, cosegregating with the disease in the described family, that displays EL over four generations. The mutation changes a conserved glutamic acid residue in an EGF-like motif, which is the major structural component of the fibrillin and is repeated throughout the polypeptide. In vitro mutagenetic studies have demonstrated the necessity of an analogous glutamic acid residue for calcium binding in an EGF-like repeat of human factor IX. This provides a possible explanation for the role of this mutation in the disease pathogenesis. 32 refs., 2 figs., 1 tab.

Loennqvist, L.; Kainulainen, K.; Puhakka, L.; Peltonen, L. (National Public Health Institute, Helsinki (Finland)); Child, A. (St. George's Hospital Medical School, London (United Kingdom)); Peltonen, L. (Duncan Guthrie Institute, Glasgow, Scotland (United Kingdom))

1994-02-01

84

Mutations in TGFBR2 gene cause spontaneous cervical artery dissection.  

PubMed

Mutations in the genes encoding transforming growth factor ? receptors 1 and 2 (TGFBR1 and TGFBR2) have recently been associated with hereditary connective tissue disorders with widespread vascular involvement, including arterial dissection. To determine whether mutations in these genes cause spontaneous cervical artery dissection (sCAD), all coding exons of TGFBR1 and TGFBR2 were sequenced in 56 consecutive patients with sCAD. Novel TGFBR2 disease causing mutations were found in two patients. The two mutations were the pK327R substitution affecting the kinase domain of TGFBR2 and the pC138R substitution falling in the extracellular domain of the protein, involved in TGF? binding and signalling. No TGFBR1 mutation was found. The findings indicate that TGFBR2 gene mutations are responsible for sCAD in 3.6% (95% CI 0.0 to 8.4) of cases, have implications in understanding the role of TGF? signalling in the pathogenesis of sCAD and emphasise the importance of considering molecular characterisation of the TGFBR2 gene in these patients, regardless of the presence of clinical features suggestive of hereditary connective tissue disorders. PMID:21270064

Pezzini, Alessandro; Drera, Bruno; Del Zotto, Elisabetta; Ritelli, Marco; Carletti, Monica; Tomelleri, Gianpaolo; Bovi, Paolo; Giossi, Alessia; Volonghi, Irene; Costa, Paolo; Magoni, Mauro; Padovani, Alessandro; Barlati, Sergio; Colombi, Marina

2011-01-26

85

Nonsense mutations in the dihydrofolate reductase gene affect RNA processing  

SciTech Connect

Steady-state dihydrofolate reductase (dhfr) mRNA levels were decreased as a result of nonsense mutations in the dhfr gene. Thirteen DHFR-deficient mutants were isolated after treatment of Chinese hamster ovary cells with UV irradiation. The positions of most point mutations were localized by RNA heteroduplex mapping, the mutated regions were isolated by cloning or by enzymatic amplification, and base changes were determined by DNA sequencing. Two of the mutants suffered large deletions that spanned the entire dhfr gene. The remaining 11 mutations consisted of nine single-base substitutions, one double-base substitution, and one single-base insertion. All of the single-base substitutions took place at the 3' position of a pyrimidine dinucleotide, supporting the idea that UV mutagenesis proceeds through the formation of pyrimidine dimers in mammalian cells. Of the 11 point mutations, 10 resulted in nonsense codons, either directly or by a frameshift, suggesting that the selection method favored a null phenotype. An examination of steady-state RNA levels in cells carrying these mutations and a comparison with similar data from other dhfr mutants showed that translation termination mutations in any of the internal exons of the gene gave rise to a low-RNA phenotype, whereas missense mutations in these exons or terminations in exon 6 (the final exon) did not affect dhfr mRNA levels. Nuclear run-on experiments showed that transcription of the mutant genes was normal. The stability of mature dhfr mRNA also was not affected, since (i) decay rates were the same in wild-type and mutant cells after inhibition of RNA synthesis with actinomycin D and (ii) intronless minigene versions of cloned wild-type and nonsense mutant genes were expressed equally after stable transfection.

Urlaub, G.; Mitchell, P.J.; Ciudad, C.J.; Chasin, L.A. (Columbia Univ., New York, NY (USA))

1989-07-01

86

Novel PRKAR1A gene mutations in Carney Complex.  

PubMed

Carney complex is a syndrome that may include cardiac and mucocutaneous myxomas, spotting skin pigmentation, and endocrine lesions. Many patients with Carney complex have been shown to have a stop codon mutation in the PRKAR1A gene in the 17q22-24 region. Here we present the case of a 57 year-old man with multiple skin lesions and cardiac myxomas. Histology of the skin lesions showed lentigenous melanocytic hyperplasia and cutaneous myxomas, confirming the diagnosis of Carney complex. Lesional and control normal tissue from the patient were identified and sequenced for the PRKAR1A gene. A germline missense mutation was identified at exon 1A. This is the first report of this mutation, and one of the few reported missense mutation associated with Carney complex. This finding strengthens the argument that there are alternative ways in which the protein kinase A 1-alpha subunit plays a role in tumorigenesis. PMID:20606737

Pan, Lorraine; Peng, Lan; Jean-Gilles, J; Zhang, Ximin; Wieczorek, Rosemary; Jain, Shilpa; Levine, Vicki; Osman, Iman; Prieto, Victor G; Lee, Peng

2010-05-10

87

Novel PRKAR1A gene mutations in Carney Complex  

PubMed Central

Carney complex is a syndrome that may include cardiac and mucocutaneous myxomas, spotting skin pigmentation, and endocrine lesions. Many patients with Carney complex have been shown to have a stop codon mutation in the PRKAR1A gene in the 17q22-24 region. Here we present the case of a 57 year-old man with multiple skin lesions and cardiac myxomas. Histology of the skin lesions showed lentigenous melanocytic hyperplasia and cutaneous myxomas, confirming the diagnosis of Carney complex. Lesional and control normal tissue from the patient were identified and sequenced for the PRKAR1A gene. A germline missense mutation was identified at exon 1A. This is the first report of this mutation, and one of the few reported missense mutation associated with Carney complex. This finding strengthens the argument that there are alternative ways in which the protein kinase A 1-alpha subunit plays a role in tumorigenesis

Pan, Lorraine; Peng, Lan; Jean-Gilles, J; Zhang, Ximin; Wieczorek, Rosemary; Jain, Shilpa; Levine, Vicki; Osman, Iman; Prieto, Victor G; Lee, Peng

2010-01-01

88

[Homozygous germline mutation in MUTYH gene in familial adenomatous polyposis].  

PubMed

Recently, MUTYH mutations have been reported to predispose to the development of polyposis. However, polyposis caused by mutations in MUTYH has been characterized as an autosomal recessive hereditary disease, different from the autosomal dominant pattern observed in polyposis caused by APC mutations. We report a 41-year-old female consulting for anemia. Colonoscopy detected multiple sessile polyps and a cecal carcinoma. The patient was operated and in the surgical piece, the tumor invaded serosa and there was lymph node involvement. Approximately 100 polyps were found. The patient received 5-fluorouracil, as adjuvant therapy. The patient had a sister (of a total of 12 brothers) with a colorectal carcinoma. The genetic study identified a homozygous mutation of the MUTYH gene, called c.340T > C, that produces an amino acid change of tyrosine for histidine called p.Y114H. The sister with colorectal cancer was a heterozygous carrier of this mutation. PMID:23677194

Alvarez, Karin; de la Fuente, Marjorie; Orellana, Paulina; Wielandt, Ana María; Heine, Claudio; Suazo, Cristóbal; Kronberg, Udo; Carvallo, Pilar; López-Köstner, Francisco

2012-11-01

89

Common MEFV gene mutations in Turkish patients with Behcet's disease.  

PubMed

Behcet's disease (BD) is a chronic systemic inflammatory disorder whose etiology has not been fully established yet. The MEditerranean FeVer (MEFV) gene has been identified as the cause of Familial Mediterranean Fever (FMF). BD shows similarities with FMF, in terms of clinical findings and treatments, as well as their geographical and ethnic co-occurrence. In this study we investigated common MEFV gene mutation frequencies in Turkish patients with BD in an area of Turkey where both diseases are frequently encountered. We screened 207 BD patients who had no symptoms and family history for FMF and 200 healthy subjects for five common MEFV gene mutations (E148Q, M680I, M694V, V726A, P369S) and clinical features. Seventy-five patients were found to carry a single MEFV mutation, and six patients were compound heterozygous. The difference in the frequency of the MEFV mutation between the BD and control groups was statistically significant (p<0.001, odds ratio [OR] 2.74, 95% confidence interval [CI] 1.75-4.29). The frequencies of E148Q and M680I mutations were significantly higher in the BD group (p=0.001, p=0.046, respectively). The frequency of uveitis was significantly lower in patients with the mutation than in patients without the mutation (p=0.029, OR 0.54, 95% CI 0.30-0.98). There was no statistical significance between carriers and non-carriers with respect to gender and other manifestations of BD. The frequency of the MEFV mutation was significantly higher in patients with BD compared to the healthy control group. Based on our results, MEFV mutations appear to have a role in the pathogenesis of BD. PMID:23973724

Tasliyurt, Turker; Yigit, Serbulent; Rustemoglu, Aydin; Gul, Ulker; Ates, Omer

2013-08-22

90

Gene expression profile study in CFTR mutated bronchial cell lines  

Microsoft Academic Search

Cystic fibrosis (CF) is caused by mutations in the gene encoding the cystic fibrosis conductance transmembrane regulator (CFTR).\\u000a Symptoms are pancreatic insufficiency, chronic obstructive lung disease, liver disease, chronic sinusitis and infertility\\u000a in male patients. The phenotypic variability may be explained only in part by the more than 1200 CFTR mutations, which are\\u000a grouped into six different classes, according to

M. R. D'Apice; F. Amati; F. Sangiuolo; A. Farcomeni; G. Chillemi; S. Bueno; A. Desideri; G. Novelli

2006-01-01

91

Mutation Analysis of the HFE Gene in Brazilian Populations  

Microsoft Academic Search

ABSTRACT: We analyzed the frequency of the C282Y and H63D mutations in the HFE gene in 227 individuals from Brazil comprising 71 Caucasians, 91 racially mixed Caucasian African-derived Amerindians (both populations from Southeast Brazil), 85 African-derived subjects (from Northeast Brazil) and 75 Parakană Indians. Allelic frequency of the mutation C. 845G(A (C282Y) was 1.4% in the Caucasian population, 1.1% in

Marcela F Agostinho; Valder R Arruda; Daniela S Basseres; Silvana Bordin; Manoel C. P Soares; Raimundo C Menezes; Fernando F Costa; Sara T. O Saad

1999-01-01

92

Mutation Analysis of the HFE Gene in Brazilian Populations  

Microsoft Academic Search

We analyzed the frequency of the C282Y and H63D mutations in the HFE gene in 227 individuals from Brazil comprising 71 Caucasians, 91 racially mixed Caucasian African-derived Amerindians (both populations from Southeast Brazil), 85 African-deriv ed subjects (from Northeast Brazil) and 75 Parakană Indians. Allelic frequency of the mutation C. 845G6A (C282Y) was 1.4% in the Caucasian population, 1.1% in

Marcela F. Agostinho; Valder R. Arruda; Daniela S. Basseres; Silvana Bordin; Manoel C. P. Soares; Raimundo C. Menezes

1999-01-01

93

A complete mutation screen of the ADPKD genes by DHPLC  

Microsoft Academic Search

A complete mutation screen of the ADPKD genes by DHPLC.BackgroundGenetic analysis is a useful diagnostic tool in autosomal dominant polycystic kidney disease (ADPKD), especially when imaging results are equivocal. However, molecular diagnostics by direct mutation screening has proved difficult in this disorder due to genetic and allelic heterogeneity and complexity of the major locus, PKD1.MethodsA protocol was developed to specifically

Sandro Rossetti; Dominique Chauveau; Denise Walker; Anand Saggar-Malik; Christopher G. Winearls; Vicente E. Torres; Peter C. Harris

2002-01-01

94

Mutations of the HFE Gene and the Risk of Hepatocellular  

Microsoft Academic Search

The discovery of the C282Y and H63D point mutations in the hereditary hemochromatosis-associated HFE gene allows us to study the molecular basis of congenital and acquired iron overload disorders. In hereditary hemochromatosis an increased frequency of the C282Y and, to a lesser extent, of the H63D mutations has been established, but their role in other conditions associated with iron overload

Omar Racchi; Rosa Mangerini; Davide Rapezzi; Gian Franco Gaetani; Maria Teresa Nobile; Antonino Picciotto; Anna Maria Ferraris

95

Mutations of the HFE Gene in Patients With Hepatocellular Carcinoma  

Microsoft Academic Search

OBJECTIVE:Hepatocellular carcinoma (HCC) is a late consequence of severe liver disease. Patients with genetic hemochromatosis may be at risk for HCC, but limited information is available on the relationship of HCC and heterozygosity for the HFE gene mutations.METHODS:HFE mutations (C282Y and H63D) were assessed in 162 consecutive patients (131 men\\/31 women) with HCC. A total of 159 patients had cirrhosis.

Edmund Cauza; Markus Peck-Radosavljevic; Herbert Ulrich-Pur; Christian Datz; Michael Gschwantler; Maximilian Schöniger-Hekele; Franz Hackl; Claudia Polli; Susanne Rasoul-Rockenschaub; Christian Müller; Friedrich Wrba; Alfred Gangl; Peter Ferenci

2003-01-01

96

Mitochondrial DNA depletion and dGK gene mutations.  

PubMed

Mitochondrial DNA depletion syndrome is a clinically heterogeneous group of disorders characterized by a reduction in mitochondrial DNA copy number. The recent discovery of mutations in the deoxyguanosine kinase (dGK) gene in patients with the hepatocerebral form of mitochondrial DNA depletion syndrome prompted us to screen 21 patients to determine the frequency of dGK mutations, further characterize the clinical spectrum, and correlate genotypes with phenotypes. We detected mutations in three patients (14%). One patient had a homozygous GATT duplication (nucleotides 763-766), and another had a homozygous GT deletion (nucleotides 609-610); both mutations lead to truncated proteins. The third patient was a compound heterozygote for two missense mutations (R142K and E227K) that affect critical residues of the protein. These mutations were associated with variable phenotypes, and their low frequencies suggests that dGK is not the only gene responsible for mitochondrial DNA depletion in liver. The patient with the missense mutations had isolated liver failure and responded well to liver transplantation, which may be a therapeutic option in selected cases. PMID:12205643

Salviati, Leonardo; Sacconi, Sabrina; Mancuso, Michelangelo; Otaegui, David; Camańo, Pilar; Marina, Alberto; Rabinowitz, Simon; Shiffman, Rebecca; Thompson, Karen; Wilson, Claire M; Feigenbaum, Annette; Naini, Ali B; Hirano, Michio; Bonilla, Eduardo; DiMauro, Salvatore; Vu, Tuan H

2002-09-01

97

Gene mutations and molecularly targeted therapies in acute myeloid leukemia  

PubMed Central

Acute myelogenous leukemia (AML) can progress quickly and without treatment can become fatal in a short period of time. However, over the last 30 years fine-tuning of therapeutics have increased the rates of remission and cure. Cytogenetics and mutational gene profiling, combined with the option of allogeneic hematopoietic stem cell transplantation offered in selected patients have further optimized AML treatment on a risk stratification basis in younger adults. However there is still an unmet medical need for effective therapies in AML since disease relapses in almost half of adult patients becoming refractory to salvage therapy. Improvements in the understanding of molecular biology of cancer and identification of recurrent mutations in AML provide opportunities to develop targeted therapies and improve the clinical outcome. In the spectrum of identified gene mutations, primarily targetable lesions are gain of function mutations of tyrosine kinases FLT3, JAK2 and cKIT for which specific, dual and multi-targeted small molecule inhibitors have been developed. A number of targeted compounds such as sorafenib, quizartinib, lestaurtinib, midostaurin, pacritinib, PLX3397 and CCT137690 are in clinical development. For loss-of-function gene mutations, which are mostly biomarkers of favorable prognosis, combined therapeutic approaches can maximize the therapeutic efficacy of conventional therapy. Apart from mutated gene products, proteins aberrantly overexpressed in AML appear to be clinically significant therapeutic targets. Such a molecule for which targeted inhibitors are currently in clinical development is PLK1. We review characteristic gene mutations, discuss their biological functions and clinical significance and present small molecule compounds in clinical development, which are expected to have a role in treating AML subtypes with characteristic molecular alterations.

Hatzimichael, Eleftheria; Georgiou, Georgios; Benetatos, Leonidas; Briasoulis, Evangelos

2013-01-01

98

Simultaneous mutation scanning for gross deletions, duplications and point mutations in the DMD gene.  

PubMed

We have developed a technique to screen for gross deletions/duplications and point mutations using one streamlined approach. Fluorescent multiplex quantitative PCR is used to determine the copy number of each exon, followed by conformation sensitive capillary electrophoresis (CSCE) of the same PCR products on a multi-capillary genetic analyser. We have developed this technique to screen all 79 exons of one of the largest human genes currently known (dystrophin) using 12 multiplex PCR assays. A blind trial of 50 male and 50 female samples, in which 84 mutations had previously been found and characterized by other techniques, showed 100% sensitivity and specificity. We then applied this method to screen over 100 patient samples previously screened for deletions and duplications of 28 exons from the two hotspot regions. Our data show that combining a full deletion/duplication screen with CSCE will detect a mutation in 98% of Duchenne muscular dystrophy patients and 93% of Becker muscular dystrophy patients where the clinical diagnosis is certain. This technique is applicable to any gene and is particularly suited to mutation screening of large genes, decreasing the time taken for a complete gene screen for nearly all mutation types. PMID:17726484

Ashton, Emma J; Yau, Shu C; Deans, Zandra C; Abbs, Stephen J

2007-08-29

99

Prevalence of haemochromatosis gene mutations in Parkinson's disease  

PubMed Central

The aim of this study was to investigate a possible association between haemochromatosis (HFE) gene mutations and the prevalence of Parkinson's disease. The HFE gene encodes a protein that modulates iron absorption. Several studies have documented increased iron levels in the basal ganglia in patients with Parkinson's disease. In a study on patients with concurrent hereditary haemochromatosis and Parkinson's disease, abnormal deposition of iron in the basal ganglia was suggested as an inductor of Parkinson's disease. In this study, genotype frequencies of the HFE mutations C282Y, H63D and S65C were estimated in 388 patients with Parkinson's disease and compared with frequencies found in comparable studies. No significant differences were found in frequencies between the patients and comparable populations. This study does not indicate increased susceptibility to Parkinson's disease in HFE gene mutation carriers in Norway.

Aamodt, Anne Hege; Stovner, Lars Jacob; Thorstensen, Ketil; Lydersen, Stian; White, Linda R; Aasly, Jan O

2007-01-01

100

Screening for mutations of the apolipoprotein B gene causing hypocholesterolemia  

Microsoft Academic Search

In this study we have performed analyses of apolipoprotein (apo) B at both the protein and gene level to search for mutations\\u000a of the apoB gene causing hypocholesterolemia among 71 Norwegian subjects. None of the subjects possessed apoB of abnormal\\u000a molecular weight as determined by SDS-polyacrylamide gel electrophoresis of lipoproteins in the 1.025 g\\/ml–1.063 g\\/ml density\\u000a range. Screening for mutations

T. P. Leren; Kari S. Bakken; Vigdis Hoel; Ingvar Hjermann; Kĺre Berg

1998-01-01

101

Gene conversion: point-mutation heterozygosities lower heteroduplex formation.  

PubMed Central

The effects of heterozygosity on meiotic gene conversion characteristics have been studied in the fungus Ascobolus immersus. The non-Mendelian segregation patterns of seven white ascospore mutants of the b2 gene were established in the presence or the absence of additional neighbouring allelic mutations. These correspond to nine different double mutants with wild-type or pseudo-wild-type phenotypes, constituted by two +1, -1 frameshift mutations of complementary phases. When heterozygous, these double point mutations decrease, by an average of one third, the gene conversion frequencies of the mutants located on their right, toward the low conversion end of the gene. The decrease corresponds either to a reduction in all classes of non-Mendelian segregation (6:2, 5:3 and aberrant 4:4 asci) or to a reduction restricted to the single class of aberrant 4:4 asci. These modifications are explained by changes in hybrid DNA parameter values: frequencies of formation and modalities of distribution (asymmetric versus symmetric ratio). Besides the nature of the non-homology, point mutation versus deletion, which leads to quantitative differential effects, the region where the non-homology is located within the gene also appears to play an important role.

Nicolas, A; Rossignol, J L

1983-01-01

102

An inherited LMNA gene mutation in atypical Progeria syndrome.  

PubMed

Hutchinson-Gilford Progeria syndrome (HGPS) is a rare genetic disorder, characterized by several clinical features that begin in early childhood, recalling an accelerated aging process. The diagnosis of HGPS is based on the recognition of common clinical features and detection of the recurrent heterozygous c.1824C>T (p.Gly608Gly) mutation within exon 11 in the Lamin A/C encoding gene (LMNA). Besides "typical HGPS," several "atypical progeria" syndromes (APS) have been described, in a clinical spectrum ranging from mandibuloacral dysplasia to atypical Werner syndrome. These patients's clinical features include progeroid manifestations, such as short stature, prominent nose, premature graying of hair, partial alopecia, skin atrophy, lipodystrophy, skeletal anomalies, such as mandibular hypoplasia and acroosteolyses, and in some cases severe atherosclerosis with metabolic complications. APS are due in several cases to de novo heterozygous LMNA mutations other than the p.Gly608Gly, or due to homozygous BAFN1 mutations in Nestor-Guillermo Progeria syndrome (NGPS). We report here and discuss the observation of a non-consanguineous Moroccan patient presenting with atypical progeria. The molecular studies showed the heterozygous mutation c.412G>A (p.Glu138Lys) of the LMNA gene. This mutation, previously reported as a de novo mutation, was inherited from the apparently healthy father who showed a somatic cell mosaicism. PMID:22991222

Doubaj, Yassamine; De Sandre-Giovannoli, Annachiara; Vera, Esteves-Vieira; Navarro, Claire Laure; Elalaoui, Siham Chafai; Tajir, Mariam; Lévy, Nicolas; Sefiani, Abdelaziz

2012-09-18

103

MADM methods in solving group decision support system on gene mutations detection simulation  

Microsoft Academic Search

Detection of gene mutation is an activity that can provide contribution in the medical field. Detection of mutated gene is needed to avoid the diseases caused by them such as cancer. The detection of gene mutations can be performed by utilizing computer-based system. Group Decision Support System (GDSS) is a computer-based system that can be utilized in detecting human gene

Ermatita; Sri Hartati; Retantyo Wardoyo; Agus Harjoko

2010-01-01

104

PTPN11 gene mutations: linking the Gln510Glu mutation to the “LEOPARD syndrome phenotype”  

Microsoft Academic Search

We describe the “LEOPARD syndrome (LS) phenotype” associated with the Gln510Glu mutation of the PTPN11 gene in two patients presenting with rapidly progressive severe biventricular obstructive hypertrophic cardiomyopathy and structural abnormalities of the mitral valve, facial anomalies, café-au-lait spots and multiple lentigines.

M. Cristina Digilio; Anna Sarkozy; Giuseppe Pacileo; Giuseppe Limongelli; Bruno Marino; Bruno Dallapiccola

2006-01-01

105

Analysis of mismatch repair gene mutations in Turkish HNPCC patients  

Microsoft Academic Search

Hereditary non-polyposis colorectal cancer (HNPCC or Lynch syndrome) is caused by the inheritance of a mutant allele of a\\u000a DNA mismatch repair gene. We aimed to investigate types and frequencies of mismatch repair (MMR) gene mutations in Turkish\\u000a patients with HNPCC and to identify specific biomarkers for early diagnosis of their non-symptomatic kindred’s. The molecular\\u000a characteristics of 28 Turkish colorectal

Berrin Tunca; Monica Pedroni; Gulsah Cecener; Unal Egeli; Enrica Borsi; Abdullah Zorluoglu; Carmela Di Gregorio; Tuncay Yilmazlar; Omer Yerci; Maurizio Ponz de Leon

2010-01-01

106

Mutational analysis of X-linked adrenoleukodystrophy gene  

Microsoft Academic Search

X-linked adrenoleukodystrophy (ALD) is an inherited peroxisomal disorder characterized by progressive neurological dysfunction,\\u000a occasionally associated with adrenal insufficiency. The clinical thenotypes of ALD are quite variable, and include childhood\\u000a ALD, adult-onset ALD, adrenomyeloneuropathy, and Addison's disease only. Although the causative gene for ALD has been identified,\\u000a the physiological role of the gene product remains to be clarified. Despite many mutations

Hiroki Takano; Ryoko Koike; Osamu Onodera; Shoji Tsuji

2000-01-01

107

Absence of beta-tubulin gene mutation in gastric carcinoma  

Microsoft Academic Search

Background. Effective chemotherapy for advanced gastric cancer is yet to be established. Taxanes, novel anticancer drugs which bind to beta-tubulin and prevent disruption of microtubules, are newly approved and promising agents for advanced and recurrent gastric cancer. To predict the chemoresistance to a taxan in gastric cancer, we examined the genetic mutations of the beta-tubulin gene. Methods. Fifty pairs of

Naomi Urano; Yoshiyuki Fujiwara; Seiichi Hasegawa; Yasuo Miyoshi; Shinzaburo Noguchi; Shuji Takiguchi; Takushi Yasuda; Masahiko Yano; Morito Monden

2003-01-01

108

Discovery of induced point mutations in maize genes by TILLING  

Microsoft Academic Search

BACKGROUND: Going from a gene sequence to its function in the context of a whole organism requires a strategy for targeting mutations, referred to as reverse genetics. Reverse genetics is highly desirable in the modern genomics era; however, the most powerful methods are generally restricted to a few model organisms. Previously, we introduced a reverse-genetic strategy with the potential for

Bradley J Till; Steven H Reynolds; Clifford Weil; Nathan Springer; Chris Burtner; Kim Young; Elisabeth Bowers; Christine A Codomo; Linda C Enns; Anthony R Odden; Elizabeth A Greene; Luca Comai; Steven Henikoff

2004-01-01

109

Telomere stability genes are not mutated in osteosarcoma cell lines  

Microsoft Academic Search

Osteosarcoma (OS), the most common primary bone tumor in adolescents and young adults, is characterized by a high degree of chromosomal abnormalities. Because telomeres are important for maintaining chromosomal integrity, it is plausible that germ-line or somatic mutations in the genes responsible for stabilizing the telomere complex could contribute to OS. We performed bi-directional sequence analysis in five OS cell

Sharon A. Savage; Brian J. Stewart; Jason S. Liao; Lee J. Helman; Stephen J. Chanock

2005-01-01

110

Phenotypic spectrum associated with mutations of the mitochondrial polymerase   gene  

Microsoft Academic Search

Mutations in the gene coding for the catalytic subunit of the mitochondrial DNA (mtDNA) polymerase g (POLG1) have recently been described in patients with diverse clinical presentations, revealing a complex relationship between genotype and phenotype in patients and their families. POLG1 was sequenced in patients from different European diagnostic and research centres to define the phenotypic spectrum and advance understanding

Rita Horvath; Gavin Hudson; Gianfrancesco Ferrari; Nancy Futterer; Sofia Ahola; Eleonora Lamantea; Holger Prokisch; Hanns Lochmuller; Robert McFarland; V. Ramesh; Thomas Klopstock; Peter Freisinger; Fabrizio Salvi; Johannes A. Mayr; Rene Santer; Marketa Tesarova; Jiri Zeman; Bjarne Udd; Robert W. Taylor; Douglass Turnbull; Michael Hanna; Doreen Fialho; Anu Suomalainen; Massimo Zeviani; Patrick F. Chinnery

2006-01-01

111

Adapting mutations in genetic algorithms using gene flow principles  

Microsoft Academic Search

Bit mutation in genetic algorithms is usually done with a single fixed probability. Methods to adapt this probability have been suggested, but they operate at the genome level. This paper describes a gene level adaption scheme, based on allele frequencies, which gives a better escape from local optima.

Garrison W. Greenwood

2003-01-01

112

Frequency of the HFE Gene Mutations in Five Italian Populations  

Microsoft Academic Search

ABSTRACTGenetic hemochromatosis is an autosomal recessive disorder characterized by iron overload and a variety of clinical manifestations such as liver cirrhosis and arthropathy. It is the most common genetic disease of northern European populations. The principal gene responsible for hereditary hemochromatosis, designated HFE, is located on chromosome 6 in the HLA region. The single point mutation 845A, changing cysteine at

Giuseppina Candore; Vilma Mantovani; Carmela Rita Balistreri; Domenico Lio; Giuseppina Colonna-Romano; Vincenzo Cerreta; Ciriaco Carru; Luca Deiana; Giovanni Pes; Giuseppe Menardi; Laura Perotti; Valeria Miotti; Elena Bevilacqua; Antonio Amoroso; Calogero Caruso

2002-01-01

113

Inactivating mutations of caspase-8 gene in colorectal carcinomas  

Microsoft Academic Search

Background & Aims: There has been evidence that dysregulation of apoptosis is involved in the pathogenesis of cancer development. Caspase-8 is an initiation caspase that activates the caspase cascade during apoptosis. The aim of this study was to explore the possibility that mutation of the caspase-8 gene might be involved in the development of colorectal cancer. Methods: We analyzed the

Hong Sug Kim; Jong Woo Lee; Young Hwa Soung; Won Sang Park; Su Young Kim; Jong Heun Lee; Jik Young Park; Youg Gu Cho; Chang Jae Kim; Seong Whan Jeong; Suk Woo Nam; Sang Ho Kim; Jung Young Lee; Nam Jin Yoo; Sug Hyung Lee

2003-01-01

114

Inactivating mutations of CASPASE7 gene in human cancers  

Microsoft Academic Search

Caspase-7 is a caspase involved in the execution phase of apoptosis. To explore the possibility that the genetic alterations of CASPASE-7 might be involved in the development of human cancers, we analysed the entire coding region and all splice sites of human CASPASE-7 gene for the detection of somatic mutations in a series of human solid cancers, including carcinomas from

Young Hwa Soung; Jong Woo Lee; Hong Sug Kim; Won Sang Park; Su Young Kim; Jong Heun Lee; Jik Young Park; Yong Gu Cho; Chang Jae Kim; Yong Gyu Park; Suk Woo Nam; Seong Whan Jeong; Sang Ho Kim; Jung Young Lee; Nam Jin Yoo; Sug Hyung Lee

2003-01-01

115

Mutations in RNA Binding Protein Gene Cause Familial Dilated Cardiomyopathy  

PubMed Central

Objectives We sought to identify a novel gene for dilated cardiomyopathy (DCM). Background DCM is a heritable, genetically heterogeneous disorder that remains idiopathic in a majority of patients. Familial cases provide an opportunity to discover unsuspected molecular bases of DCM, enabling preclinical risk detection. Methods Two large families with autosomal dominant DCM were studied. Genome-wide linkage analysis was used to identify a disease locus, followed by fine mapping and positional candidate gene sequencing. Mutation scanning was then performed in 278 unrelated subjects with idiopathic DCM, prospectively identified at the Mayo Clinic. Results Overlapping loci for DCM were independently mapped to chromosome 10q25-q26. DNA sequencing of affected individuals in each family revealed distinct heterozygous missense mutations in exon 9 of RBM20, encoding RNA binding motif protein 20. Comprehensive coding sequence analyses identified missense mutations clustered within this same exon in six additional DCM families. Mutations segregated with DCM (composite logarithm of the odds score >11.49), were absent in 480 control samples, and altered residues within a highly conserved arginine/serine (RS)-rich region. Expression of RBM20 messenger RNA was confirmed in human heart tissue. Conclusions Our findings establish RBM20 as a DCM gene and reveal a mutation hotspot in the RS domain. RBM20 is preferentially expressed in the heart and encodes motifs prototypical of spliceosome proteins that regulate alternative pre-mRNA splicing, thus implicating a functionally distinct gene in human cardiomyopathy. RBM20 mutations are associated with young age at diagnosis, end-stage heart failure, and high mortality.

Brauch, Katharine M.; Karst, Margaret L.; Herron, Kathleen J.; de Andrade, Mariza; Pellikka, Patricia A.; Rodeheffer, Richard J.; Michels, Virginia V.; Olson, Timothy M.

2009-01-01

116

Molecular basis of iduronate-2-sulphatase gene mutations in patients with mucopolysaccharidosis type II (Hunter syndrome)  

Microsoft Academic Search

Mucopolysaccharidosis type II (Hunter syndrome) is an X linked lysosomal storage disorder resulting from heterogeneous mutations in the iduronate-2-sulphatase (IDS) gene. To detect IDS gene mutations, direct sequencing of IDS cDNA fragments coupled with assays on IDS genomic amplicons was applied to 18 unrelated patients with MPS II. Seventeen mutations were detected from the 18 patients including seven missense mutations

Peining Li; Amy B Bellows; Jerry N Thompson

1999-01-01

117

Mutation analysis of BRCA1 and BRCA2 genes in Iranian high risk breast cancer families  

Microsoft Academic Search

Purpose: Germline mutations in either BRCA1 or BRCA2 genes are responsible for the majority of hereditary breast and ovarian cancers. At present, over thousand distinct BRCA1 and BRCA2 mutations have been identified. Specific mutations are found to be common within particular populations, resulting from genetic founder effects. To investigate the contribution of germline mutations in these two genes to inherited

Andrea Pietschmann; Parvin Mehdipour; Morteza Atri; Wera Hofmann; S. Said Hosseini-Asl; Siegfried Scherneck; Stefan Mundlos; Hartmut Peters

2005-01-01

118

Mutation analysis of the Ras pathway genes NRAS , HRAS , KRAS and BRAF in glioblastomas  

Microsoft Academic Search

Aberrant activation of Ras signaling is a common finding in human glioblastomas. To determine the contribution of Ras gene mutations to this aberration, we screened 94 glioblastomas for mutations in the three Ras family genes NRAS, KRAS and HRAS. All tumors were additionally analyzed for mutations in BRAF, which encodes a Ras-regulated serine\\/threonine kinase with oncogenic properties. Mutation analysis of

Christiane B. Knobbe; Julia Reifenberger; Guido Reifenberger

2004-01-01

119

Multidrug resistance decreases with mutations of melanosomal regulatory genes.  

PubMed

Whereas resistance to chemotherapy has long impeded effective treatment of metastatic melanoma, the mechanistic basis of this resistance remains unknown. One possible mechanism of drug resistance is alteration of intracellular drug distribution either by drug efflux or sequestration into intracellular organelles. Melanomas, as well as primary melanocytes from which they arise, have intracellular organelles, called melanosomes, wherein the synthesis and storage of the pigment melanin takes place. In this study, comparisons of congenic cells with and without functional molecules regulating melanosome formation show that sensitivity to the chemotherapeutic agent cis-diaminedichloroplatinum II (cis-platin) significantly increases with the mutation of genes regulating melanosome formation, concomitant disruption of melanosome morphology, and loss of mature melanosomes. Absence of the melanosomal structural protein gp100/Pmel17 causes increased cis-platin sensitivity. Independent mutations in three separate genes that regulate melanosome biogenesis (Dtnbp1, Pldn, Vps33a) also result in increased cis-platin sensitivity. In addition, a mutation of the gene encoding the integral melanosomal protein tyrosinase, resulting in aberrant melanosome formation, also causes increased cis-platin sensitivity. Furthermore, sensitivity to agents in other chemotherapeutic classes (e.g., vinblastine and etoposide) also increased with the mutation of Pldn. In contrast, a mutation in another melanosomal regulatory gene, Hps1, minimally affects melanosome biogenesis, preserves the formation of mature melanosomes, and has no effect on cis-platin or vinblastine response. Together, these data provide the first direct evidence that melanosomal regulatory genes influence drug sensitivity and that the presence of mature melanosomes likely contributes to melanoma resistance to therapy. PMID:19155314

Xie, Tong; Nguyen, Thuyen; Hupe, Melanie; Wei, Maria L

2009-01-20

120

Analysis of helicase gene mutations in Japanese Werner’s syndrome patients  

Microsoft Academic Search

The profile of helicase gene mutations was studied in 89 Japanese Werner’s syndrome (WRN) patients by examining the previously\\u000a described mutations 1– 4 as well as a new mutation found during this study, designated mutation 5. Of 178 chromosomes (89\\u000a patients), 89 chromosomes (50%) had mutation 4, 11 (6.2%) chromosomes had mutation 1, and two chromosomes (1.1%) contained\\u000a mutation 5.

Makaoto Goto; Osamu Imamura; Junro Kuromitsu; Takehisa Matsumoto; Yukako Yamabe; Yoshiki Tokutake; Noriyuki Suzuki; Brian Mason; Dennis Drayna; Minoru Sugawara; Masanobu Sugimoto; Yasuhiro Furuichi

1997-01-01

121

Mutations of the tyrosinase gene produce autosomal recessive ocular albinism  

SciTech Connect

Albinism has historically been divided into ocular (OA) and oculocutaneous (OCA) types based on the presence or absence of clinically apparent skin and hair involvement in an individual with the ocular features of albinism. The major genes for OCA include the tyrosinase gene in OCA1 and the P gene in OCA2. X-linked and autosomal recessive OA have been described and the responsible genes have not been identified. We now present six Caucasian individuals who have the phenotype of autosomal recessive OA but who have OCA1 as shown by the presence of mutations of the tyrosinase. They had white or very light hair and white skin at birth, and cutaneous pigment developed in the first decade of life. At ages ranging from 1.5-23 years, hair color was dark blond to light brown. The skin had generalized pigment and well developed tan was present on the exposed arm and face skin of four. Iris pigment was present and iris translucency varied. Molecular analysis of the tyrosinase gene, using PCR amplification and direct di-deoxy sequencing showed the following mutations: E398Z/E398Q, P406S/g346a, R402E/T373K, ?/D383N, and H211N/T373K. The homozygous individual was not from a known consanguineous mating. T373K is the most common tyrosinase gene mutation in our laboratory. Three of these mutations are associated with a total loss of tyrosinase activity (g346a splice-site, T373K, and D383N), while four are associated with residual enzyme activity (H211N, R402E, E398Q, and P406S). These studies show that mutations of the tyrosinase gene can produce the phenotype of autosomal recessive OA in an individual who has normal amounts of cutaneous pigment and the ability to tan after birth. This extends the phenotypic range of OCA1 to normal cutaneous pigment after early childhood, and suggest that mutations of the tyrosinase gene account for a significant number of individuals with autosomal recessive OA.

King, R.A.; Summers, C.G.; Oetting, W.S. [Univ. of Minnesota, Minneapolis, MN (United States)] [and others

1994-09-01

122

FLCN gene-mutated renal cell neoplasms: mother and daughter cases with a novel germline mutation.  

PubMed

Birt-Hogg-Dubé syndrome is a familial genodermatosis, of which patients frequently develop renal neoplasms, fibrofolliculomas and pneumatocele. Here, we report a mother and daughter with renal neoplasms surgically resected (69 and 46 years-of-age at surgery, respectively). The mother's tumor was diagnosed as an unclassified type renal cell carcinoma associated with microscopic tumorous nodules, whereas the daughter's tumor was a hybrid oncocytic/chromophobe tumor. The germline mutation analysis of the responsible gene, FCLN (the folliculin gene), showed a deletion of 18 bp in exon 5 (c.332_349del/p.H111_Q116del), predicting an alteration of the amino acid sequence of "HPSHPQ" replaced by a single amino acid, "L". This is a novel germline mutation of the FCLN gene that has not been previously reported. PMID:22211584

Nagashima, Yoji; Furuya, Mitsuko; Gotohda, Hiroko; Takagi, Seiji; Hes, Ondrej; Michal, Michal; Grossmann, Petr; Tanaka, Reiko; Nakatani, Yukio; Kuroda, Naoto

2011-12-29

123

Mutational analysis of the human MAOA gene  

Microsoft Academic Search

The monoamine oxidases (MAO-A and MAO-B) are the enzymes primarily responsible for the degradation of amine neurotransmitters, such as dopamine, norepinephrine, and serotonin. Wide variations in activity of these isozymes have been reported in control humans. The MAOA and MAOB genes are located next to each other in the p11.3-11.4 region of the human X chromosome. Our recent documentation of

E. A. Tivol; C. Shalish; D. E. Schuback; X. O. Breakefield; Yun-Pung Hsu

1996-01-01

124

Mutational analysis of adrenoleukodystrophy (ALD) gene in Japanese ALD patients  

SciTech Connect

Recently a putative ALD gene containing a striking homology with peroxisomal membrane protein (PMP70) has been identified. Besides childhood ALD, various clinical phenotypes have been identified with the onset in adolescence or adulthood (adrenomyeloneuropathy (AMN), adult cerebral ALD or cerebello-brainstem dominant type). The different clinical phenotypes occasionally coexist even in the same family. To investigate if there is a correlation between the clinical phenotypes and genotypes of the mutations in the ALD gene, we have analyzed 43 Japanese ALD patients. By Southern blot analysis, we identified non-overlapping deletions of 0.5 kb to 10.4 kb involving the ALD gene in 3 patients with adult onset cerebello-brainstem dominant type. By detailed direct sequence analysis, we found 4 patients who had point mutations in the coding region. An AMN patient had a point mutation leading to {sup 266}Gly{r_arrow}Arg change, and another patient with adult cerebral ALD had a 3 bp deletion resulting in the loss of glutamic acid at codon 291, which is a conserved amino acid both in ALD protein and PMP70. Two patients with childhood ALD had point mutations leading to {sup 507}Gly{r_arrow}Val, and {sup 518}Arg{r_arrow}Gln, respectively. Since amino acids from 507 to 520 are highly conserved as ATP-binding cassette transporter proteins, mutations in this region are expected to result in dramatic changes of the function of this protein. Although there is a tendancy for mutation in childhood ALD to be present within the ATP-binding site motif, we found two adult patients who had large deletions involving the region. Taken together, strong correlation between genotypes and clinical phenotypes is unlikely to exist, and some other modifying factors might well play an important role for the clinical manifestations of ALD.

Koike, R.; Onodera, O.; Tabe, H. [Miigate Univ. (Japan)] [and others

1994-09-01

125

TGFBI gene mutations in a Korean population with corneal dystrophy  

PubMed Central

Purpose To investigate the clinical and genetic features of Korean patients with corneal dystrophies associated with mutations in the human transforming growth factor-?-induced (TGFBI) gene. Methods In this study, 387 subjects (71 families and 89 individuals - 268 patients having TGFBI corneal dystrophies and 119 normal relatives) were assessed. All subjects underwent a complete ophthalmologic evaluation, including biomicroscopic inspection and dilated fundus examination. As a control, 100 individuals without corneal disease were selected from the general population. The polymerase chain reaction (PCR) and direct sequencing were used to screen for mutations in TGFBI. Results All subjects recruited exhibited a range of corneal dystrophies, including Thiel-Behnke corneal dystrophy (TBCD, R555Q; 6 families and 4 individuals), granular corneal dystrophy type 2 (GCD2, R124H; 61 families and 80 individuals), lattice corneal dystrophy (LCD; 4 families and 5 individuals; 7 with type 1 [R124C], and 2 with a variant [L527R, P542R]). The disease showed an autosomal dominant inheritance pattern in all families. Conclusions R124H in GCD2 was the most common mutation. GCD1 and Reis-Bucklers corneal dystrophy were not found. In the GCD2 patients there were a large number of laser refractive surgery-induced corneal opacities. A spontaneous R124H mutation was confirmed in an already mutated allele that resulted in a change from a heterozygous into a homozygous form. Also, a novel mutation, P527R, was identified in LCD.

Cho, Kyong Jin; Mok, Jee Won; Na, Kyung Sun; Rho, Chang Rae; Byun, Yong Soo; Hwang, Ho Sik; Hwang, Kyu Yeon

2012-01-01

126

A mutation in the enamelin gene in a mouse model.  

PubMed

Amelogenesis imperfecta is an inherited disorder affecting tooth enamel formation. We previously isolated a mouse strain with an amelogenesis imperfecta phenotype (ATE1 mice) from a dominant ethylnitrosourea screen and mapped the disease-causing defect to a 9-cM region of mouse chromosome 5. In the current study, we tested the hypothesis that there is a mutation in enamelin (ENAM) or ameloblastin (AMBN), both of which are located within the linkage region, by sequencing these two candidate genes. Analysis of our data shows that the amelogenesis imperfecta phenotype is linked to a C > T transition in exon 8 of the enamelin gene. The mutation predicts a C826T transition, which is present in the enamelin transcript and changes the glutamine (Gln) codon at position 176 into a premature stop codon (Gln176X). Conversely, no mutation could be detected in the ameloblastin gene. These results define the ATE1 mice as a model for local hypoplastic autosomal-dominant amelogenesis imperfecta (AIH2), which is caused by enamelin truncation mutations in humans. PMID:17652207

Seedorf, H; Klaften, M; Eke, F; Fuchs, H; Seedorf, U; Hrabe de Angelis, M

2007-08-01

127

PEN-2 gene mutation in a familial Alzheimer's disease case.  

PubMed

Genetic evidence indicates a central role of cerebral accumulation of beta-amyloid (Abeta) in the pathogenesis of Alzheimer's disease (AD). Beside presenilin 1 and 2, three other recently discovered proteins (Aph 1, PEN 2 and nicastrin) are associated with gamma-secretase activity, the enzymatic complex generating Abeta. Alterations in genes encoding these proteins were candidates for a role in AD. The PEN 2 gene was examined for unknown mutations and polymorphisms in sporadic and familial Alzheimer patients. Samples from age-matched controls (n=253), sporadic AD (SAD, n=256) and familial AD (FAD, n=140) were screened with DHPLC methodology followed by sequencing. Scanning the gene identified for the first time a missense mutation (D90N) in a patient with FAD. Three intronic polymorphisms were also identified, one of which had a higher presence of the mutated allele in AD subjects carrying the allele epsilon4 of apolipoprotein E than controls. The pathogenic role of the PEN-2 D90N mutation in AD is not clear, but the findings might lead to new studies on its functional and genetic role. PMID:16170650

Sala Frigerio, C; Piscopo, P; Calabrese, E; Crestini, A; Malvezzi Campeggi, L; Civita di Fava, R; Fogliarino, S; Albani, D; Marcon, G; Cherchi, R; Piras, R; Forloni, G; Confaloni, A

2005-03-16

128

Transposon-induced nuclear mutations that alter chloroplast gene expression  

SciTech Connect

The goal of this project is to use mutant phenotypes as a guide to nuclear genes that determine the timing and localization of chloroplast development The immediate goals are to identify nuclear mutants with defects in chloroplast gene expression from maize lines harboring active Mu transposons; characterize their phenotypes to determine the precise defect in gene expression; clone several of the most interesting mutations by exploiting the transposon tag; and use the clones to further define the roles of these genes in modulating chloroplast gene expression. Three mutants were described earlier that had global defects in chloroplast gene expression. We have found that two of these mutations are allelic. Both alleles have global defects in chloroplast translation initiation, as revealed by the failure to assemble chloroplast mRNAs into polysomes. We have isolated and characterized three new mutants from Mu lines that have novel defects in chloroplast RNA metabolism. We are now ready to begin the task of cloning several of these genes, by using the Mu transposon tag.

Barkan, A.

1992-01-01

129

Calpain 3 gene mutations: genetic and clinico-pathologic findings in limb-girdle muscular dystrophy  

Microsoft Academic Search

Mutations in the calpain 3 gene have been proven to be responsible for limb-girdle muscular dystrophy (LGMD) type 2A. To determine the incidence and genotypes of the calpain 3 (p94) gene mutations in Japanese LGMD patients, we sequenced the gene in 80 patients with clinical characteristics of autosomal recessive or sporadic LGMD. We identified 13 distinct pathogenic mutations in 21

Jonghee Chae; Narihiro Minami; Yuko Jin; Masahiro Nakagawa; Kumiko Murayama; Fumie Igarashi; Ikuya Nonaka

2001-01-01

130

Frequent Mutation of the p53 Gene in Human Esophageal Cancer  

Microsoft Academic Search

Sequence alterations in the p53 gene have been detected in human tumors of the brain, breast, lung, and colon, and it has been proposed that p53 mutations spanning a major portion of the coding region inactivate the tumor suppressor function of this gene. To our knowledge, neither transforming mutations in oncogenes nor mutations in tumor suppressor genes have been reported

M. C. Hollstein; R. A. Metcalf; J. A. Welsh; R. Montesano; C. C. Harris

1990-01-01

131

Screening for mutations in the PKD1 gene  

SciTech Connect

With an estimated incidence of 1:1000, polycystic kidney disease is one of the most frequent single-gene disorders in the Caucasian population. The PKD1 gene, which is involved in approximately 85% of all cases, has recently been identified. The gene, which has a very large transcript, is partly situated within a duplicated area. This fact makes mutation screening a difficult task. Thus far, few deletions have been found. Therefore it seems likely that in a large number of patients the disease is caused by point mutations, possibly resulting in stop codons which lead to truncated proteins. A truncated protein can explain a putative dominant negative effect of the mutation. We are able to screen the patients which carry such stop codons with the protein truncation test (PTT). It is relatively easy to screen large stretches of the PKD1 gene with the PTT. The screening will be done on mRNA with the aid of RT-PCR. The reverse transcription reaction can give us the opportunity to specifically obtain the PKD1 transcript.

Roelfsema, J.H.; Spruit, L.; Ommen, G.J.B. van [and others

1994-09-01

132

Heterogeneous AVPR2 gene mutations in congenital nephrogenic diabetes insipidus  

SciTech Connect

Mutations in the AVPR2 gene encoding the receptor for arginine vasopressin in the kidney (V2 ADHR) have been reported in patients with congenital nephrogenic diabetes insipidus, a predominantly X-linked disorder of water homeostasis. The authors have used restriction-enzyme analysis and direct DNA sequencing of genomic PCR product to evaluate the AVPR2 gene in 11 unrelated affected males. Each patient has a different DNA sequence variation, and only one matches a previously reported mutation. Cosegregation of the variations with nephrogenic diabetes insipidus was demonstrated for two families, and a de novo mutation was accomplished in one family. All the variations predict frameshifts, truncations, or nonconservative amino acid substitutions in evolutionarily conserved positions in the V2 ADHR and related receptors. Of interest, a 28-bp deletion is found in one patient, while another, unrelated patient has a tandem duplication of the same 28-bp segment, suggesting that both resulted from the same unusual unequal crossing-over mechanism facilitated by 9-mer direct sequence repeats. Since the V2 ADHR is a member of the seven-transmembrane-domain, G-protein-coupled receptor superfamily, the loss-of-function mutations from this study and others provide important clues to the structure-function relationship of this and related receptors. 55 refs., 4 figs., 2 tabs.

Wildin, R.S.; Antush, M.J.; Bennett, R.L.; Schoof, J.M.; Scott, C.R. (Univ. of Washington, Seattle, WA (United States))

1994-08-01

133

Mutations in SOHLH1 gene associate with nonobstructive azoospermia.  

PubMed

In a previous study, we found SOHLH1 (spermatogenesis and oogenesis-specific basic helix-loop-helix 1) as the first testis-specific basic helix-loop-helix transcription factor essential for spermatogonial differentiation. SOHLH1 therefore represents an excellent candidate gene for testicular failure such as nonobstructive azoospermia (NOA). We analyzed whether there were mutations in the SOHLH1 gene in 96 Korean patients with NOA. The sequence analysis discovered three novel variations: one intronic variant (c.346-1G>A), and two nonsynonymous exonic variants (c.91T>C and c.529C>A) with known single nucleotide polymorphisms (SNPs), which included six intronic variants, two synonymous, and two nonsynonymous variants. We examined the consequences of mutations in SOHLH1 using in vivo and in vitro assays. Analysis of transcripts from minigenes carrying the c.346-1G>A revealed that splicing site variation leads to the partial deletion at a cryptic splicing site within exon 4. This deletion results in SOHLH1 with a truncated bHLH domain. Transient transfection assay showed that the SOHLH1 mutant with the truncated domain disrupted the transcriptional activity of KIT promoter, whereas two missense mutations harboring either p.Arg37Gln or p.Pro269Ser did not have a significant effect on its transactivation. Our findings indicate that a splice-acceptor site mutation that probably causes a nonfunctional SOHLH1 protein results in nonobstructive azoospermia by the lack of normal spermatogenesis. PMID:20506135

Choi, Youngsok; Jeon, Sanghyun; Choi, Mikyung; Lee, Min-ho; Park, Miseon; Lee, Dong Ryul; Jun, Kyu-Yeon; Kwon, Youngjoo; Lee, Ok-Hee; Song, Seung-Hun; Kim, Ji-Young; Lee, Kyung-Ah; Yoon, Tae Ki; Rajkovic, Aleksandar; Shim, Sung Han

2010-07-01

134

Mutational analysis of the BRAF gene in human tumor cells.  

PubMed

Genes of the RAF family, which mediate cellular responses to growth signals, encode kinases that are regulated by RAS and participate in the RAS, RAF, mitogen/extracellular signal-regulated kinase, extracellular signal-regulated kinase and mitogen-activated protein kinase pathway. As BRAF is a serine/threonine kinase that is commonly activated by somatic point mutation, it may provide possible diagnostic and therapeutic targets in human malignant tumors. We analyzed exon 15 of the BRAF gene for mutations in 58 lung, 12 breast, six kidney, 14 cervical, four endometrial and 10 ovarian carcinoma cell lines by PCR-SSCP and direct sequencing. The T1796A transversion was found in one (2.9%) of 34 small cell lung carcinoma and one (8.3%) of 12 breast carcinoma cell lines, resulting in a valine-to-glutamate substitution at residue 599 (V599E). One (4.2%) of 24 non-small cell lung carcinoma cell line showed the C1786G transversion, leading to a leucine-to-valine substitution at residue 596 (L596V). No BRAF point mutations were found in any of the other cell lines examined. Our present results suggest that BRAF may not be a frequent target of mutations involved in the pathogenesis of human lung, breast, kidney, cervical, endometrial and ovarian carcinomas. PMID:18397470

Ueda, Masatsugu; Toji, Eisaku; Nunobiki, Osamu; Izuma, Shinji; Okamoto, Yoshiaki; Torii, Kiyo; Noda, Sadamu

2008-05-01

135

Mutational analysis of the GALT gene in filipino patients.  

PubMed

Classic galactosemia is an inherited metabolic disorder due to mutations in the galactose-1-phosphate uridyltransferase (GALT) gene. This study describes the results of the GALT gene analysis of four unrelated Filipino patients with Classic Galactosemia. DNA extracted from dried blood spots and peripheral blood of the patients, age one month to two and a half years, underwent PCR-amplification with subsequent bidirectional sequencing of all eleven exons with their flanking intronic regions following standard protocols. Clinical data of these patients were reviewed. The patients presented with jaundice, hepatomegaly, diarrhea, vomiting, poor feeding and seizures during their neonatal period. They were diagnosed with elevated blood galactose and galactose-1-phosphate and absent GALT activity. Four missense mutations were found wherein two were previously reported (p.V168L and p.A345D) and two were novel (p.L116P and p.M178R). The most frequent mutation in our cohort is p.V168L. This study suggests that GALT mutations are ethnic-specific and that galactosemia is a heterogeneous disorder at the molecular level. The importance of early detection, immediate and proper medical management and genetic counseling of the patients and their families cannot be overemphasized. PMID:24045215

Estrada, Sylvia C; Canson, Daffodil M; Silao, Catherine Lynn T

2013-08-09

136

Spontaneous Mutation in the Escherichia Coli Laci Gene  

PubMed Central

To gain more detailed insight into the nature and mechanisms of spontaneous mutations, we undertook a DNA sequence analysis of a large collection of spontaneous mutations in the N-terminal region of the Escherichia coli lacI gene. This region of circa 210 base pairs is the target for dominant lacI mutations (i(-d)) and is suitable for studies of mutational specificity since it contains a relatively high density of detectable mutable sites. Among 414 independent i(-d) mutants, 70.8% were base substitutions, 17.2% deletions, 7.7% additions and 4.3% single-base frameshifts. The base substitutions were both transitions (60%) and transversions (40%), the largest single group being G.C->A.T (47% of base substitutions). All four transversions were observed. Among the 71 deletions, a hotspot (37 mutants) was present: an 87-bp deletion presumably directed by an 8-bp repeated sequence at its endpoints. The remaining 34 deletions were distributed among 29 different mutations, either flanked (13/34) or not flanked (21/34) by repeated sequences. The 32 additions comprised 29 different events, with only two containing a direct repeat at the endpoints. The single-base frameshifts were the loss of a single base from either repeated (67%) or nonrepeated (33%) bases. A comparison with the spectrum obtained previously in strains defective in DNA mismatch correction (mutH, mutL, mutS strains) yielded information about the apparent efficiency of mismatch repair. The overall effect was 260-fold but varied substantially among different classes of mutations. An interesting asymmetry was uncovered for the two types of transitions, A.T->G.C and G.C->A.T being reduced by mismatch repair 1340- and 190-fold, respectively. Explanations for this asymmetry and its possible implications for the origins of spontaneous mutations are discussed.

Schaaper, R. M.; Dunn, R. L.

1991-01-01

137

Mutational analysis of ATP7B gene in Egyptian children with Wilson disease: 12 novel mutations  

Microsoft Academic Search

The aim of this work was to study the mutations within ATP7B in Egyptian children with Wilson disease and to evaluate any potential correlation between genotype and phenotype in this\\u000a cohort. The study consisted of 48 children with Wilson disease from 32 independent families. The 21 exons of the ATP7B gene were amplified in a thermal cycler. Direct sequencing of

Tawhida Y. Abdelghaffar; Solaf M. Elsayed; Ezzat Elsobky; Bettina Bochow; Janine Büttner; Hartmut Schmidt

2008-01-01

138

Mutations and expressions of the tropomyosin gene and the troponin C gene of Caenorhabditis elegans.  

PubMed

How does muscle gene mutation affect the muscle structure and function of an animal? Mutant animals of the tropomyosin and troponin C genes of Caenorhabditis elegans show Pat (paralyzed, arrested elongation at twofold) phenotypes together with abnormal muscle filament assembly. We present evidence that the mutation sites of lev-11 gene was in the tropomyosin gene, tmy-1 and that of pat-10 was in the troponin C gene, tnc-1, of the worm, respectively. The lev-11 (st557) mutation occurred at the splice donor site of exon 1 and results in translation termination. Although the gene product from heterozygous (+/st557) animal was not detected, our result could be the reason for the Pat phenotype of this mutation. The lev-11(x12) mutation, isolated as an allele of levamisole resistance, occurred in exon 7 and results in amino acid substitution at 234 from Glu to Lys. This substitution give a charge change from - to + at this point which is common in three isoforms. There may be functional importance of this region for molecular interaction of the tropomyosin. Mutation site of pat-10(st575) was Asp64 to Asn and Trp153 to termination in the troponin C. The first mutation site was in the second calcium binding site and the second mutation raised the deletion of H helix in the troponin C. Both might affect the calcium binding or the retaining of the conformation for its function. Results presented here will be useful to understand the interaction site between the tropomyosin and troponin complex. PMID:9113409

Kagawa, H; Takuwa, K; Sakube, Y

1997-02-01

139

Unverricht-Lundborg disease: homozygosity for a new splicing mutation in the cystatin B gene.  

PubMed

Unverricht-Lundborg disease is the most common form of progressive myoclonic epilepsy (PME). It is due to cystatin B gene (CSTB) mutations. Several mutations in CSTB gene have been published, but few in homozygosity. We describe a patient with a new splicing alteration. Mutation Gln22Gln leads to abnormal splicing and partial inclusion of intronic sequence. This is one of the few cases of homozygosity for a non-classic mutation and adds to mutational heterogeneity of CSTB. PMID:22154554

Pinto, Eugénia; Freitas, Joel; Duarte, Ana Joana; Ribeiro, Isaura; Ribeiro, Diogo; Lima, J Lopes; Chaves, Joăo; Amaral, Olga

2011-12-10

140

TGFBI gene mutations in Brazilian patients with corneal dystrophy  

Microsoft Academic Search

PurposeTo investigate the transforming growth factor beta-induced gene (TGFBI) mutations in Brazilian patients with corneal dystrophy and to evaluate the phenotype–genotype correlation in these patients.MethodsA total of 11 unrelated families were studied. The diagnosis of corneal dystrophy was based on clinical and histopathological findings. Genomic DNA was extracted from peripheral blood leucocytes, and exons 4 and 12 of the TGFBIgene

H P Solari; M P Ventura; A B A Perez; J M F Sallum; M N Burnier; R Belfort

2007-01-01

141

Mutational analysis of the BRAF gene in human tumor cells  

Microsoft Academic Search

Genes of the RAF family, which mediate cellular responses to growth signals, encode kinases that are regulated by RAS and\\u000a participate in the RAS, RAF, mitogen\\/extracellular signal-regulated kinase, extracellular signal-regulated kinase and mitogen-activated\\u000a protein kinase pathway. As BRAF is a serine\\/threonine kinase that is commonly activated by somatic point mutation, it may\\u000a provide possible diagnostic and therapeutic targets in human

Masatsugu Ueda; Eisaku Toji; Osamu Nunobiki; Shinji Izuma; Yoshiaki Okamoto; Kiyo Torii; Sadamu Noda

2008-01-01

142

Human lysozyme gene mutations cause hereditary systemic amyloidosis  

Microsoft Academic Search

HEREDITARY non-neuropathic systemic amyloidosis (Ostertag-type)1 is a rare autosomal dominant disease in which amyloid deposition in the viscera is usually fatal by the fifth decade. In some families it is caused by mutations in the apolipoprotein AI gene2,3 but in two unrelated English families under our care the amyloid deposits did not contain apoAI, despite a report that this may

M. B. Pepys; P. N. Hawkins; D. R. Booth; D. M. Vigushin; G. A. Tennent; A. K. Soutar; N. Totty; O. Nguyen; C. C. F. Blake; C. J. Terry; T. G. Feest; A. M. Zalin; J. J. Hsuan

1993-01-01

143

Inherited Mutations in Breast Cancer Genes—Risk and Response  

Microsoft Academic Search

Germ-line mutations in BRCA1 and BRCA2 confer a high risk of developing breast cancer. They account, however, for only 40% of strongly familial breast cancer cases.\\u000a Intensive genome-wide searches for other highly-penetrant BRCA genes that, individually account for a sizeable fraction of the remaining heritability has not identified any plausible candidates.\\u000a The “missing heritability” is thought to be due to

Andrew Y. Shuen; William D. Foulkes

2011-01-01

144

Tau gene mutation in familial progressive subcortical gliosis  

Microsoft Academic Search

Familial forms of frontotemporal dementias are associated with mutations in the tau gene. A kindred affected by progressive subcortical gliosis (PSG), a rare form of presenile dementia, has genetic linkage to chromosome 17q21-22 (refs. 1,2, 3). This kindred (PSG-1) is included in the 'frontotemporal dementias and Parkinsonism linked to chromosome 17' group along with kindreds affected by apparently different forms

M. G. Spillantini; R. A. Crowther; S. G. Chen; P. Parchi; M. Tabaton; D. J. Lanska; W. R. Markesbery; K. C. Wilhelmsen; D. W. Dickson; R. B. Petersen; M. Goedert; P. Gambetti

1999-01-01

145

Oncological implications of RET gene mutations in Hirschsprung's disease  

Microsoft Academic Search

Background—Germline mutations of the RET proto-oncogene identical to those found in the tumour predisposition syn- drome multiple endocrine neoplasia type 2A (MEN2A), were detected in 2.5-5% of sporadic and familial cases of Hirschs- prung's disease. Some patients with Hir- schsprung's disease may therefore be exposed to a highly increased risk of tumours. Aims—To define clinical use of RET gene testing

R. H. Sijmons; R. M. W. Hofstra; F. A. Wijburg; T. P. Links; R. P. Zwierstra; A. Vermey; D. C. Aronson; G. Tan-Sindhunata; G. J. Brouwers-Smalbraak; S. M. Maas; C. H. C. M. Buys

1998-01-01

146

Frequencies in the Japanese Population of HFE Gene Mutations  

Microsoft Academic Search

We studied the frequencies of C282Y and H63Dmutations in the HFE gene, thought to be responsible forhereditary hemochromatosis (HH), in 504 chromosomesobtained from 252 unrelated Japanese. Allele-specific PCR and PCRrestriction fragment lengthpolymorphism methods revealed that the C282Y mutationwas not found and the H63D mutation was low in frequency(at only 0.99%) compared with data from European people. Since most HH is

Tetsuro Sohda; Junichi Yanai; Hidenobu Soejima; Kazuo Tamura

1999-01-01

147

Mutations in the Pericentrin (PCNT) Gene Cause Primordial Dwarfism  

Microsoft Academic Search

Fundamental processes influencing human growth can be revealed by studying extreme short stature. Using genetic linkage analysis, we find that biallelic loss-of-function mutations in the centrosomal pericentrin (PCNT) gene on chromosome 21q22.3 cause microcephalic osteodysplastic primordial dwarfism type II (MOPD II) in 25 patients. Adults with this rare inherited condition have an average height of 100 centimeters and a brain

Anita Rauch; Christian T. Thiel; Detlev Schindler; Ursula Wick; Yanick J. Crow; Arif B. Ekici; Anthonie J. van Essen; Timm O. Goecke; Lihadh Al-Gazali; Krystyna H. Chrzanowska; Christiane Zweier; Han G. Brunner; Kristin Becker; Cynthia J. Curry; Bruno Dallapiccola; Koenraad Devriendt; Arnd Dörfler; Esther Kinning; André Megarbane; Peter Meinecke; Robert K. Semple; Stephanie Spranger; Annick Toutain; Richard C. Trembath; Egbert Voss; Louise Wilson; Raoul Hennekam; Francis de Zegher; Helmuth-Günther Dörr; André Reis

2008-01-01

148

Mutational analysis of the adeno-associated virus rep gene.  

PubMed Central

The replication (rep) gene of the human parvovirus adeno-associated virus (AAV) is a pleiotropic effector of numerous viral functions and experts profound effects on cellular transformation. Of the four Rep proteins, the primarily nuclear Rep78 and Rep68 direct AAV DNA replication, trans activation of the capsid (cap) gene promoter, and inhibition of cellular proliferation mediated by various oncogenes. In an initial attempt to define functional domains in Rep78, we have constructed a comprehensive set of XhoI linker insertion and deletion mutations in the rep gene. Each of the mutant genes has been expressed in cell culture and assayed for the following functions: (i) nuclear localization, (ii) AAV DNA replication, (iii) trans activation of the AAV capsid gene transcription promoter, and (iv) suppression of cellular transformation mediated by the adenovirus E1a and an activated ras oncogene pair. Modest disruptions in the normal conformation of Rep78 inactivated its AAV DNA replication function and trans activation of the cap gene promoter. Linker insertion mutations in the amino-terminal one-third of the protein inactivated Rep78's ability to suppress oncogene-mediated cellular transformation. The transformation suppression domains are not limited to the amino-terminal regions, however, since deletions throughout the protein altered its suppression capabilities. A putative nuclear localization signal that is essential for each of the above functions was found in the Rep proteins. These results provide a preliminary screening of the functional domains in the AAV Rep proteins and pave the way for more subtle mutational analysis. Images

Yang, Q; Kadam, A; Trempe, J P

1992-01-01

149

Kinetochore KMN network gene CASC5 mutated in primary microcephaly.  

PubMed

Several genes expressed at the centrosome or spindle pole have been reported to underlie autosomal recessive primary microcephaly (MCPH), a neurodevelopmental disorder consisting of an important brain size reduction present since birth, associated with mild-to-moderate mental handicap and no other neurological feature nor associated malformation. Here, we report a mutation of CASC5 (aka Blinkin, or KNL1, or hSPC105) in MCPH patients from three consanguineous families, in one of which we initially reported the MCPH4 locus. The combined logarithm of odds score of the three families was >6. All patients shared a very rare homozygous mutation of CASC5. The mutation induced skipping of exon 18 with subsequent frameshift and truncation of the predicted protein. CASC5 is part of the KMN network of the kinetochore and is required for proper microtubule attachment to the chromosome centromere and for spindle-assembly checkpoint (SAC) activation during mitosis. Like MCPH gene ASPM, CASC5 is upregulated in the ventricular zone (VZ) of the human fetal brain. CASC5 binds BUB1, BUBR1, ZWINT-1 and interestingly it binds to MIS12 through a protein domain which is truncated by the mutation. CASC5 localized at the equatorial plate like ZWINT-1 and BUBR1, while ASPM, CEP152 and PCTN localized at the spindle poles in our patients and in controls. Comparison of primate and rodent lineages indicates accelerated evolution of CASC5 in the human lineage. Our data provide strong evidence for CASC5 as a novel MCPH gene, and underscore the role of kinetochore integrity in proper volumetric development of the human brain. PMID:22983954

Genin, Anne; Desir, Julie; Lambert, Nelle; Biervliet, Martine; Van Der Aa, Nathalie; Pierquin, Genevieve; Killian, Audrey; Tosi, Mario; Urbina, Montse; Lefort, Anne; Libert, Frederick; Pirson, Isabelle; Abramowicz, Marc

2012-09-13

150

Somatic mutations in the transcriptional corepressor gene BCORL1 in adult acute myelogenous leukemia  

PubMed Central

To further our understanding of the genetic basis of acute myelogenous leukemia (AML), we determined the coding exon sequences of ? 18 000 protein-encoding genes in 8 patients with secondary AML. Here we report the discovery of novel somatic mutations in the transcriptional corepressor gene BCORL1 that is located on the X-chromosome. Analysis of BCORL1 in an unselected cohort of 173 AML patients identified a total of 10 mutated cases (6%) with BCORL1 mutations, whereas analysis of 19 AML cell lines uncovered 4 (21%) BCORL1 mutated cell lines. The majority (87%) of the mutations in BCORL1 were predicted to inactivate the gene product as a result of nonsense mutations, splice site mutation, or out-of-frame insertions or deletions. These results indicate that BCORL1 by genetic criteria is a novel candidate tumor suppressor gene, joining the growing list of genes recurrently mutated in AML.

Li, Meng; Collins, Roxane; Jiao, Yuchen; Ouillette, Peter; Bixby, Dale; Erba, Harry; Vogelstein, Bert; Kinzler, Kenneth W.

2011-01-01

151

A substitution mutation in the myosin binding protein C gene in ragdoll hypertrophic cardiomyopathy.  

PubMed

Familial hypertrophic cardiomyopathy (HCM) is a primary myocardial disease with a prevalence of 1 in 500 in human beings. Causative mutations have been identified in several sarcomeric genes, including the cardiac myosin binding protein C (MYBPC3) gene. Heritable HCM also exists in a large-animal model, the cat, and we have previously reported a mutation in the MYBPC3 gene in the Maine coon breed. We now report a separate mutation in the MYBPC3 gene in ragdoll cats with HCM. The mutation changes a conserved arginine to tryptophan and appears to alter the protein structure. The ragdoll is not related to the Maine coon and the mutation identified is in a domain different from that of the previously identified feline mutation. The identification of two separate mutations within this gene in unrelated breeds suggests that these mutations occurred independently rather than being passed on from a common founder. PMID:17521870

Meurs, Kathryn M; Norgard, Michelle M; Ederer, Martina M; Hendrix, Kristina P; Kittleson, Mark D

2007-05-22

152

Large Scale Identification of Genes Involved in Cell Surface Biosynthesis and Architecture in Saccharomyces Cerevisiae  

PubMed Central

The sequenced yeast genome offers a unique resource for the analysis of eukaryotic cell function and enables genome-wide screens for genes involved in cellular processes. We have identified genes involved in cell surface assembly by screening transposon-mutagenized cells for altered sensitivity to calcofluor white, followed by supplementary screens to further characterize mutant phenotypes. The mutated genes were directly retrieved from genomic DNA and then matched uniquely to a gene in the yeast genome database. Eighty-two genes with apparent perturbation of the cell surface were identified, with mutations in 65 of them displaying at least one further cell surface phenotype in addition to their modified sensitivity to calcofluor. Fifty of these genes were previously known, 17 encoded proteins whose function could be anticipated through sequence homology or previously recognized phenotypes and 15 genes had no previously known phenotype.

Lussier, M.; White, A. M.; Sheraton, J.; di-Paolo, T.; Treadwell, J.; Southard, S. B.; Horenstein, C. I.; Chen-Weiner, J.; Ram, AFJ.; Kapteyn, J. C.; Roemer, T. W.; Vo, D. H.; Bondoc, D. C.; Hall, J.; Wei Zhong, W.; Sdicu, A. M.; Davies, J.; Klis, F. M.; Robbins, P. W.; Bussey, H.

1997-01-01

153

Exposed epitopes on a Trypanosoma equiperdum variant surface glycoprotein altered by point mutations.  

PubMed Central

African trypanosomes are covered by a dense protein layer that is immunologically distinct on different trypanosome isolates and is termed the variant surface glycoprotein (VSG). The different VSGs are expressed in a general order, where some VSGs appear preferentially early in infection and others only later. The exposed epitopes on a late antigen, VSG 78, of T.equiperdum were studied by the technique of monoclonal antibody (MAb) escape selection. MAbs that neutralize trypanosomes bearing VSG 78 reacted with the VSG only when it was attached to the trypanosome surface, suggesting that the most immunogenic surface epitopes are conformational. Trypanosome clones resistant to one of the MAbs yet still expressing VSG 78 or 78(20) were isolated in vitro. Two independent variants resistant to MAb H3 changed Ser192 to Arg by a single base change in the VSG gene and a variant resistant to MAb H21 had a single base change that converted Gln172 to Glu. A variant resistant to MAb H7 had several changes in the VSG gene, a gene conversion in the 5' region and an isolated mutation in codon 220 that is proposed to be responsible for the resistance phenotype. The isotypic bias of the MAbs against VSG 78 and an analysis of the natural variants that are resistant to MAb 78H21 suggest that glycosylation plays a role in the immunogenicity of these proteins. The analysis defines some of the exposed amino acid residues and demonstrates that VSG genes are altered by mutations and small gene conversions as well as replaced by large gene conversion-like events. The results provide biological data supporting the model of VSG structure obtained by crystallographic studies. Images

Baltz, T; Giroud, C; Bringaud, F; Eisen, H; Jacquemot, C; Roth, C W

1991-01-01

154

Clinical and Neuropathological Features of the Arctic APP Gene Mutation Causing Early-Onset Alzheimer Disease  

Microsoft Academic Search

Background: A majority of mutations within the - amyloid region of the amyloid precursor protein (APP) gene cause inherited forms of intracerebral hemor- rhage. Most of these mutations may also cause cognitive impairment, but the Arctic APP mutation is the only known intra--amyloid mutation to date causing the more typical clinical picture of Alzheimer disease. Objective: To describe features of

Hans Basun; Nenad Bogdanovic; Martin Ingelsson; Ove Almkvist; Jan Naslund; Karin Axelman; Thomas D. Bird; David Nochlin; Gerard D. Schellenberg; Lars-Olof Wahlund; Lars Lannfelt

2008-01-01

155

Epidermal growth factor receptor gene mutations in atypical adenomatous hyperplasias of the lung  

Microsoft Academic Search

Activating epidermal growth factor receptor (EGFR) gene mutations are frequently detected in lung adenocarcinomas, especially adenocarcinomas with a nonmucinous bronchioloalveolar carcinoma component. EGFR-mutated lung adenocarcinomas respond well to EGFR tyrosine kinase inhibitors. We previously found that most (88%) pure nonmucinous bronchioloalveolar carcinomas (adenocarcinoma in situ) already harbor EGFR mutations, indicating that the mutations are an early genetic event in the

Yuji Sakuma; Shoichi Matsukuma; Mitsuyo Yoshihara; Yoshiyasu Nakamura; Haruhiko Nakayama; Yoichi Kameda; Eiju Tsuchiya; Yohei Miyagi

2007-01-01

156

Mutational analysis of the amyloid precursor protein gene in Japanese familial Alzheimer's disease kindreds  

Microsoft Academic Search

We sequenced the entire coding region of the amyloid precursor protein (APP) genes of 11 unrelated patients with Japanese familial Alzheimer's disease (FAD) in order to determine the exact frequency of known APP gene mutations and to search for novel mutations responsible for FAD. Three out of 11 (27.3%) FAD patients showed the known Val to Ile mis-sense mutation at

Hiroto Fujigasaki; Satoshi Naruse; Kiyotoshi Kaneko; Hideto Hirasawa; Shoji Tsuji; Tadashi Miyatake

1994-01-01

157

A new Thr49Pro transthyretin gene mutation associated with leptomeningeal amyloidosis  

Microsoft Academic Search

Leptomeningeal amyloidosis is a rare central nervous system manifestation of systemic amyloidosis from transthyretin (TTR) mutation. Ten TTR gene mutations associated with this condition have been described. We report the clinical, radiological, and pathological features of a case of leptomeningeal amyloidosis from a novel Thr49Pro TTR gene mutation. A 53 year-old man presented with recurrent episodes of transient aphasia and

Kazuma Nakagawa; Sarah I. Sheikh; Matija Snuderl; Matthew P. Frosch; Steven M. Greenberg

2008-01-01

158

Spectrum of mutations in the Fanconi anaemia group G gene, FANCG\\/XRCC9  

Microsoft Academic Search

FANCG was the third Faconi anaemia gene identified and proved to be identical to the previously cloned XRCC9 gene. We present the pathogenic mutations and sequence variants we have so far identified in a panel of FA-G patients. Mutation screening was performed by PCR, single strand conformational polymorphism analysis and protein truncation tests. Altogether 18 mutations have been determined in

Ilja Demuth; Marcin Wlodarski; Alex J Tipping; Neil V Morgan; Johan P de Winter; Michaela Thiel; Sonja Gräsl; Detlev Schindler; Alan D D'Andrea; Cigdem Altay; Hülya Kayserili; Adriana Zatterale; Jürgen Kunze; Wolfram Ebell; Christopher G Mathew; Hans Joenje; Karl Sperling; Martin Digweed

2000-01-01

159

Prognostic significance of p53 gene mutations in squamous cell carcinoma of the lung.  

PubMed

The aim of the present study was to analyze the prevalence and clinical importance of p53 gene mutations in surgically treated squamous cell lung carcinoma. Sixty patients were included. Fifty-one patients in stages I to IIIa were submitted to radical resection. Twenty-five samples tested positive for the p53 immunohistochemistry assay, and were analyzed for p53 gene mutations. Eleven mutations were found. Patients harboring p53 gene mutations suffered a higher incidence of recurrence and a higher mortality rate. Disease-free interval and overall survival were shorter for patients with mutated p53 gene (p=0.03 and p=0.005, respectively). PMID:9683822

Sánchez-Pernaute, A; Torres, A; Iniesta, P; Hernando, F; Gómez, A; González, O; De Juan, C; Pérez-Aguirre, E; Maestro, M L; López-Asenjo, J A; Benito, M; Balibrea, J L

160

BSE Case Associated with Prion Protein Gene Mutation  

PubMed Central

Bovine spongiform encephalopathy (BSE) is a transmissible spongiform encephalopathy (TSE) of cattle and was first detected in 1986 in the United Kingdom. It is the most likely cause of variant Creutzfeldt-Jakob disease (CJD) in humans. The origin of BSE remains an enigma. Here we report an H-type BSE case associated with the novel mutation E211K within the prion protein gene (Prnp). Sequence analysis revealed that the animal with H-type BSE was heterozygous at Prnp nucleotides 631 through 633. An identical pathogenic mutation at the homologous codon position (E200K) in the human Prnp has been described as the most common cause of genetic CJD. This finding represents the first report of a confirmed case of BSE with a potential pathogenic mutation within the bovine Prnp gene. A recent epidemiological study revealed that the K211 allele was not detected in 6062 cattle from commercial beef processing plants and 42 cattle breeds, indicating an extremely low prevalence of the E211K variant (less than 1 in 2000) in cattle.

Richt, Jurgen A.; Hall, S. Mark

2008-01-01

161

Factor V gene G1691A mutation, prothrombin gene G20210A mutation, and MTHFR gene C677T mutation are not risk factors for pulmonary thromboembolism in Chinese population  

Microsoft Academic Search

A mutation in coagulant factor V gene, a substitution in the 3? untranslated region of prothrombin gene, and a variant in 5,10-methylenetetrahydrofolate reductase (MTHFR) gene have been reported to be related to venous thromboembolism in Caucasians, but this relationship remains in debate in other populations. In this case–control study, we aimed to determine the prevalence of these three mutations in

Yanhui Lu; Yanfen Zhao; Guozhang Liu; Xiaoling Wang; Zhihong Liu; Baiping Chen; Rutai Hui

2002-01-01

162

Cell Surface Fucosylation Does Not Affect Development of Colon Tumors in Mice with Germline Smad3 Mutation  

Microsoft Academic Search

Background\\/Aims: Neoplasia-related alterations in cell surface ?(1,2)fucosylated glycans have been reported in multiple tumors including colon, pancreas, endometrium, cervix, bladder, lung and choriocarcinoma. Spontaneous colorectal tumors from mice with a germline null mutation of transforming growth factor-? signaling gene Smad3 (Madh3) were tested for ?(1,2)fucosylated glycan expression. Methods:Ulex europaeus agglutinin-I (UEA-I) lectin staining, fucosyltransferase gene Northern blot analysis, and a

Steven E. Domino; David M. Karnak; Elizabeth A. Hurd

2007-01-01

163

Molecular Basis of Human CD36 Gene Mutations  

PubMed Central

CD36 is a transmembrane glycoprotein of the class B scavenger receptor family. The CD36 gene is located on chromosome 7 q11.2 and is encoded by 15 exons. Defective CD36 is a likely candidate gene for impaired fatty acid metabolism, glucose intolerance, atherosclerosis, arterial hypertension, diabetes, cardiomyopathy, Alzheimer disease, and modification of the clinical course of malaria. Contradictory data concerning the effects of antiatherosclerotic drugs on CD36 expression indicate that further investigation of the role of CD36 in the development of atherosclerosis may be important for the prevention and treatment of this disease. This review summarizes current knowledge of CD36 gene structure, splicing, and mutations and the molecular, metabolic, and clinical consequences of these phenomena.

Rac, Monika Ewa; Safranow, Krzysztof; Poncyljusz, Wojciech

2007-01-01

164

Novel CFTR gene mutation in a patient with CBAVD.  

PubMed

We report a novel mutation detected in a 33 year old Chinese man with congenital bilateral absence of the vas deferens (CBAVD), a past history of pulmonary meliodosis infection and a past history of bronchiolitis obliterans organising pneumonia. A novel splice site mutation in intron 6b (1001+5 G-->A) in the homozygous state was identified, and was predicted to lead to inefficient splicing. He was also homozygous at all intragenic and flanking polymorphic markers. Quantitative realtime PCR analysis showed that there were 2 copies of the CFTR gene present, ruling out the possibility of a deletion, and strongly suggesting the possibility of uniparental isodisomy involving at least a part of chromosome 7. PMID:17398169

Goh, Denise L M; Zhou, Youyou; Chong, Samuel S; Ngiam, Nicola S P; Goh, Daniel Y T

2007-03-29

165

Optimal control of gene mutation in DNA replication.  

PubMed

We propose a molecular-level control system view of the gene mutations in DNA replication from the finite field concept. By treating DNA sequences as state variables, chemical mutagens and radiation as control inputs, one cell cycle as a step increment, and the measurements of the resulting DNA sequence as outputs, we derive system equations for both deterministic and stochastic discrete-time, finite-state systems of different scales. Defining the cost function as a summation of the costs of applying mutagens and the off-trajectory penalty, we solve the deterministic and stochastic optimal control problems by dynamic programming algorithm. In addition, given that the system is completely controllable, we find that the global optimum of both base-to-base and codon-to-codon deterministic mutations can always be achieved within a finite number of steps. PMID:22454557

Yu, Juanyi; Li, Jr-Shin; Tarn, Tzyh-Jong

2012-01-22

166

Simultaneous mutation detection of three homoeologous genes in wheat by High Resolution Melting analysis and Mutation Surveyor®  

Microsoft Academic Search

BACKGROUND: TILLING (Targeting Induced Local Lesions IN Genomes) is a powerful tool for reverse genetics, combining traditional chemical mutagenesis with high-throughput PCR-based mutation detection to discover induced mutations that alter protein function. The most popular mutation detection method for TILLING is a mismatch cleavage assay using the endonuclease CelI. For this method, locus-specific PCR is essential. Most wheat genes are

Chongmei Dong; Kate Vincent; Peter Sharp

2009-01-01

167

Four novel and three recurrent mutations of the BTK gene and pathogenic effects of putative splice mutations  

Microsoft Academic Search

X-linked agammaglobulinemia is caused by mutations in the human BTK gene, leading to recurrent pyogenic infections. We describe four novel and three known BTK-mutations in seven patients from seven (six Thai and one Burmese) families. All but one were sporadic cases. Patients 1 and 2 had recurrent mutations in exon 10 (R288W) and exon 17 (R562W), respectively. Patient 3, a previously healthy

Duangrurdee Wattanasirichaigoon; Suwat Benjaponpitak; Chonnamet Techasaensiri; Wasu Kamchaisatian; Pakit Vichyanond; Sucheela Janwityanujit; Lulin Choubtum; Sayomporn Sirinavin

2006-01-01

168

Influence of missense mutation and silent mutation of LH?-subunit gene in Japanese patients with ovulatory disorders  

Microsoft Academic Search

The frequency of variant LH? containing two point mutations (T986–C and T1008–C) and its relationship to reproductive disorders differ widely between ethnic groups. In a Japanese population, variant luteinizing hormone (LH) correlates with ovulatory disorders. Here we examined the relationship between two missense mutations and five silent mutations (C894–T, G1018–C, C1036–A, C1098-T and C1423–T) in the LH? gene, and ovulatory

Kentaro Takahashi; Kenji Karino; Haruhiko Kanasaki; Hiroko Kurioka; Tomoya Ozaki; Toshie Yonehara; Kohji Miyazaki

2003-01-01

169

Phase variable genes of Campylobacter jejuni exhibit high mutation rates and specific mutational patterns but mutability is not the major determinant of population structure during host colonization.  

PubMed

Phase variation of surface structures occurs in diverse bacterial species due to stochastic, high frequency, reversible mutations. Multiple genes of Campylobacter jejuni are subject to phase variable gene expression due to mutations in polyC/G tracts. A modal length of nine repeats was detected for polyC/G tracts within C. jejuni genomes. Switching rates for these tracts were measured using chromosomally-located reporter constructs and high rates were observed for cj1139 (G8) and cj0031 (G9). Alteration of the cj1139 tract from G8 to G11 increased mutability 10-fold and changed the mutational pattern from predominantly insertions to mainly deletions. Using a multiplex PCR, major changes were detected in 'on/off' status for some phase variable genes during passage of C. jejuni in chickens. Utilization of observed switching rates in a stochastic, theoretical model of phase variation demonstrated links between mutability and genetic diversity but could not replicate observed population diversity. We propose that modal repeat numbers have evolved in C. jejuni genomes due to molecular drivers associated with the mutational patterns of these polyC/G repeats, rather than by selection for particular switching rates, and that factors other than mutational drift are responsible for generating genetic diversity during host colonization by this bacterial pathogen. PMID:22434884

Bayliss, Christopher D; Bidmos, Fadil A; Anjum, Awais; Manchev, Vladimir T; Richards, Rebecca L; Grossier, Jean-Philippe; Wooldridge, Karl G; Ketley, Julian M; Barrow, Paul A; Jones, Michael A; Tretyakov, Michael V

2012-03-20

170

Phase variable genes of Campylobacter jejuni exhibit high mutation rates and specific mutational patterns but mutability is not the major determinant of population structure during host colonization  

PubMed Central

Phase variation of surface structures occurs in diverse bacterial species due to stochastic, high frequency, reversible mutations. Multiple genes of Campylobacter jejuni are subject to phase variable gene expression due to mutations in polyC/G tracts. A modal length of nine repeats was detected for polyC/G tracts within C. jejuni genomes. Switching rates for these tracts were measured using chromosomally-located reporter constructs and high rates were observed for cj1139 (G8) and cj0031 (G9). Alteration of the cj1139 tract from G8 to G11 increased mutability 10-fold and changed the mutational pattern from predominantly insertions to mainly deletions. Using a multiplex PCR, major changes were detected in ‘on/off’ status for some phase variable genes during passage of C. jejuni in chickens. Utilization of observed switching rates in a stochastic, theoretical model of phase variation demonstrated links between mutability and genetic diversity but could not replicate observed population diversity. We propose that modal repeat numbers have evolved in C. jejuni genomes due to molecular drivers associated with the mutational patterns of these polyC/G repeats, rather than by selection for particular switching rates, and that factors other than mutational drift are responsible for generating genetic diversity during host colonization by this bacterial pathogen.

Bayliss, Christopher D.; Bidmos, Fadil A.; Anjum, Awais; Manchev, Vladimir T.; Richards, Rebecca L .; Grossier, Jean-Philippe; Wooldridge, Karl G.; Ketley, Julian M.; Barrow, Paul A.; Jones, Michael A.; Tretyakov, Michael V.

2012-01-01

171

Horizontal gene transfer and mutation: Ngrol genes in the genome of Nicotiana glauca  

PubMed Central

Ngrol genes (NgrolB, NgrolC, NgORF13, and NgORF14) that are similar in sequence to genes in the left transferred DNA (TL-DNA) of Agrobacterium rhizogenes have been found in the genome of untransformed plants of Nicotiana glauca. It has been suggested that a bacterial infection resulted in transformation of Ngrol genes early in the evolution of the genus Nicotiana. Although the corresponding four rol genes in TL-DNA provoked hairy-root syndrome in plants, present-day N. glauca and plants transformed with Ngrol genes did not exhibit this phenotype. Sequenced complementation analysis revealed that the NgrolB gene did not induce adventitious roots because it contained two point mutations. Single-base site-directed mutagenesis at these two positions restored the capacity for root induction to the NgrolB gene. When the NgrolB, with these two base substitutions, was positioned under the control of the cauliflower mosaic virus 35S promoter (P35S), transgenic tobacco plants exhibited morphological abnormalities that were not observed in P35s-RirolB plants. In contrast, the activity of the NgrolC gene may have been conserved after an ancient infection by bacteria. Discussed is the effect of the horizontal gene transfer of the Ngrol genes and mutations in the NgrolB gene on the phenotype of ancient plants during the evolution of N. glauca.

Aoki, Seishiro; Syono, Kunihiko

1999-01-01

172

40 CFR 798.5300 - Detection of gene mutations in somatic cells in culture.  

Code of Federal Regulations, 2013 CFR

...CONTROL ACT (CONTINUED) HEALTH EFFECTS TESTING GUIDELINES Genetic Toxicity § 798.5300 Detection of gene mutations in somatic...kinase locus in L5178Y mouse lymphoma cells. I. Application to genetic toxicology testing,â Mutation Research,...

2013-07-01

173

Novel MEK1 Mutation Identified by Mutational Analysis of Epidermal Growth Factor Receptor Signaling Pathway Genes in Lung Adenocarcinoma  

Microsoft Academic Search

Genetic lesions affecting a number of kinases and other elements within the epidermal growth factor receptor (EGFR) signaling pathway have been implicated in the pathogenesis of human non-small-cell lung cancer (NSCLC). We performed mutational profiling of a large cohort of lung adenocarcino- mas to uncover other potential somatic mutations in genes of this pathway that could contribute to lung tumorigenesis.

Dhananjay Chitale; Ben Golas; Michael D. McLellan; Yumi Kasai; Elaine R. Mardis; Richard K. Wilson; David Solit; Ross Levine; Kathrin Michel; Roman K. Thomas; Valerie W. Rusch; Marc Ladanyi; William Pao

174

Screening for mutations in Spanish families with myotonia. Functional analysis of novel mutations in CLCN1 gene.  

PubMed

Myotonia congenita is an inherited muscle disorder caused by mutations in the CLCN1 gene, a voltage-gated chloride channel of skeletal muscle. We have studied 48 families with myotonia, 32 out of them carrying mutations in CLCN1 gene and eight carry mutations in SCN4A gene. We have found 26 different mutations in CLCN1 gene, including 13 not reported previously. Among those 26 mutations, c.180+3A>T in intron 1 is present in nearly one half of the Spanish families in this series, the largest one analyzed in Spain so far. Although scarce data have been published on the frequency of mutation c.180+3A>T in other populations, our data suggest that this mutation is more frequent in Spain than in other European populations. In addition, expression in HEK293 cells of the new missense mutants Tyr137Asp, Gly230Val, Gly233Val, Tyr302His, Gly416Glu, Arg421Cys, Asn567Lys and Gln788Pro, demonstrated that these DNA variants are disease-causing mutations that abrogate chloride currents. PMID:22094069

Mazón, María J; Barros, Francisco; De la Peńa, Pilar; Quesada, Juan F; Escudero, Adela; Cobo, Ana M; Pascual-Pascual, Samuel I; Gutiérrez-Rivas, Eduardo; Guillén, Encarna; Arpa, Javier; Eraso, Pilar; Portillo, Francisco; Molano, Jesús

2011-11-16

175

Mutation analysis in the BRCA1 gene in Chinese breast cancer families  

Microsoft Academic Search

Objective: To study the mutation of BRCA1 gene in Chinese breast cancer families.Methods: Fifteen families were selected, involving 41 members, consisting of 23 breast cancer patients. Using polymerase chain reaction\\u000a and single stranded conformation polymorphism (PCR-SSCP), and subsequent DNA sequencing, the mutation of BRCA1 genes were\\u000a analyzed.Results: Four mutations were found in all families, and the proportion of mutation was

Wu Zhengyan; Zhen Linlin; Fan Ping

2003-01-01

176

Missense mutation of the sodium channel gene SCN2A causes Dravet syndrome  

Microsoft Academic Search

Mutations of the gene encoding the ?2 subunit of the neuronal sodium channel, SCN2A, have been found in benign familial neonatal-infantile seizures (BFNIS). In Dravet syndrome, only one nonsense mutation of SCN2A was identified, while hundreds of mutations were found in the paralogue gene, SCN1A, which encodes the ?1 subunit. This study examines whether SCN2A mutations are associated with Dravet

Xiuyu Shi; Sawa Yasumoto; Eiji Nakagawa; Tatsuya Fukasawa; Satoshi Uchiya; Shinichi Hirose

2009-01-01

177

Distal myopathy with rimmed vacuoles: novel mutations in the GNE gene.  

PubMed

The authors present three novel missense mutations in the UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE) gene, the causative gene for hereditary inclusion body myopathy, in Japanese patients with distal myopathy with rimmed vacuoles. Seven out of nine patients had homozygous V572L mutation, one was a compound heterozygote with C303V and V572L mutations, and the remaining patient bore homozygous A631V mutation. PMID:12177386

Tomimitsu, H; Ishikawa, K; Shimizu, J; Ohkoshi, N; Kanazawa, I; Mizusawa, H

2002-08-13

178

The nature of dominant mutations of rhodopsin and implications for gene therapy  

Microsoft Academic Search

Mutations in the rhodopsin gene are the most common cause of retinitis pigmentosa (RP) among human patients. The nature of\\u000a the rhodopsin mutations has critical implications for the design of strategies for gene therapy. Nearly all rhodopsin mutations\\u000a are dominant. Although dominance does not arise because of haploinsufficiency, it is unclear whether it is caused by gain-of-function\\u000a or dominant-negative mutations.

John H. Wilson; Theodore G. Wensel

2003-01-01

179

High frequency of MEFV gene mutations in patients with myeloid neoplasm  

Microsoft Academic Search

We aimed to investigate the rate of MEFV, the gene mutated in familial Mediterranean fever, mutations in patients with myeloid neoplasm and to determine if known\\u000a mutations of MEFV cause a tendency for myeloid neoplasms. The frequency of the five most common MEFV gene mutations (M694V, M680I, V726A, E148Q and M694I) was determined in 26 patients with myeloid neoplasm. We

Cagatay Oktenli; Ozkan Sayan; Serkan Celik; Alev A. Erikci; Yusuf Tunca; Hakan M. Terekeci; Elcin Erkuvan Umur; Yavuz S. Sanisoglu; Deniz Torun; Fatih Tangi; Burak Sahan; Selim Nalbant

2010-01-01

180

PIK3CA gene is frequently mutated in breast carcinomas and hepatocellular carcinomas  

Microsoft Academic Search

A recent report revealed that phosphoinositide-3-kinase, catalytic, alpha (PIK3CA) gene is somatically mutated in several types of human cancer, suggesting the mutated PIK3CA gene as an oncogene in human cancers. However, because the previous report focused the mutational search primarily on colon cancers, the data on PIK3CA mutations in other types of human cancers have been largely unknown. Here, we

Jong Woo Lee; Young Hwa Soung; Su Young Kim; Hae Woo Lee; Won Sang Park; Suk Woo Nam; Sang Ho Kim; Jung Young Lee; Nam Jin Yoo; Sug Hyung Lee

2005-01-01

181

Detection of cystic fibrosis mutations in a GeneChip{trademark} assay format  

SciTech Connect

We are developing assays for the detection of cystic fibrosis mutations based on DNA hybridization. A DNA sample is amplified by PCR, labeled by incorporating a fluorescein-tagged dNTP, enzymatically treated to produce smaller fragments and hybridized to a series of short (13-16 bases) oligonucleotides synthesized on a glass surface via photolithography. The hybrids are detected by eqifluorescence and mutations are identified by the specific pattern of hybridization. In a GeneChip assay, the chip surface is composed of a series of subarrays, each being specific for a particular mutation. Each subarray is further subdivided into a series of probes (40 total), half based on the mutant sequence and the remainder based on the wild-type sequence. For each of the subarrays, there is a redundancy in the number of probes that should hybridize to either a wild-type or a mutant target. The multiple probe strategy provides sequence information for a short five base region overlapping the mutation site. In addition, homozygous wild-type and mutant as well as heterozygous samples are each identified by a specific pattern of hybridization. The small size of each probe feature (250 x 250 {mu}m{sup 2}) permits the inclusion of additional probes required to generate sequence information by hybridization.

Miyada, C.G.; Cronin, M.T.; Kim, S.M. [Affymetrix, Santa Clara, CA (United States)] [and others

1994-09-01

182

Mutations within the MGC4607 gene cause cerebral cavernous malformations.  

PubMed

Cerebral cavernous malformations (CCM) are hamartomatous vascular malformations characterized by abnormally enlarged capillary cavities without intervening brain parenchyma. They cause seizures and focal neurological deficits due to cerebral hemorrhages. CCM loci have already been assigned to chromosomes 7q (CCM1), 7p (CCM2), and 3q (CCM3) and have been identified in 40%, 20%, and 40%, respectively, of families with CCM. Loss-of-function mutations have been identified in CCM1/KRIT1, the sole CCM gene identified to date. We report here the identification of MGC4607 as the CCM2 gene. We first reduced the size of the CCM2 interval from 22 cM to 7.5 cM by genetic linkage analysis. We then hypothesized that large deletions might be involved in the disorder, as already reported in other hamartomatous conditions, such as tuberous sclerosis or neurofibromatosis. We performed a high-density microsatellite genotyping of this 7.5-cM interval to search for putative null alleles in 30 unrelated families, and we identified, in 2 unrelated families, null alleles that were the result of deletions within a 350-kb interval flanked by markers D7S478 and D7S621. Additional microsatellite and single-nucleotide polymorphism genotyping showed that these two distinct deletions overlapped and that both of the two deleted the first exon of MGC4607, a known gene of unknown function. In both families, one of the two MGC4607 transcripts was not detected. We then identified eight additional point mutations within MGC4607 in eight of the remaining families. One of them led to the alteration of the initiation codon and five of them to a premature termination codon, including one nonsense, one frameshift, and three splice-site mutations. All these mutations cosegregated with the disease in the families and were not observed in 192 control chromosomes. MGC4607 is so far unrelated to any known gene family. Its implication in CCMs strongly suggests that it is a new player in vascular morphogenesis. PMID:14740320

Denier, C; Goutagny, S; Labauge, P; Krivosic, V; Arnoult, M; Cousin, A; Benabid, A L; Comoy, J; Frerebeau, P; Gilbert, B; Houtteville, J P; Jan, M; Lapierre, F; Loiseau, H; Menei, P; Mercier, P; Moreau, J J; Nivelon-Chevallier, A; Parker, F; Redondo, A M; Scarabin, J M; Tremoulet, M; Zerah, M; Maciazek, J; Tournier-Lasserve, E

2004-01-22

183

Mutations within the MGC4607 Gene Cause Cerebral Cavernous Malformations  

PubMed Central

Cerebral cavernous malformations (CCM) are hamartomatous vascular malformations characterized by abnormally enlarged capillary cavities without intervening brain parenchyma. They cause seizures and focal neurological deficits due to cerebral hemorrhages. CCM loci have already been assigned to chromosomes 7q (CCM1), 7p (CCM2), and 3q (CCM3) and have been identified in 40%, 20%, and 40%, respectively, of families with CCM. Loss-of-function mutations have been identified in CCM1/KRIT1, the sole CCM gene identified to date. We report here the identification of MGC4607 as the CCM2 gene. We first reduced the size of the CCM2 interval from 22 cM to 7.5 cM by genetic linkage analysis. We then hypothesized that large deletions might be involved in the disorder, as already reported in other hamartomatous conditions, such as tuberous sclerosis or neurofibromatosis. We performed a high-density microsatellite genotyping of this 7.5-cM interval to search for putative null alleles in 30 unrelated families, and we identified, in 2 unrelated families, null alleles that were the result of deletions within a 350-kb interval flanked by markers D7S478 and D7S621. Additional microsatellite and single-nucleotide polymorphism genotyping showed that these two distinct deletions overlapped and that both of the two deleted the first exon of MGC4607, a known gene of unknown function. In both families, one of the two MGC4607 transcripts was not detected. We then identified eight additional point mutations within MGC4607 in eight of the remaining families. One of them led to the alteration of the initiation codon and five of them to a premature termination codon, including one nonsense, one frameshift, and three splice-site mutations. All these mutations cosegregated with the disease in the families and were not observed in 192 control chromosomes. MGC4607 is so far unrelated to any known gene family. Its implication in CCMs strongly suggests that it is a new player in vascular morphogenesis.

Denier, C.; Goutagny, S.; Labauge, P.; Krivosic, V.; Arnoult, M; Cousin, A.; Benabid, A. L.; Comoy, J.; Frerebeau, P.; Gilbert, B.; Houtteville, J. P.; Jan, M.; Lapierre, F.; Loiseau, H.; Menei, P.; Mercier, P.; Moreau, J. J.; Nivelon-Chevallier, A.; Parker, F.; Redondo, A. M.; Scarabin, J. M.; Tremoulet, M.; Zerah, M.; Maciazek, J.; Tournier-Lasserve, E.

2004-01-01

184

Mutation analysis of ATP7B gene in Turkish Wilson disease patients: identification of five novel mutations.  

PubMed

Wilson disease is an autosomal recessive disorder of copper metabolism caused by mutations in the ATP7B gene that encodes a P-type copper transporting ATPase. The aim of this study was to screen and detect mutations of the ATP7B gene in unrelated Turkish Wilson disease patients (n = 46) and control group (n = 52). Mutations were screened and detected by DNA sequencing. 30 out of 46 patients had mutations. 24 different Wilson disease related mutations were identified in those patients. The distribution of mutations in ATP7B gene was as follow: 17 missense, 3 nonsense, 1 silent, 3 frameshift (1 insertion, 2 deletion). None of them were not found in the control group. Five out of 24 mutations were found to be novel. Four of them were missense (c.2363C > T, c.3106G > A, c.3451C > T, c.3733C > A). The last one was deletion (c.3111delC). 10 single nucleotide polymorphisms (SNPs) given in the literature were found in both control and patients groups. Moreover one new polymorphism in exon 18 (c.3727G > A) not reported previously was discovered in both groups. It was striking that most of the mutations were found in exons 8, 12-14. This is the first study covering Turkish Wilson disease patients and control groups for mutation screening in all the coding regions of ATP7B gene by DNA sequencing method and adding five new mutations and one polymorphism into the HUGO Wilson disease mutation database. PMID:23333878

Simsek Papur, Ozlenen; Akman, Sezin Asik; Cakmur, Raif; Terzioglu, Orhan

2013-01-17

185

PORCN mutations and variants identified in patients with focal dermal hypoplasia through diagnostic gene sequencing.  

PubMed

Focal dermal hypoplasia (FDH) is an X-linked dominant disorder caused by mutations in the gene PORCN, which encodes a protein required for the secretion and signaling of Wnt proteins. While deletions are responsible for a small percentage of FDH-causing mutations, the vast majority of mutations are single-nucleotide substitutions or small deletions or insertions that can be identified by sequence analysis. In 2007, we implemented a PORCN gene sequencing test for individuals with a clinical diagnosis of FDH. To date, we have detected 12 novel PORCN mutations and 6 previously reported mutations in 53 such unrelated patients. The pathogenic PORCN mutations included nine nonsense mutations, three missense mutations, one small deletion, two small duplications, and three splice-site mutations. Of these mutations, two were found in affected men and were mosaic; one of these was found in three other affected women. The remaining 16 mutations were found only in women. All the mutations detected in women were presumed heterozygous. In addition to the disease-causing mutations, eight nucleotide variants of unknown significance were identified. Further characterization of these variants suggests that four of them are pathogenic mutations. These findings add to the heterogeneity of mutations in the PORCN gene that cause FDH. PMID:20854095

Fernandes, Priscilla H; Wen, Shu; Sutton, Vernon Reid; Ward, Patricia A; Van den Veyver, Ignatia B; Fang, Ping

2010-09-20

186

Unique and Recurrent WAS Gene Mutations in Wiskott-Aldrich Syndrome and X-Linked Thrombocytopenia  

Microsoft Academic Search

ABSTRACT: Wiskott-Aldrich syndrome (WAS) and X-linked thrombocytopenia (XLT) are allelic phenotypes caused by defects of the WAS gene. Fourteen distinct mutations including seven novel gene defects in 16 WAS and four XLT patients were identified by single strand conformation polymorphism analysis and DNA sequencing of the WAS gene. Eleven (79%) of these mutations are located within exons 1 to 4

Lisa J Thompson; Michel R. A Lalloz; D. Mark Layton

1999-01-01

187

Discovery of single-nucleotide mutations in acetolactate synthase genes by Ecotilling  

Microsoft Academic Search

TILLING (Targeting Induced Local Lesions IN Genomes) is a powerful reverse genetic technique that employs a mismatch-specific endonuclease to discover induced point mutations in genes of interest. The use of the TILLING technique to survey natural variation in genes is called Ecotilling. We report an adaptation of Ecotilling for rapid detection of single-nucleotide mutations in the acetolactate synthase (ALS) genes

Guang-Xi Wang; Mui-Keng Tan; Sujay Rakshit; Hiromasa Saitoh; Ryohei Terauchi; Toshiyuki Imaizumi; Takanori Ohsako; Tohru Tominaga

2007-01-01

188

Mutation screening of the  PTPN11 gene in hypertrophic cardiomyopathy  

Microsoft Academic Search

Hypertrophic cardiomyopathy (HCM) is a common inherited cardiac disease and a major cause of sudden death. It is an autosomal dominant disorder predominantly caused by mutations in genes encoding for sarcomeric proteins. Only 50–60% of HCM probands have mutations in known genes suggesting the presence of additional disease genes. Noonan and LEOPARD syndromes are characterised by multiple dysmorphia and cardiac

Giuseppe Limongelli; Lorraine Hawkes; Raffaele Calabro; William J. McKenna; Petros Syrris

2006-01-01

189

Genetic syndromes caused by mutations in epigenetic genes.  

PubMed

The orchestrated organization of epigenetic factors that control chromatin dynamism, including DNA methylation, histone marks, non-coding RNAs (ncRNAs) and chromatin-remodeling proteins, is essential for the proper function of tissue homeostasis, cell identity and development. Indeed, deregulation of epigenetic profiles has been described in several human pathologies, including complex diseases (such as cancer, cardiovascular and neurological diseases), metabolic pathologies (type 2 diabetes and obesity) and imprinting disorders. Over the last decade it has become increasingly clear that mutations of genes involved in epigenetic mechanism, such as DNA methyltransferases, methyl-binding domain proteins, histone deacetylases, histone methylases and members of the SWI/SNF family of chromatin remodelers are linked to human disorders, including Immunodeficiency Centromeric instability Facial syndrome 1, Rett syndrome, Rubinstein-Taybi syndrome, Sotos syndrome or alpha-thalassemia/mental retardation X-linked syndrome, among others. As new members of the epigenetic machinery are described, the number of human syndromes associated with epigenetic alterations increases. As recent examples, mutations of histone demethylases and members of the non-coding RNA machinery have recently been associated with Kabuki syndrome, Claes-Jensen X-linked mental retardation syndrome and Goiter syndrome. In this review, we describe the variety of germline mutations of epigenetic modifiers that are known to be associated with human disorders, and discuss the therapeutic potential of epigenetic drugs as palliative care strategies in the treatment of such disorders. PMID:23370504

Berdasco, María; Esteller, Manel

2013-01-31

190

Alu distribution and mutation types of cancer genes  

PubMed Central

Background Alu elements are the most abundant retrotransposable elements comprising ~11% of the human genome. Many studies have highlighted the role that Alu elements have in genetic instability and how their contribution to the assortment of mutagenic events can lead to cancer. As of yet, little has been done to quantitatively assess the association between Alu distribution and genes that are causally implicated in oncogenesis. Results We have investigated the effect of various Alu densities on the mutation type based classifications of cancer genes. In order to establish the direct relationship between Alus and the cancer genes of interest, genome wide Alu-related densities were measured using genes rather than the sliding windows of fixed length as the units. Several novel genomic features, such as the density of the adjacent Alu pairs and the number of Alu-Exon-Alu triplets, were developed in order to extend the investigation via the multivariate statistical analysis toward more advanced biological insight. In addition, we characterized the genome-wide intron Alu distribution with a mixture model that distinguished genes containing Alu elements from those with no Alus, and evaluated the gene-level effect of the 5'-TTAAAA motif associated with Alu insertion sites using a two-step regression analysis method. Conclusions The study resulted in several novel findings worthy of further investigation. They include: (1) Recessive cancer genes (tumor suppressor genes) are enriched with Alu elements (p < 0.01) compared to dominant cancer genes (oncogenes) and the entire set of genes in the human genome; (2) Alu-related genomic features can be used to cluster cancer genes into biological meaningful groups; (3) The retention of exon Alus has been restricted in the human genome development, and an upper limit to the chromosome-level exon Alu densities is suggested by the distribution profile; (4) For the genes with at least one intron Alu repeat in individual chromosomes, the intron Alu densities can be well fitted by a Gamma distribution; (5) The effect of the 5'-TTAAAA motif on Alu densities varies across different chromosomes.

2011-01-01

191

Melanocortin 3 receptor gene and melanocortin 4 receptor gene mutations: the Asian Perspective.  

PubMed

Melanocortin 4 receptor (MC4R) deficiency resulting from disruption of one or both MC4R alleles represents the commonest monogenic form of human obesity to date. Human MC4R deficiency was reported to affect 4 and 5.8% of severely obese French and British populations respectively. However, studies elsewhere reported low incidence of MC4R mutations in their obese populations. The significance of MC4R mutations in Asian obese populations has not been adequately examined, though small studies in Japan, China, and Singapore reported few or no pathogenic mutations, suggesting a low prevalence in this part of the world. There were also few common mutations described across populations, suggesting a relative lack of founder effect. The pathogenic role of melanocortin 3 receptor gene (MC3R) mutations in human obesity is not as well described and accepted as MC4R mutations, though it is gradually gaining ground. Two common single nucleotide polymorphisms Thr6Lys and Val81Ile within the coding region were associated with higher body fat and leptin levels in obese children, supported by impaired signaling activity in vitro. There were also reports of missense mutations enriched in obese populations. While MC3R mutations are unlikely to result in an autosomal dominant form of monogenic obesity given the lack of strong co-segregation in family studies, the studies so far provided evidence that MC3R can be one of the genes which contributes to increased adiposity, and exert an effect on the human phenotype. PMID:23280863

Lee, Yung Seng

2012-12-01

192

Mutations in the uromodulin gene decrease urinary excretion of Tamm-Horsfall protein  

Microsoft Academic Search

Mutations in the uromodulin gene decrease urinary excretion of Tamm-Horsfall protein.BackgroundMutations in the uromodulin (UMOD) gene that encodes Tamm-Horsfall protein (THP) cause an autosomal-dominant form of chronic renal failure. We have now investigated effects of UMOD gene mutations on protein expression by quantitatively measuring THP excretion.MethodsTHP excretion was determined by enzyme-linked immunosorbent assay (ELISA) of urine collections obtained from 16

Anthony J. Bleyer; Thomas C. Hart; ZAK SHIHABI; VICKI ROBINS; John R. Hoyer; Anthony J. Bleyer M. D

2004-01-01

193

Sporadic ALS is not associated with VAPB gene mutations in Southern Italy  

Microsoft Academic Search

Mutations in the Cu\\/Zn superoxide dismutase (Sod1) gene have been reported to cause adult-onset autosomal dominant Amyotrophic Lateral Sclerosis (FALS). In sporadic cases (SALS) de novo mutations in the Sod1 gene have occasionally been observed. The recent finding of a mutation in the VAMP\\/synaptobrevin-associated membrane protein B (VAPB) gene as the cause of amyotrophic lateral sclerosis (ALS8), prompted us to

Francesca Luisa Conforti; Teresa Sprovieri; Rosalucia Mazzei; Carmine Ungaro; Alessandro Tessitore; Gioacchino Tedeschi; Alessandra Patitucci; Angela Magariello; AnnaLia Gabriele; Vincenzo Labella; Isabella Laura Simone; Giovanni Majorana; Maria Rosaria Monsurrň; Paola Valentino; Maria Muglia; Aldo Quattrone

2006-01-01

194

HFE Gene Mutations, Serum Ferritin Level, Transferrin Saturation, and Their Clinical Correlates in a Korean Population  

Microsoft Academic Search

The aim of this study was to investigate HFE gene mutations, blood iron indices, and their clinical correlates in a Korean population. In 484 prospectively enrolled health-check\\u000a examinees, HFE gene mutations and iron indices with clinical and laboratory variables were analyzed. Although neither the C282Y nor S65C\\u000a gene mutation were found, the H63D heterozygote was detected in 41 subjects (8.5%).

Sang Hyub Lee; Jin-Wook Kim; So Hyun Shin; Kyoung Phil Kang; Hyun Cheol Choi; Sung Hee Choi; Kyoung Un Park; Hyun Young Kim; Weechang Kang; Sook-Hyang Jeong

2009-01-01

195

Two mutations in LDLR gene were found in two Chinese families with familial hypercholesterolemia  

Microsoft Academic Search

Familial hypercholesterolemia (FH) (OMIM 143890) is an autosomal dominantly inherited disease mainly caused by mutations of\\u000a the gene encoding the low density lipoprotein receptor (LDLR) and Apolipoprotein (Apo) B. First the common mutation R3500Q\\u000a in ApoB gene was determined using PCR\\/RFLP method. Then the LDLR gene was screened for mutations using Touch-down PCR, SSCP\\u000a and sequencing techniques. Furthermore, the secondary

Xiaohuan Cheng; Junfa Ding; Fang Zheng; Xin Zhou; Chenling Xiong

2009-01-01

196

Identification of two different mutations in the PDS gene in an inbred family with Pendred syndrome  

PubMed Central

Recently the gene responsible for Pendred syndrome (PDS) was isolated and several mutations in the PDS gene have been identified in Pendred patients. Here we report the occurrence of two different PDS mutations in an extended inbred Turkish family. The majority of patients in this family are homozygous for a splice site mutation (1143-2A?G) affecting the 3' splice site consensus sequence of intron 7. However, two affected sibs with non-consanguineous parents are compound heterozygotes for the splice site mutation and a missense mutation (1558T?G), substituting an evolutionarily conserved amino acid. The latter mutation has been found previously in two Pendred families originating from The Netherlands, indicating that the 1558T?G mutation may be a common mutation.???Keywords: PDS gene; Pendred syndrome

Coucke, P; Van Hauwe, P; Everett, L; Demirhan, O; Kabakkaya, Y; Dietrich, N; Smith, R; Coyle, E; Reardon, W; Trembath, R; Willems, P; Green, E; Van Camp, G

1999-01-01

197

Disease-Causing Mutations in Genes of the Complement System  

PubMed Central

Recent studies have revealed profound developmental consequences of mutations in genes encoding proteins of the lectin pathway of complement activation, a central component of the innate immune system. Apart from impairment of immunity against microorganisms, it is known that hereditary deficiencies of this system predispose one to autoimmune conditions. Polymorphisms in complement genes are linked to, for example, atypical hemolytic uremia and age-dependent macular degeneration. The complement system comprises three convergent pathways of activation: the classical, the alternative, and the lectin pathway. The recently discovered lectin pathway is less studied, but polymorphisms in the plasma pattern-recognition molecule mannan-binding lectin (MBL) are known to impact its level, and polymorphisms in the MBL-associated serine protease-2 (MASP-2) result in defects of complement activation. Recent studies have described roles outside complement and immunity of another MBL-associated serine protease, MASP-3, in the etiology of 3MC syndrome, an autosomal-recessive disorder involving a spectrum of developmental features, including characteristic facial dysmorphism. Syndrome-causing mutations were identified in MASP1, encoding MASP-3 and two additional proteins, MASP-1 and MAp44. Furthermore, an association was discovered between 3MC syndrome and mutations in COLEC11, encoding CL-K1, another molecule of the lectin pathway. The findings were confirmed in zebrafish, indicating that MASP-3 and CL-K1 underlie an evolutionarily conserved pathway of embryonic development. Along with the discovery of a role of C1q in pruning synapses in mice, these recent advances point toward a broader role of complement in development. Here, we compare the functional immunologic consequences of “conventional” complement deficiencies with these newly described developmental roles.

Degn, S?ren E.; Jensenius, Jens C.; Thiel, Steffen

2011-01-01

198

Combined Complement Gene Mutations in Atypical Hemolytic Uremic Syndrome Influence Clinical Phenotype  

PubMed Central

Several abnormalities in complement genes reportedly contribute to atypical hemolytic uremic syndrome (aHUS), but incomplete penetrance suggests that additional factors are necessary for the disease to manifest. Here, we sought to describe genotype–phenotype correlations among patients with combined mutations, defined as mutations in more than one complement gene. We screened 795 patients with aHUS and identified single mutations in 41% and combined mutations in 3%. Only 8%–10% of patients with mutations in CFH, C3, or CFB had combined mutations, whereas approximately 25% of patients with mutations in MCP or CFI had combined mutations. The concomitant presence of CFH and MCP risk haplotypes significantly increased disease penetrance in combined mutated carriers, with 73% penetrance among carriers with two risk haplotypes compared with 36% penetrance among carriers with zero or one risk haplotype. Among patients with CFH or CFI mutations, the presence of mutations in other genes did not modify prognosis; in contrast, 50% of patients with combined MCP mutation developed end stage renal failure within 3 years from onset compared with 19% of patients with an isolated MCP mutation. Patients with combined mutations achieved remission with plasma treatment similar to patients with single mutations. Kidney transplant outcomes were worse, however, for patients with combined MCP mutation compared with an isolated MCP mutation. In summary, these data suggest that genotyping for the risk haplotypes in CFH and MCP may help predict the risk of developing aHUS in unaffected carriers of mutations. Furthermore, screening patients with aHUS for all known disease-associated genes may inform decisions about kidney transplantation.

Bresin, Elena; Rurali, Erica; Caprioli, Jessica; Sanchez-Corral, Pilar; Fremeaux-Bacchi, Veronique; Rodriguez de Cordoba, Santiago; Pinto, Sheila; Goodship, Timothy H.J.; Alberti, Marta; Ribes, David; Valoti, Elisabetta; Remuzzi, Giuseppe

2013-01-01

199

Combined complement gene mutations in atypical hemolytic uremic syndrome influence clinical phenotype.  

PubMed

Several abnormalities in complement genes reportedly contribute to atypical hemolytic uremic syndrome (aHUS), but incomplete penetrance suggests that additional factors are necessary for the disease to manifest. Here, we sought to describe genotype-phenotype correlations among patients with combined mutations, defined as mutations in more than one complement gene. We screened 795 patients with aHUS and identified single mutations in 41% and combined mutations in 3%. Only 8%-10% of patients with mutations in CFH, C3, or CFB had combined mutations, whereas approximately 25% of patients with mutations in MCP or CFI had combined mutations. The concomitant presence of CFH and MCP risk haplotypes significantly increased disease penetrance in combined mutated carriers, with 73% penetrance among carriers with two risk haplotypes compared with 36% penetrance among carriers with zero or one risk haplotype. Among patients with CFH or CFI mutations, the presence of mutations in other genes did not modify prognosis; in contrast, 50% of patients with combined MCP mutation developed end stage renal failure within 3 years from onset compared with 19% of patients with an isolated MCP mutation. Patients with combined mutations achieved remission with plasma treatment similar to patients with single mutations. Kidney transplant outcomes were worse, however, for patients with combined MCP mutation compared with an isolated MCP mutation. In summary, these data suggest that genotyping for the risk haplotypes in CFH and MCP may help predict the risk of developing aHUS in unaffected carriers of mutations. Furthermore, screening patients with aHUS for all known disease-associated genes may inform decisions about kidney transplantation. PMID:23431077

Bresin, Elena; Rurali, Erica; Caprioli, Jessica; Sanchez-Corral, Pilar; Fremeaux-Bacchi, Veronique; Rodriguez de Cordoba, Santiago; Pinto, Sheila; Goodship, Timothy H J; Alberti, Marta; Ribes, David; Valoti, Elisabetta; Remuzzi, Giuseppe; Noris, Marina

2013-02-21

200

Interlocus gene conversion events introduce deleterious mutations into at least 1% of human genes associated with inherited disease  

PubMed Central

Establishing the molecular basis of DNA mutations that cause inherited disease is of fundamental importance to understanding the origin, nature, and clinical sequelae of genetic disorders in humans. The majority of disease-associated mutations constitute single-base substitutions and short deletions and/or insertions resulting from DNA replication errors and the repair of damaged bases. However, pathological mutations can also be introduced by nonreciprocal recombination events between paralogous sequences, a phenomenon known as interlocus gene conversion (IGC). IGC events have thus far been linked to pathology in more than 20 human genes. However, the large number of duplicated gene sequences in the human genome implies that many more disease-associated mutations could originate via IGC. Here, we have used a genome-wide computational approach to identify disease-associated mutations derived from IGC events. Our approach revealed hundreds of known pathological mutations that could have been caused by IGC. Further, we identified several dozen high-confidence cases of inherited disease mutations resulting from IGC in ?1% of all genes analyzed. About half of the donor sequences associated with such mutations are functional paralogous genes, suggesting that epistatic interactions or differential expression patterns will determine the impact upon fitness of specific substitutions between duplicated genes. In addition, we identified thousands of hitherto undescribed and potentially deleterious mutations that could arise via IGC. Our findings reveal the extent of the impact of interlocus gene conversion upon the spectrum of human inherited disease.

Casola, Claudio; Zekonyte, Ugne; Phillips, Andrew D.; Cooper, David N.; Hahn, Matthew W.

2012-01-01

201

Spectrum of ?-globin gene mutations in the Kerman Province of Iran.  

PubMed

Mutation of the ?-globin gene may result in ?-thalassemia (?-thal) which is characterized by a reduction or complete absence of the gene expression. In this study, 607 individuals with low levels of blood cell indices and normal Hb A(2) were referred to our laboratory for investigation of any ?-thal mutations. We used the gap-polymerase chain reaction (gap-PCR) method and an ?-globin strip assay kit to detect the mutation. Our results showed that -?(3.7) was the most common mutation (83.8%) in the overall mutated alleles of the ?-globin gene. The second and third most frequent ?-globin gene defects were codon 19 (?2) and IVS-I, -5 nt/?? (?2), 5.7 and 4.2%, respectively. We found that the spectrum of ?-globin gene mutation in Kerman Province was in accordance with what was previously reported in other Iranian provinces where malaria has selected these protective traits. PMID:20854119

Saleh-Gohari, Nasrollah; Khosravi-Mashizi, Arezo

2010-01-01

202

A single gene mutation that increases maize seed weight  

SciTech Connect

The maize endosperm-specific gene shrunken2 (Sh2) encodes the large subunit of the heterotetrameric starch synthetic enzyme adenosine diphosphoglucose pyrophosphorylase (AGP; EC 2.7.7.27). Here we exploit an in vivo, site-specific mutagenesis system to create short insertion mutations in a region of the gene known to be involved in the allosteric regulation of AGP. The site-specific mutagen is the transposable element dissociation (Ds). Approximately one-third (8 of 23) of the germinal revertants sequenced restored the wild-type sequence, whereas the remaining revertants contained insertions of 3 or 6 bp. All revertants retained the original reading frame 3 feet to the insertion site and involved the addition of tyrosine and/or serine. Each insertion revertant reduced total AGP activity and the amount of the SH2 protein. The revertant containing additional tyrosine and serine residues increased seed weight 11-18% without increasing or decreasing the percentage of starch. Other insertion revertants lacking an additional serine reduced seed weight. Reduced sensitivity to phosphate, a long-known inhibitor of AGP, was found in the high seed-weight revertant. This alteration is likely universally important since insertion of tyrosine and serine in the potato large subunit of AGP at the comparable position and expression in Escherichia coli also led to a phosphate-insensitive enzyme. These results show that single gene mutations giving rise to increased seed weight, and therefore perhaps yield, are clearly possible in a plant with a long history of intensive and successful breeding efforts. 20 refs., 5 figs., 5 tabs.

Giroux, M.J.; Shaw, J. [Univ. of Florida, Gainesville, FL (United States); Hannah, L.C. [Univ. of Florida, Gainesville, FL (United States)]|[Washington State Univ., Pullman, WA (United States)

1996-06-11

203

Mutations of the human BTK gene coding for bruton tyrosine kinase in X-linked agammaglobulinemia.  

PubMed

X-linked agammaglobulinemia (XLA) is an immunodeficiency caused by mutations in the gene coding for Bruton agammaglobulinemia tyrosine kinase (BTK). A database (BTKbase) of BTK mutations lists 544 mutation entries from 471 unrelated families showing 341 unique molecular events. In addition to mutations, a number of variants or polymorphisms have been found. Mutations in all the five domains of BTK cause the disease, the single most common event being missense mutations. Most mutations lead to truncation of the enzyme. The mutations appear almost uniformly throughout the molecule. About one-third of point mutations affect CpG sites, which usually code for arginine residues. The putative structural implications of all the missense mutations are provided in the database. BTKbase is available at http://www.uta.fi/imt/bioinfo. PMID:10220140

Vihinen, M; Kwan, S P; Lester, T; Ochs, H D; Resnick, I; Väliaho, J; Conley, M E; Smith, C I

1999-01-01

204

Surface-enhanced Raman gene probes  

SciTech Connect

We report for the first time a new type of DNA gene probe based on surface-enhanced Raman scattering (SERS) label detection. The surface-enhanced Raman gene (SERG) probes do not require the use of radioactive labels and have great potential to provide both sensitivity and selectivity. The SERG probe can be used to detect DNA biotargets (e.g., gene sequences, bacteria, viral DNA fragments) via hybridization to DNA sequences complementary to that probe. The analytical figures of merit and its applications in environmental and biomedical areas are discussed. 22 refs., 5 figs.

Vo-Dinh, T.; Houck, K.; Stokes, D.L. (Oak Ridge National Lab., TN (United States))

1994-10-15

205

Age-dependent penetrance of different germline mutations in the BRCA1 gene  

Microsoft Academic Search

Aims: BRCA1 gene mutations have been extensively studied in relation to breast and ovarian cancer susceptibility. Various genotype-phenotype correlation attempts have yielded important data pertaining to the consequences of BRCA1 mutations. However, little is known about the effects of recurrent BRCA mutations on expressivity and the age of onset of cancer in a population. This study addresses whether different exon

F Al-Mulla; J M Bland; D Serratt; J Miller; C Chu; G T Taylor

2008-01-01

206

Mutations in the epidermal growth factor receptor gene are linked to smoking-independent, lung adenocarcinoma  

Microsoft Academic Search

Epidermal growth factor receptor (EGFR) mutations are a potential predictor of the effectiveness of EGFR inhibitors for the treatment of lung cancer. Although EGFR mutations were reported to occur with high frequency in nonsmoking Japanese adenocarcinoma patients, the exact nature has not been fully elucidated. We examined EGFR gene mutations within exons 18–21 and their correlations to clinico-pathological factors and

M Sonobe; T Manabe; H Wada; F Tanaka

2005-01-01

207

Mutation Hotspots Due to Sunlight in the p53 Gene of Nonmelanoma Skin Cancers  

Microsoft Academic Search

To identify the sites in the p53 tumor suppressor gene most susceptible to carcinogenic mutation by sunlight, the entire coding region of 27 basal cell carcinomas (BCCs) of the skin was sequenced. Fifty-six percent of tumors contained mutations, and these were UV-like: primarily CC --> TT or C --> T changes at dipyrimidine sites. Such mutations can alter more than

Annemarie Ziegler; David J. Leffell; Subrahmanyam Kunala; Harsh W. Sharma; Mae Gailani; Jeffrey A. Simon; Alan J. Halperin; Howard P. Baden; Philip E. Shapiro; Allen E. Bale; Douglas E. Brash

1993-01-01

208

Diaminodiphenylsulfone resistance of Mycobacterium leprae due to mutations in the dihydropteroate synthase gene  

Microsoft Academic Search

The nucleotide sequence analysis of the dihydropteroate synthase (DHPS) gene of six diaminodiphenylsulfone-resistant Mycobacterium leprae strains revealed that the mutation was limited at highly conserved amino acid residues 53 or 55. Though the mutation at amino acid residue 55 or its homologous site has been reported in other bacteria, the mutation at residue 53 is the first case in bacteria.

Masanori Kai; Masanori Matsuoka; Noboru Nakata; Shinji Maeda; Masaichi Gidoh; Yumi Maeda; Ken Hashimoto; Kazuo Kobayashi; Yoshiko Kashiwabara

1999-01-01

209

A novel melanocortin-4 receptor gene mutation in a female patient with severe childhood obesity.  

PubMed

This study targeted the identification of mutations of melanocortin-4 receptor gene (MC4R) in obese children. Fifty-one unrelated probands with early onset severe obesity (body mass index (BMI) > 99th percentile; 21 girls, mean age 10.6 +/- 3.6 years) were analyzed for nucleotide variations in the MC4R coding region, by the polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) method followed by direct DNA sequencing. MC4R variants were detected in three patients: the known I169S variant was found in heterozygote state in two patients and a novel heterozygous Y302F mutation was detected in one 12-year-old girl (BMI = 34 kg/m(2), BMI z-score 2.7) who has been overweight since the second year of life and suffered from hyperinsulinemia (at the age of 12: fasting insulin 45 mU/ml, after oral glucose load max. 300 mU/ml). The mutation also appears in the father, although both parents are obese (BMI father: 30.2 kg/m(2); mother: 31.9 kg/m(2)). This novel mutation is located in the functionally important NPXXY motif of the seventh transmembrane domain of the receptor. Functional characterization revealed reduction in cell surface expression and an alteration in signal transduction properties. These results add to the growing list of loss-of-function MC4R mutations in early onset obese patients and suggest an orexigenic effect of novel Y302F mutation. PMID:19214805

Roth, Christian L; Ludwig, Michael; Woelfle, Joachim; Fan, Zhen-Chuan; Brumm, Harald; Biebermann, Heike; Tao, Ya-Xiong

2009-02-12

210

[Detection of isocitrate dehydrogenase 1 gene mutation in 205 AML patients and its clinical significance].  

PubMed

This study was purposed to detect the mutation of isocitrate dehydrogenase 1 (IDH-1) gene in patients with acute myeloid leukemia (AML) and to explore its clinical significance. The genomic DNA was extracted from mononuclear cells (MNC) of bone marrow or peripheral blood in 205 adult AML patients, the exon 4 of IDH1 gene was amplified by PCR, then the sequencing and comparison were performed. The results showed that IDH1 mutation was detected in 9 (4.39%) of 205 AML patients. There were 6 cases of R132H mutation, 1 of R132L mutation, 1 of R132G mutation and 1 of R132S mutation. Significantly more IDH1 aberrations were detected in AML-M2 (P = 0.002) than other types. And the 9 patients with IDH1 mutation were characterized by low platelet count which was lower than patients with wild type IDH1 (P = 0.003). IDH1 mutation combined with FLT3/ITD mutation was found in 5 cases, c-kit mutation in 1, NPM1 mutation in 2, and IDH1 mutation with CEBPA or WT1 mutation was not found, which revealed a significant interaction between IDH1 mutation and the FLT3/ITD positive genotype or the CEBPA wild-type. IDH1 mutation were detected in 4 of 71 (5.63%) CN-AML. There was no significant difference of IDH1 mutation incidence between the normal and abnormal karyotypes. It is concluded that the rate of IDH1 mutation was 4.39% in Chinese AML patients. IDH1 mutation is significantly associated with AML-M2, lower platelet counts in peripheral blood, FLT3/ITD mutation and CEBPA wild-type, but not with age, white blood cell count in peripheral blood, karyotype, NPM1, c-kit or WT1 mutation. PMID:23257422

Shang, Zhen; Wang, Di; Xiao, Ming; Geng, Zhe; Wang, Hai-Xia; Wang, Jue; Xu, Yan-Ling; Li, Tong-Juan; Zhou, Jian-Feng; Li, Chun-Rui

2012-12-01

211

Mutation screening of the DYT6/THAP1 gene in Serbian patients with primary dystonia.  

PubMed

Primary dystonia (PrD) is characterized by sustained muscle contractions, causing twisting and repetitive movements and abnormal postures. Besides DYT1/TOR1A gene, DYT6/THAP1 gene is the second gene known to cause primary pure dystonia. We screened 281 Serbian primary dystonia patients and 106 neurologically healthy control individuals for the GAG deletion in TOR1A gene and for mutations in THAP1 gene by direct sequencing. Nine subjects were found to have the GAG deletion in TOR1A gene. Four coding mutations, including two novel mutations, were identified in the THAP1 gene in five unrelated patients. Two mutations were missense, one was nonsense, and one was 24 bp duplication. None of the coding mutations were seen in 106 control individuals. In addition, one novel nucleotide change in the 5'UTR region of THAP1 gene was detected in two unrelated patients. The mutation frequency of THAP1 gene in Serbian patients with primary dystonia was 1.8 %, similar to the mutation frequency in other populations. Most of the patients reported here with THAP1 mutations had the clinical features of predominantly laryngeal or oromandibular dystonia. Our data expand the genotypic spectrum of THAP1 and strengthen the association with upper body involvement, including the cranial and cervical regions that are usually spared in DYT1-PrD. PMID:23180184

Dobri?i?, Valerija S; Kresojevi?, Nikola D; Svetel, Marina V; Jankovi?, Milena Z; Petrovi?, Igor N; Tomi?, Aleksandra D; Novakovi?, Ivana V; Kosti?, Vladimir S

2012-11-20

212

Mutation analysis of LMX1B gene in nail-patella syndrome patients.  

PubMed Central

Nail-patella syndrome (NPS), a pleiotropic disorder exhibiting autosomal dominant inheritance, has been studied for >100 years. Recent evidence shows that NPS is the result of mutations in the LIM-homeodomain gene LMX1B. To determine whether specific LMX1B mutations are associated with different aspects of the NPS phenotype, we screened a cohort of 41 NPS families for LMX1B mutations. A total of 25 mutations were identified in 37 families. The nature of the mutations supports the hypothesis that NPS is the result of haploinsufficiency for LMX1B. There was no evidence of correlation between aspects of the NPS phenotype and specific mutations.

McIntosh, I; Dreyer, S D; Clough, M V; Dunston, J A; Eyaid, W; Roig, C M; Montgomery, T; Ala-Mello, S; Kaitila, I; Winterpacht, A; Zabel, B; Frydman, M; Cole, W G; Francomano, C A; Lee, B

1998-01-01

213

Asymptomatic carriers for homozygous novel mutations in the FKRP gene: the other end of the spectrum  

Microsoft Academic Search

Autosomal recessive limb-girdle muscular dystrophy linked to 19q13.3 (LGMD2I) was recently related to mutations in the fukutin-related protein gene (FKRP) gene. Pathogenic changes in the same gene were detected in congenital muscular dystrophy patients (MDC1C), a severe disorder. We have screened 86 LGMD genealogies to assess the frequency and distribution of mutations in the FKRP gene in Brazilian LGMD patients.

Flavia de Paula; Natássia Vieira; Alessandra Starling; Lydia Uraco Yamamoto; Bruno Lima; Rita de Cássia Pavanello; Mariz Vainzof; Vincenzo Nigro; Mayana Zatz

2003-01-01

214

Triple A syndrome: two novel mutations in the AAAS gene  

PubMed Central

Triple A syndrome is a rare disease of autosomal recessive inheritance. It was first described in 1978. The typical triad includes adrenocorticotrophic-hormone-resistant glucocorticoid insufficiency, reduced or absent tearing (alacrima) and achalasia. But clinical symptoms can be extremely heterogeneous and of variable clinically expression. This report describes a 7-year-old boy with a 1 year history of fatigue and muscle weakness. Physical examination showed skin and mucosal hyperpigmentation, and hormonal analysis revealed isolated glucocorticoid function. Medical history was marked by megaoesophagus and achalasia. The absence of tears when crying had been noted since birth. In the presence of the classical triad, triple A syndrome was diagnosed. Clinical diagnosis was confirmed by molecular analysis of the AAAS gene on chromosome 12q13. The novel compound heterozygous mutation c.1304delA and c.1292-1294delTTCinsA was found.

Thummler, Susanne; Huebner, Angela; Baechler-Sadoul, Elisabeth

2009-01-01

215

Mutational analysis of 9 different tumour-associated genes in human malignant mesothelioma cell lines.  

PubMed

Seven tumour suppressor genes (Chk1, Chk2, Apaf1, Rb1, p53, p16(INK4a) and p14(ARF)) and two oncogenes (N-ras and BRAF) were screened in nine human malignant melanoma (HMM) cell lines for point mutations or small deletions/insertions by DGGE, TGGE and SCCP analysis. For the first time in human mesothelioma, Chk1 gene mutations were detected in two of the nine investigated HMM cell lines. P53 gene mutations were found in three cell lines and p16(INK4a) mutations in 5. Mutation of the Chk1 gene implies a novel disruption mechanism of the p53 pathway in HMM, without affecting p53 itself. According to our knowledge, this is the first mutation screening of Chk1, Chk2, Apaf1 and Rb1 in human malignant mesothelioma. PMID:16077986

Kumar, Krishan; Rahman, Qamar; Schipper, Holger; Matschegewski, Claudia; Schiffmann, Dietmar; Papp, Thilo

2005-09-01

216

A mitochondrial tRNA(His) gene mutation causing pigmentary retinopathy and neurosensorial deafness.  

PubMed

We have identified a heteroplasmic G to A mutation at position 12,183 of the mitochondrial transfer RNA Histidine (tRNA(His)) gene in three related patients. These phenotypes varied according to mutation heteroplasmy: one had severe pigmentary retinopathy, neurosensorial deafness, testicular dysfunction, muscle hypotrophy, and ataxia; the other two had only retinal and inner ear involvement. The mutation is in a highly conserved region of the T(psi)C stem of the tRNA(His) gene and may alter secondary structure formation. This is the first described pathogenic, maternally inherited mutation of the mitochondrial tRNA(His) gene. PMID:12682337

Crimi, M; Galbiati, S; Perini, M P; Bordoni, A; Malferrari, G; Sciacco, M; Biunno, I; Strazzer, S; Moggio, M; Bresolin, N; Comi, G P

2003-04-01

217

Mutation of the BTK Gene and Clinical Feature of X-Linked Agammaglobulinemia in Mainland China  

Microsoft Academic Search

Introduction  X-Linked agammaglobulinemia is a prototypical humoral immunodeficiency with the mutation of the Bruton’s tyrosine kinase gene.\\u000a \\u000a \\u000a \\u000a Methods  We investigated the gene mutation and clinical features of 30 Chinese X-linked agammaglobulinemia (XLA) patients from 27 families.\\u000a There were 26 mutations, including 11 novel and 15 recurrent mutations, distributing over the entire gene. The nucleotide\\u000a and amino acid aberration, 1129C>T(H333Y) and 1196T>A(I355N), in

Ying Wang; Hirokazu Kanegane; Xiaochuan Wang; Xiaohua Han; Qian Zhang; Shunying Zhao; Yeheng Yu; Jingyi Wang; Toshio Miyawaki

2009-01-01

218

A novel mutation in the cathepsin C gene in a Pakistani family with Papillon-Lefevre Syndrome  

PubMed Central

Papillon-Lefevre syndrome (PLS; OMIM 245000) is an autosomal recessive disease caused by cathepsin C (CTSC) gene and is clinically characterized by palmoplantar keratoderma, psoriasiform lesion over the extensor surfaces and ginigivitis followed by teeth loss. CTSC gene is known to be expressed in several tissues including the skin and immune system. In the skin CTSC is thought to play a role in differentiation and desquamation. In the immune system it activates serine proteases. Here we investigated a patient from Pakistan with features of PLS and determined a novel deletion mutation designated c.21delG (Leu7PhefsX57) in exon 1 of the CTSC gene, that most likely results in absent CTSC protein, further extending the spectrum of mutations in the CTSC gene.

Cheng, T; Kurban, M; Wajid, M; Kiuru, M; Shimomura, Y; Christiano, AM

2010-01-01

219

Mutation screening of the RYR1 gene in malignant hyperthermia: Detection of a novel Tyr to ser mutation in a pedigree with associated centrl cores  

Microsoft Academic Search

The ryanodine receptor gene (RYR1) has been shown to be mutated in a small number of malignant hyperthermia (MH) predigrees. Missense mutations in this gene have also been identified in two families with central core disease (CCD), a rare myopathy closely associated with MH. In an effort to identify other RYR1 mutations responsible for MH and CCD, we used a

K. A. Quane; K. E. Keating; J. M. S. Healy

1994-01-01

220

Third complementarity-determining region of mutated VH immunoglobulin genes contains shorter V, D, J, P, and N components than non-mutated genes.  

PubMed

The third complementarity-determining region (CDR3) of immunoglobulin variable genes for the heavy chain (VH) has been shown to be shorter in length in hypermutated antibodies than in non-hypermutated antibodies. To determine which components of CDR3 contribute to the shorter length, and if there is an effect of age on the length, we analysed 235 cDNA clones from human peripheral blood of VH6 genes rearranged to immunoglobulin M (IgM) constant genes. There was similar use of diversity (D) and joining (JH) gene segments between clones from young and old donors, and there was similar use of D segments among the mutated and non-mutated heavy chains. However, in the mutated heavy chains, there was increased use of shorter JH4 segments and decreased use of longer JH6 segments compared to the non-mutated proteins. The overall length of CDR3 did not change with age within the mutated and non-mutated categories, but was significantly shorter by three amino acids in the mutated clones compared to the non-mutated clones. Analyses of the individual components that comprise CDR3 indicated that they were all shorter in the mutated clones. Thus, there were more nucleotides deleted from the ends of VH, D, and JH gene segments, and fewer P and N nucleotides added. The results suggest that B cells bearing immunoglobulin receptors with shorter CDR3s have been selected for binding to antigen. A smaller CDR3 may allow room in the antibody binding pocket for antigen to interact with CDRs 1 and 2 as well, so that as the VDJ gene undergoes hypermutation, substitutions in all three CDRs can further contribute to the binding energy. PMID:11412305

Rosner, K; Winter, D B; Tarone, R E; Skovgaard, G L; Bohr, V A; Gearhart, P J

2001-06-01

221

An infrequent point mutation of the p53 gene in human nasopharyngeal carcinoma.  

PubMed Central

Point mutations in the p53 gene have been detected in a variety of human cancers; the mutations are clustered in four "hot-spots" located in the coding region of exons 5, 7, and 8, which coincide with the four most highly conserved regions of the gene. We report the finding of a heterozygous G----C mutation at codon 280 (exon 8), position 2, of the p53 gene in a nasopharyngeal carcinoma (NPC) cell line, originating from Guangdong, a province in the People's Republic of China that leads the world in NPC incidence. A survey of nasopharyngeal tissues and NPC biopsies revealed that 1 out of 12 NPC samples from Hunan, another province in the People's Republic of China with high NPC incidence, had the same heterozygous mutation at codon 280 of p53, and none of 10 biopsies from Taiwan showed a mutation within exons 5-8 of the p53 gene. No other alteration of gene structure, including gross rearrangement or loss of heterozygosity or abnormality of gene expression was detected in NPC cell lines or NPC biopsies. We conclude from this study that mutational or other alterations of the p53 gene are not common in nasopharyngeal carcinogenesis and that a codon-280 mutation of p53 may be involved in less than 10% of NPC cases. This result contrasts with the relatively high frequency of p53 mutations associated with several other human carcinomas and suggests the importance of other genes in NPC genesis. Images

Sun, Y; Hegamyer, G; Cheng, Y J; Hildesheim, A; Chen, J Y; Chen, I H; Cao, Y; Yao, K T; Colburn, N H

1992-01-01

222

Dynamic evolution of plant mitochondrial genomes: Mobile genes and introns and highly variable mutation rates  

Microsoft Academic Search

We summarize our recent studies showing that angiosperm mitochondrial (mt) genomes have experienced remarkably high rates of gene loss and concomitant transfer to the nucleus and of intron acquisition by horizontal transfer. Moreover, we find substantial lineage-specific variation in rates of these structural mutations and also point mutations. These findings mostly arise from a Southern blot survey of gene and

Jeffrey D. Palmer; Keith L. Adams; Yangrae Cho; Christopher L. Parkinson; Yin-Long Qiu; Keming Song

2000-01-01

223

Functional mutation in the promoter region of thrombomodulin gene in relation to carotid atherosclerosis  

Microsoft Academic Search

Thrombomodulin is an important endothelial anticoagulant protein that decreases thrombin activity and activates protein C. Our recent study has shown that the G-33A promoter mutation of thrombomodulin gene is associated with coronary artery disease. This study was conducted to determine whether the G-33A mutation in the promoter region of thrombomodulin gene is a genetic risk factor for ischemic stroke or

Yi-Heng Li; Chih-Hung Chen; Poh-Shiow Yeh; Huey-Juan Lin; Bi-Ing Chang; Jia-Chung Lin; How-Ran Guo; Hua-Lin Wu; Guey-Yueh Shi; Ming-Liang Lai; Jyh-Hong Chen

2001-01-01

224

Operator derepressed mutations in the proline utilisation gene cluster of Aspergillus nidulans  

Microsoft Academic Search

The proline utilisation gene cluster of Aspergillus nidulans can be repressed efficiently only when both repressing nitrogen and repressing carbon sources are present. We show that two cis-acting mutations in this cluster permit the efficient transcription of the prnB gene under repressing conditions, resulting in direct or indirect derepression of two other transcripts of the pathway. These mutations are transitions

Vicky Sophianopoulou; Teresa Suárez; George Diallinas; Claudio Scazzocchio

1993-01-01

225

Mutation analysis of the MECP2 gene in British and Italian Rett syndrome females  

Microsoft Academic Search

Rett syndrome is an X-linked dominant neurological disorder, which appears to be the commonest genetic cause of profound combined intellectual and physical disability in Caucasian females. Recently, this syndrome has been associated with mutations of the MECP2 gene, a transcriptional repressor of still unknown target genes. Here we report a detailed mutational analysis of 62 patients from UK and Italian

Marcella Vacca; Francesco Filippini; Alberta Budillon; Valeria Rossi; Grazia Mercadante; Elisa Manzati; Francesca Gualandi; Stefania Bigoni; Cecilia Trabanelli; Giorgio Pini; Elisa Calzolari; Alessandra Ferlini; Ilaria Meloni; Giuseppe Hayek; Michele Zappella; Alessandra Renieri; Michele D'Urso; Maurizio D'Esposito; Fiona MacDonald; Alison Kerr; Seema Dhanjal; Maj Hultén

2001-01-01

226

Association between heterozygosity for HFE gene mutations and hepatitis viruses in hepatocellular carcinoma  

Microsoft Academic Search

Hepatitis B virus (HBV) and hepatitis C virus (HCV) infections are strong and independent risk factors for hepatocellular carcinoma (HCC) development. Patients with hereditary hemochromatosis (HH) are considered at risk of developing cancer. However, the interaction between HFE gene mutations and hepatitis viruses for HCC development has not been systematically searched for. To assess the interaction between HFE gene mutations

Anna Ludovica Fracanzani; Silvia Fargion; Maria Antonietta Stazi; Luca Valenti; Pietro Amoroso; Elisabetta Cariani; Angelo Sangiovanni; Maurizio Tommasini; Angelo Rossini; Cristina Bertelli; Erika Fatta; Valeria Patriarca; Sonia Brescianini; Tomaso Stroffolini

2005-01-01

227

Mutations in the gene encoding gap junction protein ?–3 associated with autosomal dominant hearing impairment  

Microsoft Academic Search

Hearing impairment is the most commonly occurring condition that affects the ability of humans to communicate. More than 50% of the cases of profound early-onset deafness are caused by genetic factors. Over 40 loci for non-syndromic deafness have been genetically mapped, and mutations in several genes have been shown to cause hearing loss. Mutations in the gene encoding connexin 26

Chun-yu Liu; Bei-sha Tang; Qian Pan; Lei Huang; He-ping Dai; Bao-rong Zhang; Wei Xie; Dong-xu Hu; Duo Zheng; Xiao-liu Shi; De-an Wang; Kun Xia; Kuan-ping Yu; Xiao-dong Liao; Yong Feng; Yi-feng Yang; Jian-yun Xiao; Ding-hua Xie; Jian-zheng Huang

1999-01-01

228

Gene replacement without selection: regulated suppression of amber mutations in Escherichia coli  

Microsoft Academic Search

We have developed a method called ‘gene gorging’ to make precise mutations in the Escherichia coli genome at frequencies high enough (1–15%) to allow direct identification of mutants by PCR or other screen rather than by selection. Gene gorging begins by establishing a donor plasmid carrying the desired mutation in the target cell. This plasmid is linearized by in vivo

Christopher D. Herring; Jeremy D. Glasner; Frederick R. Blattner

2003-01-01

229

Mutations in the Glucocerebrosidase Gene and Parkinson's Disease in Ashkenazi Jews  

Microsoft Academic Search

background A clinical association has been reported between type 1 Gaucher's disease, which is caused by a glucocerebrosidase deficiency owing to mutations in the glucocerebrosi- dase gene ( GBA ), and parkinsonism. We examined whether mutations in the GBA gene are relevant to idiopathic Parkinson's disease. methods A clinic-based case series of 99 Ashkenazi patients with idiopathic Parkinson's dis- ease,

Judith Aharon-Peretz; Hanna Rosenbaum; Ruth Gershoni-Baruch

2010-01-01

230

Recurrent and novel LDL receptor gene mutations causing heterozygous familial hypercholesterolemia in La Habana  

Microsoft Academic Search

The molecular basis of familial hypercholesterolemia (FH) in three families of Spanish descent from La Habana was investigated by the candidate gene approach. The Arg3500Gln mutation of apolipoprotein B-100 was not found. Identification of low density lipoprotein receptor (LDLR) gene haplotypes segregating with FH guided the characterisation of three point mutations by automated sequencing. One, a Val408?Met missense mutation, a

Erasmo Pereira; Raoul Ferreira; Brigitte Hermelin; Ginette Thomas; Chantal Bernard; Véronique Bertrand; Hadad Nassiff; Dora Mendez Del Castillo; Gilbert Bereziat; Pascale Benlian

1995-01-01

231

Identification of two different mutations in the PDS gene in an inbred family with Pendred syndrome  

Microsoft Academic Search

Recently the gene responsible for Pendred syndrome (PDS) was isolated and several mutations in the PDS gene have been identified in Pendred patients. Here we report the occurrence of two different PDS mutations in an extended inbred Turkish family. The majority of patients in this family are homozygous for a splice site mutation (1143-2A?G) affecting the 3? splice site consensus

P J Coucke; P Van Hauwe; L A Everett; O Demirhan; Y Kabakkaya; N L Dietrich; R J H Smith; E Coyle; W Reardon; R Trembath; P J Willems; E D Green; G Van Camp

1999-01-01

232

Co-segregation of LMNA and PMP22 gene mutations in the same family  

Microsoft Academic Search

We report here clinical, electrophysiological, and molecular findings in a family affected with two inherited genetic diseases: limb girdle muscular dystrophy type 1B (LGMD1B) and hereditary neuropathy with liability to pressure palsies (HNPP). Members of the family carry a novel missense mutation in the LMNA gene and a nonsense mutation in the PMP22 gene. Interestingly, the double LMNA\\/PMP22 mutations carriers

Elena Pegoraro; Bruno F. Gavassini; Sara Benedetti; Immacolata Menditto; Gabriella Zara; Roberta Padoan; Maria Luisa Mostacciuolo; Maurizio Ferrari; Corrado Angelini

2005-01-01

233

Mutations of the p53 Gene Are Involved in Ewing's Sarcomas but not in Neuroblastomas1  

Microsoft Academic Search

We have investigated the frequency of p53 gene mutations in Ewing's sarcoma (ES) and neuroblastoma (NB) by using polymerase chain reac tion-single strand conformation polymorphism analysis for genomic DNA or complementary DNA generated from total RNA. Mutations of the p53 gene were found in six of seven ES cell lines: a missense mutation of TGC (Cys)-»TAC (Try) at codon 141

Hiruaki Komuro; Yasuhide Hayashi; Machiko Kawamura; Kenshi Hayashi; Yasuhiko Kaneko; Shigehiko Kamoshita; Ryoji Hanada; Keiko Vaniamolo; Teruaki Hongo; Masao Yantada; Yoshiaki Tsuchida

234

Point mutations in the RUNX1\\/AML1 gene: another actor in RUNX leukemia  

Microsoft Academic Search

The RUNX1\\/AML1 gene is the most frequent target for chromosomal translocation in leukemia. In addition, recent studies have demonstrated point mutations in the RUNX1 gene as another mode of genetic alteration in development of leukemia. Monoallelic germline mutations in RUNX1 result in familial platelet disorder predisposed to acute myelogenous leukemia (FPD\\/AML). Sporadic point mutations are frequently found in three leukemia

Motomi Osato

2004-01-01

235

Six Novel Mutations in the Vasopressin V2 Receptor Gene Causing Nephrogenic Diabetes insipidus  

Microsoft Academic Search

X-linked nephrogenic diabetes insipidus (NDI) is a rare disease caused by mutations in the vasopressin V2 receptor (AVPR2) gene. We analyzed the AVPR2 gene in 6 unrelated Korean families with X-linked NDI, and found 6 novel mutations. Two of them were missense point mutations, 2 were short deletions causing frameshifts, 1 was a duplication of 9 bases, and 1 was

Hae Il Cheong; Hye Won Park; Il Soo Ha; HyungNam Moon; Yong Choi; Kwang Wook Ko; Jong Kwan Jun

1997-01-01

236

A novel gain-of-function mutation of c- kit gene in gastrointestinal stromal tumors  

Microsoft Academic Search

Background & Aims: The c-kit gene encodes a receptor tyrosine kinase (KIT). Recently, we found gain-of-function mutations of the c-kit gene in gastrointestinal stromal tumors (GISTs). All mutations were confined within the 11 amino acids (Lys-550 to Val-560) in the juxtamembrane domain, but one GIST showed a novel deletion-type mutation at codon 579 (Asp) in the juxtamembrane domain. The aim

Masanori Nakahara; Koji Isozaki; Seiichi Hirota; Jun-Ichiro Miyagawa; Naoko Hase-Sawada; Masahiko Taniguchi; Toshirou Nishida; Suji Kanayama; Yukihiko Kitamura; Yasuhisa Shinomura; Yuji Matsuzawa

1998-01-01

237

Mutation Analysis of the Aspartoacylase Gene in Non-Jewish Patients with Canavan Disease  

Microsoft Academic Search

Whereas two mutations in the ASPA gene account for more than 98% of all mutant alleles causing Canavan disease in the Ashkenazi\\u000a Jewish population, many different mutations can be found in non-Jewish individuals with Canavan disease. In our investigation\\u000a of 40 non-Jewish patients with Canavan disease, we have found 24 novel mutations and one new polymorphism in the ASPA gene.

Bai-Jin Zeng; Gregory M. Pastores; Paola Leone; Srinivasa Raghavan; Zhao-Hui Wang; Lucilene A. Ribeiro; Paola Torres; Elton Ong; Edwin H. Kolodny

238

Tyrosinase gene mutations in oculocutaneous albinism 1 (OCA1): definition of the phenotype.  

PubMed

Oculocutaneous albinism (OCA) is a common human genetic condition resulting from mutations in at least twelve different genes. OCA1 results from mutations of the tyrosinase gene and presents with the life-long absence of melanin pigment after birth (OCA1A) or with the development of minimal-to-moderate amounts of cutaneous and ocular pigment (OCA1B). Other types of OCA have variable amounts of cutaneous and ocular pigment. We hypothesized that white hair at birth indicates OCA1 and tested this in a sample of 120 probands with OCA and white hair at birth. We found that 102 (85%) of the probands had OCA1 with one or two identifiable tyrosinase gene mutations, with 169 (83%) of the 204 OCA1 tyrosinase gene alleles having identifiable mutations and 35 (17%) having no identifiable change in the coding, splice junction, or proximal promoter regions of the gene. The inability to identify the mutation was more common with OCA1B (24/35, 69%) than with OCA1A (11/35, 31%) alleles. Seven probands with no tyrosinase gene mutations were found to have OCA2 with one or two P gene mutations, and in eleven, no mutations were detected in either gene. We conclude that (1) the presence of white hair at birth is a useful clinical tool suggesting OCA1 in a child or adult with OCA, although OCA2 may also have this presentation; (2) the molecular analysis of the tyrosinase and P genes are necessary for precise diagnosis; and (3) the presence of alleles without identifiable mutations of the tyrosinase gene, particularly in OCA1B, suggests that more complex mutation mechanisms of this gene are common in OCA. PMID:13680365

King, Richard A; Pietsch, Jacy; Fryer, James P; Savage, Sarah; Brott, Marcia J; Russell-Eggitt, Isabelle; Summers, C Gail; Oetting, William S

2003-09-10

239

Mutational screening of the USH2A gene in Spanish USH patients reveals 23 novel pathogenic mutations  

PubMed Central

Background Usher Syndrome type II (USH2) is an autosomal recessive disorder, characterized by moderate to severe hearing impairment and retinitis pigmentosa (RP). Among the three genes implicated, mutations in the USH2A gene account for 74-90% of the USH2 cases. Methods To identify the genetic cause of the disease and determine the frequency of USH2A mutations in a cohort of 88 unrelated USH Spanish patients, we carried out a mutation screening of the 72 coding exons of this gene by direct sequencing. Moreover, we performed functional minigene studies for those changes that were predicted to affect splicing. Results As a result, a total of 144 DNA sequence variants were identified. Based upon previous studies, allele frequencies, segregation analysis, bioinformatics' predictions and in vitro experiments, 37 variants (23 of them novel) were classified as pathogenic mutations. Conclusions This report provide a wide spectrum of USH2A mutations and clinical features, including atypical Usher syndrome phenotypes resembling Usher syndrome type I. Considering only the patients clearly diagnosed with Usher syndrome type II, and results obtained in this and previous studies, we can state that mutations in USH2A are responsible for 76.1% of USH2 disease in patients of Spanish origin.

2011-01-01

240

Novel nonsense mutation in the platelet glycoprotein Ibbeta gene associated with Bernard-Soulier syndrome.  

PubMed

Bernard-Soulier syndrome (BSS) is an autosomal recessive bleeding disorder caused by quantitative or qualitative abnormalities in the glycoprotein (GP) Ib/IX/V complex, the platelet receptor for von Willebrand factor. This complex is composed of four subunits, GPIbalpha, GPIbbeta, GPIX, and GPV, and the coordinated assembly of GPIbalpha, GPIbbeta, and GPIX is required for the efficient surface expression of a functional complex. We report here a novel nonsense mutation of the GPIbbeta gene associated with BSS. Flow cytometric analysis of the patient's platelets showed markedly reduced GPIbalpha and absent GPIX surface expression. Immunoblot analysis of solubilized platelets showed that a small amount of GPIbalpha was detected; however, GPIbbeta and GPIX were undetectable. DNA sequencing analysis revealed a novel nonsense mutation of the GPIbbeta gene that converts Trp (TGG) to a stop codon (TAG) at residue 123. Transient transfection studies revealed that the mutant GPIbbeta polypeptide was not detected in the transfected 293T cells, suggesting that null expression of the mutant GPIbbeta impairs expression of the GPIbalpha and GPIX subunits and results in a BSS phenotype in the patient. PMID:12447957

Kunishima, Shinji; Matsushita, Tadashi; Ito, Takahiko; Kamiya, Tadashi; Saito, Hidehiko

2002-12-01

241

Detecting recurrent gene mutation in interaction network context using multi-scale graph diffusion  

PubMed Central

Background Delineating the molecular drivers of cancer, i.e. determining cancer genes and the pathways which they deregulate, is an important challenge in cancer research. In this study, we aim to identify pathways of frequently mutated genes by exploiting their network neighborhood encoded in the protein-protein interaction network. To this end, we introduce a multi-scale diffusion kernel and apply it to a large collection of murine retroviral insertional mutagenesis data. The diffusion strength plays the role of scale parameter, determining the size of the network neighborhood that is taken into account. As a result, in addition to detecting genes with frequent mutations in their genomic vicinity, we find genes that harbor frequent mutations in their interaction network context. Results We identify densely connected components of known and putatively novel cancer genes and demonstrate that they are strongly enriched for cancer related pathways across the diffusion scales. Moreover, the mutations in the clusters exhibit a significant pattern of mutual exclusion, supporting the conjecture that such genes are functionally linked. Using multi-scale diffusion kernel, various infrequently mutated genes are found to harbor significant numbers of mutations in their interaction network neighborhood. Many of them are well-known cancer genes. Conclusions The results demonstrate the importance of defining recurrent mutations while taking into account the interaction network context. Importantly, the putative cancer genes and networks detected in this study are found to be significant at different diffusion scales, confirming the necessity of a multi-scale analysis.

2013-01-01

242

[Frontotemporal dementia (FTD) and genetic mutations including progranulin gene].  

PubMed

Research on familial frontotemporal lobar degeneration (FTLD) has led to the discovery of disease-causing genes: microtubule-associated protein tau (MAPT), progranulin (PGRN) and valosin-containing protein (VCP). TAR DNA-binding protein of 43 kDa (TDP-43) has been identified as a major component of tau-negative ubiquitin-positive inclusions in familial and sporadic FTLD and amyotrophic lateral sclerosis (ALS), which are now referred to as TDP-43 proteinopathy. Recent findings of mutations in TDP-43 gene in familial and sporadic ALS cases confirm the pathogenetic role for TDP-43 in neurodegeneration. TDP-43 proteinopathies have been classified into 4 pathological subtypes. Type 1 is characterized by numerous dystrophic neurites (DNs), Type 2 has numerous neuronal cytoplasmic inclusions (NCIs), Type 3 has NCIs and DNs and Type 4 has neuronal intranuclear inclusions (NIIs) and DNs. There is a close relationship between such pathological subtypes of TDP-43 proteinopathy and the immunoblot pattern of C-terminal fragments of accumulated TDP-43. These results parallel our earlier findings of differing C-terminal tau fragments in progressive supranuclear palsy and corticobasal degeneration, despite identical composition of tau isoforms. Taken together, these results suggest that elucidating the mechanism of C-terminal fragment origination may shed light on the pathogenesis of several neurodegenerative disorders involving TDP-43 proteinopathy and tauopathy. PMID:19198141

Arai, Tetsuaki; Hasegawa, Masato; Nishihara, Masugi; Nonaka, Takashi; Kametani, Fuyuki; Yoshida, Mari; Hashizume, Yoshio; Beach, Thomas G; Morita, Mitsuya; Nakano, Imaharu; Oda, Tatsuro; Tsuchiya, Kuniaki; Akiyama, Haruhiko

2008-11-01

243

A Novel Mutation in ABCC8 Gene in a Newborn with Congenital Hyperinsulinism -A Case Report.  

PubMed

Congenital hyperinsulinism (CHI) is the most common cause of persistent hypoglycemia in infancy. The genetic basis of CHI includes a variety of defects in key genes regulating insulin secretion. Mutations in at least seven genes are found in 50% of cases. The most common forms of medically unresponsive CHI, which requires a near-total pancreatectomy are associated with autosomal recessive mutations in the ABCC8 and KCNJ11 genes encoding the two subunits of the pancreatic ?-cell ATP-sensitive potassium channel. We report a neonate with CHI and have a novel homozygous splicing mutation in the ABCC8 gene. PMID:23607867

Ustün, Nuran Uzunalic; Dilli, Dilek; Kundak, Ahmet Afsin; Okumus, Nurullah; Erdo?an, Derya; Apayd?n, Sema

2013-04-22

244

NUCLEAR GENE-INDUCED PLASTOME MUTATIONS IN OENOTHERA HOOKERI. I. GENETIC ANALYSIS  

Microsoft Academic Search

A nuclear gene mutation in Oenothera hookeri increases the frequency of variegated sectors. The gene is recessive; the variegation is cytoplasmically transmitted. Once variegation is induced, the mutant gene is not required for its continued expression. The induced sectors may differ one from another. The gene expresses unique patterns of penetrance and of maternal effect. The genetic data implicate the

MELVIN D. EPP

245

A mouse homeo box - containing gene maps near a developmental mutation  

Microsoft Academic Search

Mouse genes containing homeo box domains are predicted to fulfill important functions in embryogenesis. Using recombinant inbred mouse strains, we have mapped a mouse gene which contains a homeo box with homology to the Drosophila engrailed gene. This gene maps to mouse chromosome 1 near or at the dominant hemimelia locus which is a known mouse developmental mutation.Copyright © 1987

R. E. Hill; A. E. Hall; C. M. Sime; N. D. Hastie

1987-01-01

246

High Levels of Patched Gene Mutations in Basal-Cell Carcinomas from Patients with Xeroderma Pigmentosum  

Microsoft Academic Search

Recently, hptc, a human gene homologous to the Drosophila segment polarity gene patched (ptc), has been implicated in the nevoid basal-cell carcinoma (BCC) syndrome, and somatic mutations of hptc also have been found in sporadic BCCs, the most frequent cancers found in the white population. We have analyzed the hptc gene, postulated to be a tumor suppressor gene, in 22

Nathalie Bodak; Sophie Queille; Marie Francoise Avril; Bakar Bouadjar; Christiane Drougard; Alain Sarasin; Leela Daya-Grosjean

1999-01-01

247

PHEX gene mutation in a Chinese family with six cases of X-linked hypophosphatemic rickets.  

PubMed

Abstract Objective: X-linked hypophosphatemic (XLH) rickets is caused by inactivating mutations in the PHEX gene, which encodes a metalloprotease that cleaves small peptide hormone. So far there are only a few reports on XLH patients from China. In the present study, we report on six XLH patients from one family. A PHEX missense mutation was found in exon 22, and a literature review on the mutations of Chinese patients was undertaken. Case description: The family included six XLH patients with five females and one male (the proband). All the patients showed a low serum phosphorus, increased blood alkaline phosphatase and normal calcium levels. Mutation analysis revealed a PHEX mutation in exon 22 (c.2237G>A). In total, 15 PHEX mutations have been reported in Chinese populations at this time. Conclusion: These data extend the spectrum of mutations in the PHEX gene in Chinese populations. PMID:23813354

Yang, Lili; Yang, Jianbin; Huang, Xinwen

2013-01-01

248

[Mutation of isocitrate dehydrogenase 2 (IDH2) gene in Chinese AML patients and its clinical significance].  

PubMed

This study was purposed to analyze the frequency and of isocitrate dehydrogenase 2 (IDH2) gene mutation in acute myeloid leukemia (AML) and its clinic significance. The multiplex polymerase chain reaction (PCR) and sequencing were performed to screen 192 AML patients for exon 4 of the IDH2 gene. FLT3, NPM1, CEBPA, c-kit and WT1 mutations were also included in analysis. The results showed that IDH2 mutation was found in 14 (7.29%) of 192 patients. There were 9 AML patients with R140Q mutation, 1 patient with R140W mutation, and 1 patient with R172K mutation. IDH2 aberrations significantly more were detected in French-American-British (FAB) M5 (P < 0.005) than other types. There was no statistical difference in age, sex, WBC, platelet count, bone marrow blasts count, hemoglobin as compared with IDH2 wild-type. For imunotype analysis, IDH2 mutation patients were more likely to express CD34 and CD13, less CD36. IDH2 mutation combined with FLT3/ITD mutation was found in 7 cases, with CEBPA mutation in 4 cases, with NPM1 mutation in 4 cases, with Dnmt3a mutation in 5 cases, neither with c-kit, IDH1 or WT1 mutation for no one, which revealed a significant interaction between IDH2 mutation and the FLT3/ITD positive genotype, Dnmt3a mutated, and IDH1 wild-type. IDH2 mutation was detected in 5 (8.47%) of 59 CN-AML. There was no significant difference of IDH2 mutation incidence between the normal and abnormal karyotype. The CR rate was higher in IDH2 R140 mutated patients than wild-type ones, but there was no significant in the two group. It is concluded that the rate of IDH2 mutation is 7.29% in Chinese AML patients and 7.81% in CN-AML. IDH2 mutation is significantly associated with AML-M5, FLT3/ITD, Dnmt3a, IDH1 wild-type and fusion gene wild-type, but not with age, leucocyte and platelet counts in peripheral blood, karyotype, NPM1, CEBPA, c-kit or WT1 mutation. And IDH2 R140 mutation has no impact on CR rate. PMID:23815907

Shang, Zhen; Wang, Di; Xiao, Ming; Wang, Jue; Li, Tong-Juan; Zhao, Yue-Chao; Li, Chun-Rui; Zhou, Jian-Feng

2013-06-01

249

Two novel mutations of the MYBPC3 gene identified in Chinese families with hypertrophic cardiomyopathy  

PubMed Central

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is one of the most common genetic cardiovascular disorders. Mutations in the MYBPC3 gene are one of the most frequent genetic causes of HCM. OBJECTIVES: To screen MYBPC3 gene mutations in Chinese patients with HCM, and analyze the correlation between the genotype and the phenotype. METHODS: The 35 exons of the MYBPC3 gene were amplified by polymerase chain reaction in the 11 consecutive unrelated Chinese pedigrees. The sequences of the products were analyzed and the mutation sites were determined. The clinical data of genotype-positive families were collected, and the correlation between genotype and phenotype was analyzed. RESULTS: Two mutations of the MYBPC3 gene were confirmed among 11 pedigrees. A frameshift mutation (Pro459fs) was identified in exon 17 in family H8, and a splice mutation (IVS5+5G?C) was identified in intron 5 in family H3. These two mutations were first identified in Chinese patients with familial HCM and were absent in 110 chromosomes of healthy controls. Seven known polymorphisms were found in the cohort. CONCLUSIONS: Compared with what was reported abroad, the MYBPC3 gene is a common pathogenic gene responsible for HCM in Chinese patients, and the phenotypes of these two mutations in their respective families may have their own clinical characteristics.

Lin, Jia; Zheng, Dong-Dong; Tao, Qin; Yang, Jun-Hua; Jiang, Wen-Ping; Yang, Xiang-Jun; Song, Jian-Ping; Jiang, Ting-Bo; Li, Xun

2010-01-01

250

A Mutator Affecting the Region of the Iso-1-Cytochrome c Gene in Yeast  

PubMed Central

The mutator gene DEL1 in the yeast Saccharomyces cerevisiae causes a high rate of formation of multisite mutations that encompass the following three adjacent genes: CYC1, which determines the structure of iso-1-cytochrome c; RAD7, which controls UV sensitivity; and OSM1, which controls osomotic sensitivity. The simplest hypothesis is that these multisite mutations are deletions, although it has not been excluded that they may involve other types of gross chromosomal aberrations. In contrast, normal strains do not produce such multisite mutations even after mutagenic treatments.—The multisite mutations arise at a rate of approximately 10-5 to 10-6 per cell per division in DEL1 strains, which is much higher than rates observed for mutation of genes in normal strains. For example, normal strains produce all types of cyc1 mutants at a low rate of approximately 10-8 to 10-9. No evidence for multisite mutations was obtained upon analysis of numerous spontaneous ade1, ade2, met2 and met15 mutants isolated in a DEL1 strain. DEL1 segregates as a single Mendelian gene closely linked to the CYC1 locus. DEL1 appears to be both cis- and trans-dominant. The location of the DEL1 gene and the lack of effect on other genes suggest that the mutator acts only on a region adjacent to itself.

Liebman, Susan W.; Singh, Arjun; Sherman, Fred

1979-01-01

251

A missense mutation (Q279R) in the Fumarylacetoacetate Hydrolase gene, responsible for hereditary tyrosinemia, acts as a splicing mutation  

PubMed Central

Background Tyrosinemia type I, the most severe disease of the tyrosine catabolic pathway is caused by a deficiency in fumarylacetoacetate hydrolase (FAH). A patient showing few of the symptoms associated with the disease, was found to be a compound heterozygote for a splice mutation, IVS6-1g->t, and a putative missense mutation, Q279R. Analysis of FAH expression in liver sections obtained after resection for hepatocellular carcinoma revealed a mosaic pattern of expression. No FAH was found in tumor regions while a healthy region contained enzyme-expressing nodules. Results Analysis of DNA from a FAH expressing region showed that the expression of the protein was due to correction of the Q279R mutation. RT-PCR was used to assess if Q279R RNA was produced in the liver cells and in fibroblasts from the patient. Normal mRNA was found in the liver region where the mutation had reverted while splicing intermediates were found in non-expressing regions suggesting that the Q279R mutation acted as a splicing mutation in vivo. Sequence of transcripts showed skipping of exon 8 alone or together with exon 9. Using minigenes in transfection assays, the Q279R mutation was shown to induce skipping of exon 9 when placed in a constitutive splicing environment. Conclusion These data suggest that the putative missense mutation Q279R in the FAH gene acts as a splicing mutation in vivo. Moreover FAH expression can be partially restored in certain liver cells as a result of a reversion of the Q279R mutation and expansion of the corrected cells.

Dreumont, Natacha; Poudrier, Jacques A; Bergeron, Anne; Levy, Harvey L; Baklouti, Faouzi; Tanguay, Robert M

2001-01-01

252

A case of restless leg syndrome in a family with LRRK2 gene mutation.  

PubMed

LRRK2 gene mutations (PARK8) are a common cause of genetic Parkinson disease (PD). G2019S, the most frequent mutation, is responsible for both familial and sporadic cases of PD. The clinical picture is usually indistinguishable from that observed in idiopathic PD; however, a wide range of clinical presentations and pathological findings has been described. Restless leg syndrome (RLS) is a disabling sleep-related sensorimotor disorder whose pathogenesis is likely related to dopaminergic dysfunction. We report a 77-year-old woman with RLS and familial history of parkinsonism. The father, one sister, two cousins and one uncle were affected by PD. The proband and her sister were analyzed for mutations in LRRK2 gene and resulted to carry one heterozygous G2019S mutation in LRRK2 gene. The association between RLS and LRRK2 gene mutation may be casual, but it can hypothesized that RLS is a possible phenotypic presentation in PARK8. PMID:23227859

De Rosa, Anna; Guacci, Anna; Peluso, Silvio; Del Gaudio, Luigi; Massarelli, Marco; Barbato, Stefano; Criscuolo, Chiara; De Michele, Giuseppe

2013-02-04

253

Expanding spectrum of TNFRSF1A gene mutations among patients with idiopathic recurrent acute pericarditis.  

PubMed

Although idiopathic recurrent acute pericarditis (IRAP) is generally presumed to derive from an autoimmune process, increasing interest is currently being devoted to autoinflammatory diseases, a group of disorders of the innate immune system caused by mutations of genes involved in the regulation or activation of the inflammatory response, without any apparent involvement of autoimmunity. The tumour necrosis factor receptor-1-associated periodic syndrome is the most common autosomal dominant autoinflammatory disorder and is caused by mutations in the TNFRSF1A gene encoding the 55-kD receptor for tumour necrosis factor-?. IRAP patients carrying TNFRSF1A gene mutations have been recently described. We report herein the first IRAP patients carrying the rare R104Q and D12E?TNFRSF1A gene mutations, thus expanding the spectrum of tumour necrosis factor receptor-1-associated periodic syndrome mutations in IRAP patients. PMID:23745996

Cantarini, L; Lucherini, O M; Vitale, A; Sabadini, L; Brizi, M G; Frediani, B; Muscari, I; Galeazzi, M

2013-06-01

254

Mutations in origin recognition complex gene ORC4 cause Meier-Gorlin syndrome.  

PubMed

Meier-Gorlin syndrome is a rare autosomal recessive genetic condition whose primary clinical hallmarks include small stature, small external ears and small or absent patellae. Using marker-assisted mapping in multiple families from a founder population and traditional coding exon sequencing of positional candidate genes, we identified three different mutations in the gene encoding ORC4, a component of the eukaryotic origin recognition complex, in five individuals with Meier-Gorlin syndrome. In two such individuals that were negative for mutations in ORC4, we found potential mutations in ORC1 and CDT1, two other genes involved in origin recognition. ORC4 is well conserved in eukaryotes, and the yeast equivalent of the human ORC4 missense mutation was shown to be pathogenic in functional assays of cell growth. This is the first report, to our knowledge, of a germline mutation in any gene of the origin recognition complex in a vertebrate organism. PMID:21358631

Guernsey, Duane L; Matsuoka, Makoto; Jiang, Haiyan; Evans, Susan; Macgillivray, Christine; Nightingale, Mathew; Perry, Scott; Ferguson, Meghan; LeBlanc, Marissa; Paquette, Jean; Patry, Lysanne; Rideout, Andrea L; Thomas, Aidan; Orr, Andrew; McMaster, Chris R; Michaud, Jacques L; Deal, Cheri; Langlois, Sylvie; Superneau, Duane W; Parkash, Sandhya; Ludman, Mark; Skidmore, David L; Samuels, Mark E

2011-02-27

255

White matter abnormalities in Parkinson's disease patients with glucocerebrosidase gene mutations.  

PubMed

Glucocerebrosidase gene mutations represent a genetic risk factor for the development of Parkinson's disease. This study investigated brain alterations in Parkinson's disease patients carrying heterozygous glucocerebrosidase gene mutations using structural and diffusion tensor magnetic resonance imaging. Among 360 Parkinson's disease patients screened for glucocerebrosidase gene mutations, 19 heterozygous mutation carriers (5.3%) were identified. Of these, 15 patients underwent a neuropsychological evaluation and a magnetic resonance imaging scan. Sixteen age- and sex-matched healthy controls and 14 idiopathic Parkinson's disease patients without glucocerebrosidase gene mutations were also studied. Tract-based spatial statistics was used to perform a white matter voxel-wise analysis of diffusion tensor magnetic resonance imaging metrics. Mean fractional anisotropy values were obtained from white matter tracts of interest. Voxel-based morphometry was used to assess gray-matter atrophy. Cognitive deficits were found in 9 mutation carrier patients (60%). Compared with controls, Parkinson's disease patients carrying glucocerebrosidase gene mutations showed decreased fractional anisotropy in the olfactory tracts, corpus callosum, and anterior limb of the internal capsule bilaterally, as well as in the right anterior external capsule, and left cingulum, parahippocampal tract, parietal portion of the superior longitudinal fasciculus, and occipital white matter. Mutation carrier patients also had decreased fractional anisotropy of the majority of white matter tracts compared with Parkinson's disease patients with no mutations. No white matter abnormalities were found in Parkinson's disease patients without glucocerebrosidase gene mutations. No gray matter difference was found between patients and controls. In Parkinson's disease patients, verbal fluency scores correlated with white matter abnormalities. Parkinson's disease patients carrying glucocerebrosidase gene mutations experience a distributed pattern of white matter abnormalities involving the interhemispheric, frontal corticocortical, and parahippocampal tracts. White matter pathology in these patients may have an impact on the clinical manifestations of the disease, including cognitive impairment. PMID:23418083

Agosta, Federica; Kostic, Vladimir S; Davidovic, Kristina; Kresojevi?, Nikola; Sarro, Lidia; Svetel, Marina; Stankovi?, Iva; Comi, Giancarlo; Klein, Christine; Filippi, Massimo

2013-02-15

256

Two novel point mutations of mitochondrial tRNA genes in histologically confirmed Parkinson disease  

Microsoft Academic Search

  \\u000a Mutations in mitochondrially encoded tRNA genes have been described in a variety of neurological disorders. One such mutation,\\u000a the A to G transition at nucleotide position 4336 of the mitochondrial tRNA(Gln) gene, has been associated with both Alzheimer\\u000a and Parkinson disease. We have now performed a complete sequence analysis of all 22 mitochondrially encoded tRNA genes in\\u000a 20 cases

Eva M. Grasbon-Frodl; Siegfried Kösel; Mathias Sprinzl; Ulrich von Eitzen; Parviz Mehraein; Manuel B. Graeber

1999-01-01

257

Location of mutations within the PKD2 gene influences clinical outcome  

Microsoft Academic Search

Location of mutations within the PKD2 gene influences clinical outcome.BackgroundSince the cloning of the gene for autosomal dominant polycystic kidney disease type 2 (PKD2), approximately 40 different mutations of that gene have been reported to be associated with the disease. The relationship between the PKD2 genotype and phenotype, however, remains unclear.MethodsDetailed clinical information was collected for PKD2 families in which

Nick Hateboer; Barbera Veldhuisen; Dorien Peters; Martijn H Breuning; José L San-Millán; Nadja Bogdanova; Eliecer Coto; Marjan A V Dijk; Ali R Afzal; Steve Jeffery; Anand K Saggar-Malik; Roser Torra; Dimitar Dimitrakov; Isabel Martinez; Saturnino Sanz De Castro; Michael Krawczak; David Ravine

2000-01-01

258

Variegate porphyria: identification of a nonsense mutation in the protoporphyrinogen oxidase gene.  

PubMed

The porphyrias are disorders of porphyrin metabolism that result from inherited or acquired aberrations in the control of the heme biosynthetic pathway. Variegate porphyria is characterized by a partial reduction in the activity of protoporphyrinogen oxidase. In this study, we identified the first nonsense mutation in a family with variegate porphyria. The mutation consisted of a previously unreported G-to-T transversion in exon 5 of the protoporphyrinogen oxidase gene, resulting in the substitution of glutamic acid by a nonsense codon, designated E133X. Our investigation establishes that a nonsense mutation in the protoporphyrinogen oxidase gene is the underlying mutation in this family with variegate porphyria. PMID:9540990

Frank, J; Jugert, F K; Kalka, K; Goerz, G; Merk, H F; Christiano, A M

1998-04-01

259

Detection of BRAF gene mutation in primary choroidal melanoma tissue.  

PubMed

Numerous BRAF mutations have been detected in melanoma biopsy specimens and cell lines. In contrast, several studies report lack of BRAF mutations in uveal melanoma including primary and metastatic choroidal and ciliary body melanomas. To our knowledge, for the first time, here we report a case of choroidal melanoma harboring the BRAF mutation (V600E). The activation of RAF/MEK/ERK pathway, although independent of BRAF mutation, was reported in uveal melanoma. The presence of V600E mutation indicates that the RAF/MEK/ERK pathway, in addition to cutaneous melanoma progression, may play a role in the choroidal melanoma development. PMID:16410717

Malaponte, Grazia; Libra, Massimo; Gangemi, Pietro; Bevelacqua, Valentina; Mangano, Katia; D'Amico, Fabio; Mazzarino, Maria C; Stivala, Franca; McCubrey, James A; Travali, Salvatore

2006-02-20

260

Severe and mild mutations in cis for the methylenetetrahydrofolate reductase (MTHFR) gene, and description of five novel mutations in MTHFR.  

PubMed Central

Methylenetetrahydrofolate reductase (MTHFR) catalyzes the synthesis of 5-methyltetrahydrofolate, a methyl donor in the conversion of homocysteine to methionine. Patients with severe MTHFR deficiency have hyperhomocysteinemia, hypomethioninemia, and a range of neurological and vascular findings with a variable age at onset. We have previously described nine mutations in patients with severe MTHFR deficiency. A mild form of MTHFR deficiency, associated with a thermolabile enzyme, has been proposed as a genetic risk factor for cardiovascular disease and for neural tube defects. We have shown that a common missense mutation (an alanine-to-valine substitution) encodes this thermolabile variant. We now report an additional five mutations causing severe MTHFR deficiency and an analysis of genotype (alanine/valine status) and enzyme thermolability in 22 patients with this inborn error of metabolism. Six of these patients have four mutations in the MTHFR gene-two rare mutations causing severe deficiency and two mutations for the common alanine-to-valine mutation that results in thermolability. Even in severe MTHFR deficiency, the thermolabile variant is frequently observed, and there is a strong relationship between the presence of this variant and increased enzyme thermolability. Images Figure 1 Figure 2

Goyette, P.; Christensen, B.; Rosenblatt, D. S.; Rozen, R.

1996-01-01

261

Severe and mild mutations in cis for the methylenetetrahydrofolate reductase (MTHFR) gene, and description of five novel mutations in MTHFR.  

PubMed

Methylenetetrahydrofolate reductase (MTHFR) catalyzes the synthesis of 5-methyltetrahydrofolate, a methyl donor in the conversion of homocysteine to methionine. Patients with severe MTHFR deficiency have hyperhomocysteinemia, hypomethioninemia, and a range of neurological and vascular findings with a variable age at onset. We have previously described nine mutations in patients with severe MTHFR deficiency. A mild form of MTHFR deficiency, associated with a thermolabile enzyme, has been proposed as a genetic risk factor for cardiovascular disease and for neural tube defects. We have shown that a common missense mutation (an alanine-to-valine substitution) encodes this thermolabile variant. We now report an additional five mutations causing severe MTHFR deficiency and an analysis of genotype (alanine/valine status) and enzyme thermolability in 22 patients with this inborn error of metabolism. Six of these patients have four mutations in the MTHFR gene-two rare mutations causing severe deficiency and two mutations for the common alanine-to-valine mutation that results in thermolability. Even in severe MTHFR deficiency, the thermolabile variant is frequently observed, and there is a strong relationship between the presence of this variant and increased enzyme thermolability. PMID:8940272

Goyette, P; Christensen, B; Rosenblatt, D S; Rozen, R

1996-12-01

262

One novel Dravet syndrome causing mutation and one recurrent MAE causing mutation in SCN1A gene.  

PubMed

Mutations in SCN1A gene, encoding the voltage-gated sodium channel ?1-subunit, are found to be associated with severe myoclonic epilepsy in infancy or Dravet syndrome (DS), but only rarely with the myoclonic astatic epilepsy (MAE, or Doose syndrome). We report on two patients with SCN1A mutations and severe epilepsy within the spectrum of generalized epilepsy with febrile seizures plus syndrome (GEFS+), the phenotypes being consistent with DS and MAE, respectively. Analysis of SCN1A revealed a heterozygous de novo frameshift mutation (c.4205_4208delGAAA) in the patient with DS, and a recurrent missense mutation (c.3521C>G) in that suffering from MAE. The missense mutation has been reported in patients with neurological diseases of various manifestations, which suggests that this variability is likely to result from the modifying effects of other genetic or environmental factors. DS phenotype has been mainly found associated with truncation mutations, while predominantly missense mutations and very few prematurely terminating substitutions have been reported in GEFS+ patients. PMID:21396429

Yordanova, Iglika; Todorov, Tihomir; Dimova, Petia; Hristova, Dimitrina; Tincheva, Radka; Litvinenko, Ivan; Yotovska, Olga; Kremensky, Ivo; Todorova, Albena

2011-03-15

263

Phenylalanine hydroxylase gene mutations in the United States: report from the Maternal PKU Collaborative Study.  

PubMed Central

The major cause of hyperphenylalaninemia is mutations in the gene encoding phenylalanine hydroxylase (PAH). The known mutations have been identified primarily in European patients. The purpose of this study was to determine the spectrum of mutations responsible for PAH deficiency in the United States. One hundred forty-nine patients enrolled in the Maternal PKU Collaborative Study were subjects for clinical and molecular investigations. PAH gene mutations associated with phenylketonuria (PKU) or mild hyperphenylalaninemia (MHP) were identified on 279 of 294 independent mutant chromosomes, a diagnostic efficiency of 95%. The spectrum is composed of 71 different mutations, including 47 missense mutations, 11 splice mutations, 5 nonsense mutations, and 8 microdeletions. Sixteen previously unreported mutations were identified. Among the novel mutations, five were found in patients with MHP, and the remainder were found in patients with PKU. The most common mutations were R408W, IVS12nt1g-->a, and Y414C, accounting for 18.7%, 7.8%, and 5.4% of the mutant chromosomes, respectively. Thirteen mutations had relative frequencies of 1%-5%, and 55 mutations each had frequencies < or = 1%. The mutational spectrum corresponded to that observed for the European ancestry of the U.S. population. To evaluate the extent of allelic variation at the PAH locus within the United States in comparison with other populations, we used allele frequencies to calculate the homozygosity for 11 populations where >90% ascertainment of mutations has been obtained. The United States was shown to contain one of the most heterogeneous populations, with homozygosity values similar to Sicily and ethnically mixed sample populations in Europe. The extent of allelic heterogeneity must be a major determining factor in the choice of mutation-detection methodology for molecular diagnosis in PAH deficiency. Images Figure 1

Guldberg, P.; Levy, H. L.; Hanley, W. B.; Koch, R.; Matalon, R.; Rouse, B. M.; Trefz, F.; de la Cruz, F.; Henriksen, K. F.; Guttler, F.

1996-01-01

264

Mutations in the MATP gene in five German patients affected by oculocutaneous albinism type 4.  

PubMed

Oculocutaneous albinism (OCA) is caused by a deficiency of melanin synthesis and characterized by generalized hypopigmentation of skin, hair, and eyes. Due to the hypopigmentation of the retinal pigment epithelium, OCA is usually associated with congenital visual impairment, in addition to an increased risk of skin cancer. OCA is a genetically heterogeneous disease with distinct types resulting from mutations in different genes involved in the pathway which results in pigmentation. OCA1 is associated with mutations in the TYR gene encoding tyrosinase. OCA2 results from mutations in the P gene encoding the P protein and is the most common form of OCA. OCA3, also known as rufous/red albinism, is caused by mutations in the TYRP1 gene, which encodes the tyrosinase-related protein 1. Recently, OCA4 was described as a new form of OCA in a single patient with a splice site mutation in the MATP gene (or AIM1), the human ortholog of the murine underwhite gene. The similarity of MATP to transporter proteins suggests its involvement in transport functions, although its actual substrate is still unclear. We screened 176 German patients with albinism for mutations within the MATP gene and identified five individuals with OCA4. In this first report on West European patients, we describe 10 so far unpublished mutations, as well as two intronic variations, in addition to two known polymorphisms. PMID:14722913

Rundshagen, Uta; Zühlke, Christine; Opitz, Sven; Schwinger, Eberhard; Käsmann-Kellner, Barbara

2004-02-01

265

Amelogenin signal peptide mutation: Correlation between mutations in the amelogenin gene (AMGX) and manifestations of X-linked amelogenesis imperfecta  

SciTech Connect

Formation of tooth enamel is a poorly understood biological process. In this study the authors describe a 9-bp deletion in exon 2 of the amelogenin gene (AMGX) causing X-linked hypoplastic amelogenesis imperfecta, a disease characterized by defective enamel. The mutation results in the loss of 3 amino acids and exchange of 1 in the signal peptide of the amelogenin protein. This deletion in the signal peptide probably interferes with translocation of the amelogenin protein during synthesis, resulting in the thin enamel observed in affected members of the family. The authors compare this mutation to a previously reported mutation in the amelogenin gene that causes a different disease phenotype. The study illustrates that molecular analysis can help explain the various manifestations of a tooth disorder and thereby provide insights into the mechanisms of tooth enamel formation. 16 refs., 2 figs., 1 tab.

Lagerstroem-Fermer, M.; Nilsson, M.; Pettersson, U. [Univ. of Uppsala (Sweden)] [and others

1995-03-01

266

Splice Site Mutations in the P-Cadherin Gene Underlie Hypotrichosis with Juvenile Macular Dystrophy  

PubMed Central

Background Hypotrichosis with juvenile macular dystrophy (HJMD; OMIM 601553) is a rare autosomal recessive disorder characterized by hypotrichosis with short scalp hair and progressive macular dystrophy leading to blindness between the second and the fourth decades of life. HJMD is caused by mutations in the P-cadherin gene (CDH3), a member of the family of classical cadherins. Methods We analyzed the DNA from members of 2 consanguineous Pakistani families with HJMD for mutations in the P-cadherin gene through direct sequencing. Results We identified 2 splice site mutations in the P-cadherin gene in these families. One was a novel mutation, Ivs12-2A?G and the other a recurrent mutation, Ivs10-1G?T. A screening assay for the novel mutation ruled out the possibility of a polymorphism. Using haplotype analysis, we determined that the mutation, Ivs10-1G?T, is a founder mutation in the Pakistani population. Conclusion We identified 2 splice site mutations in the CDH3 gene leading to HJMD, further enriching our understanding of HJMD versus ectodermal dysplasia, ectrodactyly and macular dystrophy syndrome.

Shimomura, Y.; Wajid, M.; Kurban, M.; Christiano, A.M.

2010-01-01

267

Mutational Analysis of a Histone Deacetylase in Drosophila melanogaster: Missense Mutations Suppress Gene Silencing Associated With Position Effect Variegation  

Microsoft Academic Search

For many years it has been noted that there is a correlation between acetylation of histones and an increase in transcriptional activity. One prediction, based on this correlation, is that hypomorphic or null mutations in histone deacetylase genes should lead to increased levels of histone acetylation and result in increased levels of transcription. It was therefore surprising when it was

Randy Mottus; Richard E. Sobel; Thomas A. Grigliatti

2000-01-01

268

Gene amplification, mutation, and protein expression of EGFR and mutations of ERBB2 in serous ovarian carcinoma  

Microsoft Academic Search

EGFR and erbB-2 are targets for specific cancer therapy. The purpose of this study was to examine the frequency and clinicopathological correlations of gene amplification, protein expression, and mutations of EGFR and ERBB2 in serous carcinoma, the most common and aggressive type of ovarian cancer. Tissue microarray constructed of 398 carcinomas was examined by chromogenic in situ hybridization (CISH) and

Heini Lassus; Harri Sihto; Arto Leminen; Heikki Joensuu; Jorma Isola; Nina N. Nupponen; Ralf Butzow

2006-01-01

269

p53 gene mutations, p53 protein accumulation and compartmentalization in colorectal adenocarcinoma.  

PubMed Central

p53 accumulation may occur in the nucleus and/or cytoplasm of neoplastic cells. Cytoplasmic accumulation has been reported to be an unfavorable, but not established, prognostic indicator in colorectal cancer. Different types of p53 intracellular compartmentalization could depend either on p53 gene mutations or on the interaction with p53 protein ligands. The purposes of our study were (1) to assess whether the different patterns of p53 accumulation are selectively associated with p53 mutations and (2) to evaluate the clinical significance of p53 mutations in colorectal carcinomas. We evaluated p53 gene mutations in colorectal carcinomas. We evaluated p53 gene mutations in exons 5 through 8, by polymerase chain reaction and single-strand conformation polymorphism analysis; p53 accumulation and intracellular compartmentalization were detected immunocytochemically with the antibodies PAb1801 and CM1. p53 mutations were found in 74 of 126 carcinomas (59%). Nuclear p53PAb1801 accumulation was associated with p53 gene mutations (P < 0.001) whereas cytoplasmic p53 CM1 accumulation was more likely to occur with the wild-type p53 gene (P = 0.048). Overall, 112 carcinomas (89%) displayed p53 gene mutations and/or p53 accumulations of any type. p53 mutations were not correlated with important clinicopathological parameters and were not related to patient survival. Our data suggest that mechanisms other than mutations may also play a role in inhibiting p53 tumor-suppressing functions in colorectal carcinomas. Cytoplasmic p53CM1 accumulation frequently does not depend on p53 mutations. Images Figure 1

Bosari, S.; Viale, G.; Roncalli, M.; Graziani, D.; Borsani, G.; Lee, A. K.; Coggi, G.

1995-01-01

270

[Determination of K-ras gene mutation in colorectal cancer tissue by capillary electrophoresis].  

PubMed

The codons 12/13 of K-ras genomic DNA from 76 colorectal cancer tissues and normal tissues were amplified by PCR. The amplified 152 samples were purified, denatured, and then detected using capillary electrophoresis (CE)-laser induced fluorescence (LIF) with single-strand conformation polymorphism (SSCP). The abnormal samples were further confirmed by direct-sequencing. The 30 patients of the 76 colorectal cancer patients were found gene mutation, of which the results of base G --> A point mutation were confirmed by the gene sequence. To detect K-ras gene mutation that has important role in clinical forecast, diagnosis, therapy and prognosis, the CE-LIF with SSCP was applied for detecting K-ras gene. It becomes a promising tool to analyse K-ras gene mutation in the clinical diagnosis and therapy of colorectal cancer tissue. PMID:24063200

Shi, Dongqin; Wang, Rong; Xie, Hua; Tian, Wei; Jia, Zhengping; Guo, Jiankui

2013-06-01

271

Spectrum of mutations in the HFE gene implicated in haemochromatosis and porphyria.  

PubMed

Mutation analysis was performed on DNA samples of 965 individuals from four different ethnic groups in South Africa, in an attempt to determine the spectrum of sequence variants in the haemochromatosis ( HFE ) gene. This population screening approach, utilizing a combined heteroduplex and single-strand conformation polymorphism (HEX-SSCP) method, revealed three previously described and four novel missense mutations. Novel variants V53M and V59M were identified in exon 2, Q127H in exon 3 and R330M in exon 5. The exon 5 variant was identified in one of 13 patients referred for a molecular diagnosis of hereditary haemochromatosis (HH), who tested negative for the known C282Y and H63D mutations. Mutation Q127H was detected in exon 3 of the HFE gene together with mutation H63D in an apparently severely affected patient previously shown to carry the protoporphyrinogen oxidase ( PPOX ) gene mutation R59W, which accounts for dominantly inherited variegate porphyria (VP) in >80% of affected South Africans. The mutant allele frequency of the C282Y mutation was found to be significantly lower in 73 apparently unrelated VP patients with the R59W mutation than in 102 controls drawn from the same population ( P = 0.005). The population screening approach used in this study revealed considerable genotypic variation in the HFE gene and supports previous data on the involvement of this gene in the porphyria phenotype. PMID:10401000

de Villiers, J N; Hillermann, R; Loubser, L; Kotze, M J

1999-08-01

272

Excess of de novo deleterious mutations in genes associated with glutamatergic systems in nonsyndromic intellectual disability.  

PubMed

Little is known about the genetics of nonsyndromic intellectual disability (NSID). We hypothesized that de novo mutations (DNMs) in synaptic genes explain an important fraction of sporadic NSID cases. In order to investigate this possibility, we sequenced 197 genes encoding glutamate receptors and a large subset of their known interacting proteins in 95 sporadic cases of NSID. We found 11 DNMs, including ten potentially deleterious mutations (three nonsense, two splicing, one frameshift, four missense) and one neutral mutation (silent) in eight different genes. Calculation of point-substitution DNM rates per functional and neutral site showed significant excess of functional DNMs compared to neutral ones. De novo truncating and/or splicing mutations in SYNGAP1, STXBP1, and SHANK3 were found in six patients and are likely to be pathogenic. De novo missense mutations were found in KIF1A, GRIN1, CACNG2, and EPB41L1. Functional studies showed that all these missense mutations affect protein function in cell culture systems, suggesting that they may be pathogenic. Sequencing these four genes in 50 additional sporadic cases of NSID identified a second DNM in GRIN1 (c.1679_1681dup/p.Ser560dup). This mutation also affects protein function, consistent with structural predictions. None of these mutations or any other DNMs were identified in these genes in 285 healthy controls. This study highlights the importance of the glutamate receptor complexes in NSID and further supports the role of DNMs in this disorder. PMID:21376300

Hamdan, Fadi F; Gauthier, Julie; Araki, Yoichi; Lin, Da-Ting; Yoshizawa, Yuhki; Higashi, Kyohei; Park, A-Reum; Spiegelman, Dan; Dobrzeniecka, Sylvia; Piton, Amélie; Tomitori, Hideyuki; Daoud, Hussein; Massicotte, Christine; Henrion, Edouard; Diallo, Ousmane; Shekarabi, Masoud; Marineau, Claude; Shevell, Michael; Maranda, Bruno; Mitchell, Grant; Nadeau, Amélie; D'Anjou, Guy; Vanasse, Michel; Srour, Myriam; Lafreničre, Ronald G; Drapeau, Pierre; Lacaille, Jean Claude; Kim, Eunjoon; Lee, Jae-Ran; Igarashi, Kazuei; Huganir, Richard L; Rouleau, Guy A; Michaud, Jacques L

2011-03-03

273

Detection of Mutations in Genes Associated with Hearing Loss Using a Microarray-Based Approach  

PubMed Central

Knowing the etiology of hearing loss in a person has implications for counseling and management of the condition. More than 50% of cases of early onset, nonsyndromic sensorineural hearing loss are attributable to genetic factors. However, deafness is a genetically heterogeneous condition and it is therefore currently not economically and practically feasible to screen for mutations in all known deafness genes. We have developed a microarray-based hybridization biochip assay for the detection of known mutations. The current version of the hearing loss biochip detects nine common mutations in the connexin 26 gene, four mutations in the pendrin gene, one mutation in the usherin gene, and one mutation in mitochondrial DNA. The biochip was validated using DNA from 250 people with apparent nonsyndromic, moderate to profound sensorineural hearing loss. The hearing loss biochip detected with 100% accuracy the mutations it was designed for. No false-positives or false-negative results were seen. The biochip can easily be expanded to test for additional mutations in genes associated with hearing impairment or other genetic conditions.

Siemering, Kirby; Manji, Shehnaaz S.M.; Hutchison, Wendy M.; Du Sart, Desiree; Phelan, Dean; Dahl, Hans-Henrik M.

2006-01-01

274

Mutation spectrum of the fibrillin-1 (FBN1) gene in Taiwanese patients with Marfan syndrome.  

PubMed

The aim of this study was to establish a national database of mutations in the fibrillin-1 (FBN1) gene that cause Marfan syndrome (MFS) in the Taiwanese population. In this study, we screened 294 patients from 157 families for the presence of FBN1 mutations using polymerase chain reaction/ denaturing high performance liquid chromatography (PCR/DHPLC). We identified 56 mutations in 62 of the 157 (40%) families including 49 single-base substitutions (36 missense mutations, seven nonsense mutations, and six splicing sites), one small insertion, four small deletions, one small indel (insertion and deletion), and one exonic deletion (Exon 36). When family history was taken into consideration, the mutation detection rate rose to 91% (29 of 32). We further investigated the phenotypic data and found that one third (47 of 157) of the families fit the Ghent criteria for MFS. Based on that data, the mutation rate was 98% (46/47). That finding implies that family history and the Ghent criteria play a more important role than clinical manifestations in establishing a clinical diagnosis of Marfan syndrome. Among the 56 mutations found in this study, 40 (71%) have not been registered in the Human Gene Mutation Database (HGMD) or in the Universal Mutation Database (UMD). This is the first study of the mutation spectrum of MFS in a cohort of patients in Taiwan. The database is expected to considerably improve genetic counseling for and medical care of MFS families. PMID:19839986

Hung, Chia-Cheng; Lin, Shin-Yu; Lee, Chien-Nan; Cheng, Hui-Yu; Lin, Shuan-Pei; Chen, Ming-Ren; Chen, Chih-Ping; Chang, Chien-Hui; Lin, Chiou-Ya; Yu, Chih-Chieh; Chiu, Hsin-Hui; Cheng, Wen-Fang; Ho, Hong-Nerng; Niu, Dau-Ming; Su, Yi-Ning

2009-11-01

275

Sixteen novel mutations in the arylsulfatase A gene causing metachromatic leukodystrophy.  

PubMed

Metachromatic leukodystrophy (MLD) is a lysosomal storage disorder caused mainly by mutations in the arylsulfatase A (ARSA) gene. In this manuscript we report sixteen novel mutations identified in the ARSA gene of fifteen unrelated patients affected with MLD. Of these 16 mutations nine were missense mutations (p.L11Q, p.S44P, p.L81P, p.R84L, p.V177D, p.P284S, p.R288S, p.G301R, p.P425S), three were nonsense mutations (p.Q51X, p.Y149X, p.C156X), three were frame shift mutations (c.28delG, c.105C>A+106_124dup, c.189delC) and one was a splice-site mutation (c.1102-2A>G). In addition, three previously reported mutations were identified on an allelic background different from the one in the original reports. Two mutations, p.G309S and p.E312D, were identified on the background of the so-called pseudodeficiency (Pd) allele while previously they were reported alone. On the other hand, mutation p.R311X was identified in two unrelated patients not in cis with the Pd mutations, as previously reported. PMID:24001781

Luzi, Paola; Rafi, Mohammad A; Rao, Han Zhi; Wenger, David A

2013-08-31

276

Separation of mutational and transcriptional enhancers in immunoglobulin genes  

PubMed Central

Secondary immunoglobulin (Ig) gene diversification relies on activation-induced cytidine deaminase (AID) to create U:G mismatches that are subsequently fixed by mutagenic repair pathways. AID activity is focused to Ig loci by cis-regulatory DNA sequences named targeting elements. Here we show that in contrast to prevailing thought in the field, the targeting elements in the chicken IGL locus are distinct from classical transcriptional enhancers. These mutational enhancer elements (MEEs) are required over and above transcription to recruit AID-mediated mutagenesis to Ig loci. We identified a small 222 bp fragment in the chicken IGL locus that enhances mutagenesis without boosting transcription, and this sequence represents a key component of a MEE. Lastly, MEEs are evolutionarily conserved amongst birds, both in sequence and function, and contain several highly conserved sequence modules that are likely involved in recruiting trans-acting targeting factors. We propose that MEEs represent a novel class of cis-regulatory elements whose function is to control genomic integrity.

Kothapalli, Naga Rama; Collura, Kaitlin M.; Norton, Darrell D.; Fugmann, Sebastian D.

2011-01-01

277

Separation of mutational and transcriptional enhancers in Ig genes.  

PubMed

Secondary Ig gene diversification relies on activation-induced cytidine deaminase (AID) to create U:G mismatches that are subsequently fixed by mutagenic repair pathways. AID activity is focused to Ig loci by cis-regulatory DNA sequences named targeting elements. In this study, we show that in contrast to prevailing thought in the field, the targeting elements in the chicken IGL locus are distinct from classical transcriptional enhancers. These mutational enhancer elements (MEEs) are required over and above transcription to recruit AID-mediated mutagenesis to Ig loci. We identified a small 222-bp fragment in the chicken IGL locus that enhances mutagenesis without boosting transcription, and this sequence represents a key component of an MEE. Lastly, MEEs are evolutionarily conserved among birds, both in sequence and function, and contain several highly conserved sequence modules that are likely involved in recruiting trans-acting targeting factors. We propose that MEEs represent a novel class of cis-regulatory elements for which the function is to control genomic integrity. PMID:21844395

Kothapalli, Naga Rama; Collura, Kaitlin M; Norton, Darrell D; Fugmann, Sebastian D

2011-08-15

278

Functional dominant-negative mutation of sodium channel subunit gene SCN3B associated with atrial fibrillation in a Chinese GeneID population  

PubMed Central

Atrial fibrillation (AF) is the most common cardiac arrhythmia in the clinic, and accounts for more than 15% of strokes. Mutations in cardiac sodium channel ?, ?1 and ?2 subunit genes (SCN5A, SCN1B, and SCN2B) have been identified in AF patients. We hypothesize that mutations in the sodium channel ?3 subunit gene SCN3B are also associated with AF. To test this hypothesis, we carried out a large scale sequencing analysis of all coding exons and exon-intron boundaries of SCN3B in 477 AF patients (28.5% lone AF) from the GeneID Chinese Han population. A novel A130V mutation was identified in a 46 year-old patient with lone AF, and the mutation was absent in 500 controls. Mutation A130V dramatically decreased the cardiac sodium current density when expressed in HEK293/Nav1.5 stable cell line, but did not have significant effect on kinetics of activation, inactivation, and channel recovery from inactivation. When co-expressed with wild type SCN3B, the A130V mutant SCN3B negated the function of wild type SCN3B, suggesting that A130V acts by a dominant negative mechanism. Western blot analysis with biotinylated plasma membrane protein extracts revealed that A130V did not affect cell surface expression of Nav1.5 or SCN3B, suggesting that mutant A130V SCN3B may not inhibit sodium channel trafficking, instead may affect conduction of sodium ions due to its malfunction as an integral component of the channel complex. This study identifies the first AF-associated mutation in SCN3B, and suggests that mutations in SCN3B may be a new pathogenic cause of AF.

Wang, Pengyun; Yang, Qinbo; Wu, Xiaofen; Yang, Yanzong; Shi, Lisong; Wang, Chuchu; Wu, Gang; Xia, Yunlong; Yang, Bo; Zhang, Rongfeng; Xu, Chengqi; Cheng, Xiang; Li, Sisi; Zhao, Yuanyuan; Fu, Fenfen; Liao, Yuhua; Fang, Fang; Chen, Qiuyun; Tu, Xin; Wang, Qing K.

2010-01-01

279

Software and database for the analysis of mutations in the human LDL receptor gene.  

PubMed Central

The low-density lipoprotein receptor (LDLr) plays a pivotal role in cholesterol homeostasis. Mutations in the LDLr gene (LDLR), which is located on chromosome 19, cause familial hypercholesterolemia (FH), an autosomal dominant disorder characterized by severe hypercholesterolemia associated with premature coronary atherosclerosis. To date almost 300 mutations have been identified in the LDLR gene. To facilitate the mutational analysis of the LDLR gene, and promote the analysis of the relationship between genotype and phenotype, a software package along with a computerized database (currently listing 210 entries) have been created.

Varret, M; Rabes, J P; Collod-Beroud, G; Junien, C; Boileau, C; Beroud, C

1997-01-01

280

SurfaceomeDB: a cancer-orientated database for genes encoding cell surface proteins  

PubMed Central

Cell surface proteins (CSPs) are excellent targets for the development of diagnostic and therapeutic reagents, and it is estimated that 10–20% of all genes in the human genome encode CSPs. In an effort to integrate all data publicly available for genes encoding cell surface proteins, a database (SurfaceomeDB) was developed. SurfaceomeDB is a gene-centered portal containing different types of information, including annotation for gene expression, protein domains, somatic mutations in cancer, and protein-protein interactions for all human genes encoding CSPs. SurfaceomeDB was implemented as an integrative and relational database in a user-friendly web interface, where users can search for gene name, gene annotation, or keywords. There is also a streamlined graphical representation of all data provided and links to the most important data repositories and databases, such as NCBI, UCSC Genome Browser, and EBI.

de Souza, Jorge Estefano Santana; Galante, Pedro Alexandre Favoretto; de Almeida, Renan Valieris Bueno; da Cunha, Julia Pinheiro Chagas; Ohara, Daniel Takatori; Ohno-Machado, Lucila; Old, Lloyd J.; de Souza, Sandro Jose

2012-01-01

281

Targeted resequencing for analysis of clonal composition of recurrent gene mutations in chronic lymphocytic leukaemia.  

PubMed

Recurrent gene mutations contribute to the pathogenesis of chronic lymphocytic leukaemia (CLL). We developed a next-generation sequencing (NGS) platform to determine the genetic profile, intratumoural heterogeneity, and clonal structure of two independent CLL cohorts. TP53, SF3B1, and NOTCH1 were most frequently mutated (16·3%, 16·9%, 10·7%). We found evidence for subclonal mutations in 67·5% of CLL cases with mutations of cancer consensus genes. We observed selection of subclones and found initial evidence for convergent mutations in CLL. Our data suggest that assessment of (sub)clonal structure may need to be integrated into analysis of the mutational profile in CLL. PMID:24032483

Jethwa, Alexander; Hüllein, Jennifer; Stolz, Tatjana; Blume, Carolin; Sellner, Leopold; Jauch, Anna; Sill, Martin; Kater, Arnon P; Te Raa, G Doreen; Geisler, Christian; van Oers, Marinus; Dietrich, Sascha; Dreger, Peter; Ho, Anthony D; Paruzynski, Anna; Schmidt, Manfred; von Kalle, Christof; Glimm, Hanno; Zenz, Thorsten

2013-08-27

282

Mutations in the EXT1 and EXT2 genes in Spanish patients with multiple osteochondromas  

PubMed Central

Multiple osteochondromas is an autosomal dominant skeletal disorder characterized by the formation of multiple cartilage-capped tumours. Two causal genes have been identified, EXT1 and EXT2, which account for 65% and 30% of cases, respectively. We have undertaken a mutation analysis of the EXT1 and EXT2 genes in 39 unrelated Spanish patients, most of them with moderate phenotype, and looked for genotype-phenotype correlations. We found the mutant allele in 37 patients, 29 in EXT1 and 8 in EXT2. Five of the EXT1 mutations were deletions identified by MLPA. Two cases of mosaicism were documented. We detected a lower number of exostoses in patients with missense mutation versus other kinds of mutations. In conclusion, we found a mutation in EXT1 or in EXT2 in 95% of the Spanish patients. Eighteen of the mutations were novel.

Sarrion, P.; Sangorrin, A.; Urreizti, R.; Delgado, A.; Artuch, R.; Martorell, L.; Armstrong, J.; Anton, J.; Torner, F.; Vilaseca, M. A.; Nevado, J.; Lapunzina, P.; Asteggiano, C. G.; Balcells, S.; Grinberg, D.

2013-01-01

283

Mutations in the EXT1 and EXT2 genes in Spanish patients with multiple osteochondromas.  

PubMed

Multiple osteochondromas is an autosomal dominant skeletal disorder characterized by the formation of multiple cartilage-capped tumours. Two causal genes have been identified, EXT1 and EXT2, which account for 65% and 30% of cases, respectively. We have undertaken a mutation analysis of the EXT1 and EXT2 genes in 39 unrelated Spanish patients, most of them with moderate phenotype, and looked for genotype-phenotype correlations. We found the mutant allele in 37 patients, 29 in EXT1 and 8 in EXT2. Five of the EXT1 mutations were deletions identified by MLPA. Two cases of mosaicism were documented. We detected a lower number of exostoses in patients with missense mutation versus other kinds of mutations. In conclusion, we found a mutation in EXT1 or in EXT2 in 95% of the Spanish patients. Eighteen of the mutations were novel. PMID:23439489

Sarrión, P; Sangorrin, A; Urreizti, R; Delgado, A; Artuch, R; Martorell, L; Armstrong, J; Anton, J; Torner, F; Vilaseca, M A; Nevado, J; Lapunzina, P; Asteggiano, C G; Balcells, S; Grinberg, D

2013-01-01

284

Interacting genes that affect microtubule function in Drosophila melanogaster: Two classes of mutation revert the failure to complement between hay sup nc2 and mutations in tubulin genes  

SciTech Connect

The recessive male sterile mutation hay{sup nc2} of Drosophila melanogaster fails to complement certain {beta}{sub 2}-tubulin and {alpha}-tubulin mutations, suggesting that the haywire product plays a role in microtubule function, perhaps as a structural component of microtubules. The genetic interaction appears to require the presence of the aberrant product encoded by hay{sup nc2}, which may act as a structural poison. Based on this observation, the authors have isolated ten new mutations with EMS that revert the failure to complement between hay{sup nc2} and B2t{sup n}. The revertants tested behaved as intragenic mutations of hay in recombination tests, and feel into two phenotypic classes, suggesting two functional domains of the hay gene product. Some revertants were hemizygous viable and less severe than hay{sup nc2} in their recessive phenotype. These mutations might revert the poison by restoring the aberrant product encoded by the hay{sup nc2} allele to more wild-type function. Most of the revertants were recessive lethal mutations, indicating that the hay gene product is essential for viability. These more extreme mutations could revert the poison by destroying the ability of the aberrant haywire{sup nc2} product to interact structurally with microtubules. Flies heterozygous for the original hay{sup nc2} allele and an extreme revertant show defects in both the structure and the function of the male meiotic spindle.

Regan, C.L.; Fuller, M.T. (Univ. of Colorado, Boulder (USA))

1990-05-01

285

Mutations in the arginine-rich protein gene (ARP) in pancreatic cancer.  

PubMed

The ARP gene encodes a highly conserved arginine-rich protein from chromosomal band 3p21.1. At the cytogenetic level this region is frequently deleted in a variety of different solid tumors, although not in pancreatic cancer. We have reported the presence of a specific mutation (ATG50-->AGG) or deletion of codon 50 of the ARP gene in different tumor types (Shridhar et al., 1996, 1996a). In the present study, we have observed mutations involving codon 50 in 11 of 37 pancreatic tumors. The frequency of codon 50 mutation is roughly the same in pancreatic tumors as in the other types of tumors previously examined. In addition, we have detected mutations at codon 51 in multiple PCR subclones in two other pancreatic tumors. Mutations in the ARP gene are thus commonly observed in pancreatic cancer, as well as many other cancers. PMID:9174057

Shridhar, V; Rivard, S; Wang, X; Shridhar, R; Paisley, C; Mullins, C; Beirnat, L; Dugan, M; Sarkar, F; Miller, O J; Vaitkevicius, V K; Smith, D I

1997-05-01

286

A Common Founder Mutation in the EDA-A1 Gene in X-Linked Hypodontia  

PubMed Central

Background X-linked recessive hypohidrotic ectodermal dysplasia (XLHED; OMIM 305100) is a rare genodermatosis characterized clinically by developmental abnormalities affecting the teeth, hair and sweat glands. Mutations in the EDA-A1 gene have been associated with XLHED. Recently, mutations in the EDA-A1 gene have also been implicated in isolated X-linked recessive hypodontia (XLRH; OMIM 313500). Methods We analyzed the DNA from members of 3 unrelated Pakistani families with XLRH for mutations in the EDA-A1 gene through direct sequencing and performed haplotype analysis. Results We identified a common missense mutation in both families designated c.1091T?C (p.M364T). Haplotype analysis revealed that this is a founder mutation in the 3 families. Conclusion XLHED is a syndrome with variable clinical presentations that contain a spectrum of findings, including hypodontia. We suggest that XLRH should be grouped under XLHED as both share several phenotypic and genotypic similarities.

Kurban, Mazen; Michailidis, Eleni; Wajid, Muhammad; Shimomura, Yutaka; Christiano, Angela M.

2010-01-01

287

Mutations in the SLC3A1 transporter gene in cystinuria  

SciTech Connect

Cystinuria is an autosomal recessive disease characterized by the development of kidney stones. Guided by the identification of the SLC3A1 amino acid-transport gene on chromosome 2, we recently established genetic linkage of cystinuria to chromosome 2p in 17 families, without evidence for locus heterogeneity. Other authors have independently identified missense mutations in SLC3A1 in cystinuria patients. In this report we describe four additional cystinuria-associated mutations in this gene: a frameshift, a deletion, a transversion inducing a critical amino acid change, and a nonsense mutation. The latter stop codon was found in all of eight Ashkenazi Jewish carrier chromosomes examined. This report brings the number of disease-associated mutations in this gene to 10. We also assess the frequency of these mutations in our 17 cystinuria families. 24 refs., 4 figs., 1 tab.

Pras, E.; Raben, N.; Aksentijevich, I. [National Heart, Lung, and Blood Institute, Bethesda, MD (United States)] [and others

1995-06-01

288

KIT Gene Mutations and Copy Number in Melanoma Subtypes  

Microsoft Academic Search

Purpose:We recently identified a KIT exon11mutation in an anorectal melanoma of ap atient who had an excellent response to treatment with imatinib.To determine the frequency of KIT mutations across melanoma subtypes, we surveyed a large series of tumors. Experimental Design: One hundred eighty-nine melanomas were screened for mutations in KIT exons 11, 13, and 17. KIT copy number was assessed

Carol Beadling; F. Stephen Hodi; Claudia Le; Andrea Warrick; Janice Patterson; Ajia Town; Amy Harlow; Frank Cruz; Sharl Azar; Brian P. Rubin; Susan Muller; Rob West; Michael C. Heinrich; Christopher L. Corless

2008-01-01

289

Revisiting MSUD in Portuguese Gypsies: evidence for a founder mutation and for a mutational hotspot within the BCKDHA gene.  

PubMed

Maple syrup urine disease (MSUD) is a rare autosomal recessive disorder of branched-chain amino acid metabolism. In the context of the wide mutational spectrum known for this disease, a few common mutations have been described in populations where founder effects played a major role in modeling diversities. In Portugal, for instance, a high proportion of patients are of Gypsy origin and all share the same mutation (c.117delC-alpha; p.R40GfsX23), causing the neonatal severe form of MSUD. In this study, we used four microsatellite markers closely flanking the BCKDHA gene (E1alpha protein) to demonstrate that c.117delC-alpha is a founder mutation responsible for the high incidence of the disorder among Portuguese Gypsies. These results are of medical relevance since carrier tests and prenatal diagnosis can be offered to families at risk, particularly because the carrier frequency of c.117delC-alpha was estimated at 1.4% among the healthy Portuguese Gypsies from the South of the country. Finally we present evidence that the genomic region of the BCKDHA gene where c.117delC-alpha is located is likely a mutational hotspot, since recurrence of c.117delC-alpha was observed in two distinct population groups. PMID:19456321

Quental, Sofia; Gusmăo, Alfredo; Rodríguez-Pombo, Pilar; Ugarte, Magdalena; Vilarinho, Laura; Amorim, António; Prata, Maria J

2009-05-01

290

BRCA1 gene mutations in women with papillary serous carcinoma of the peritoneum  

Microsoft Academic Search

Objective: To compare BRCA1 mutations in papillary serous carcinoma of the peritoneum and papillary serous ovarian carcinoma.Methods: Germline DNA from 17 consecutive patients with peritoneal carcinoma was screened for mutations in the BRCA1 gene using single-strand conformation polymorphism analysis. Shifted DNA bands were sequenced. Patients with germline BRCA1 mutations were screened for allelic loss in tumor DNA at the BRCA1

ChristinaA Bandera; MichaelG Muto; JohnO Schorge; RossS Berkowitz; StephenC Rubin; SamuelC Mok

1998-01-01

291

Analysis of NPM1 Gene Mutations in Chinese Adults with Acute Myeloid Leukemia  

Microsoft Academic Search

Many European groups have recently described that mutations at exon-12 of the nucleophosmin (NPM1) gene are the most frequent\\u000a genetic lesion in patients with acute myeloid leukemia (AML), especially in the presence of a normal karyotype. This study\\u000a explored the prevalence and clinical profile of NPM1 mutations in a cohort of 156 Chinese adults with AML. NPM1 exon-12 mutations\\u000a were

Lingzhi Yan; Suning Chen; Jianying Liang; Yufeng Feng; Jiannong Cen; Jun He; Weirong Chang; Ziling Zhu; Jinlan Pan; Yafang Wu; Yongquan Xue; Depei Wu

2007-01-01

292

Mutational analysis of Btk, the defective gene in X-linked agammaglobulinemia  

Microsoft Academic Search

Recent studies have shown that X-linked agammaglobulinemia (XLA), a disorder of B cell development, is due to mutations in an scr-like cytoplasmic tyrosine kinase, Btk. Thus far, mutations in this gene have been identified by sequencing of cDNA. To permit the detection of mutations in genomic DNA, we determined the structure of Btk and identified 19 exons in 37 kb

M. E. Conley; M. E. Fitch-Hilgenberg; J. Rohrer

1994-01-01

293

Characterization of Two Novel Missense Mutations in the AQP2 Gene Causing Nephrogenic Diabetes Insipidus  

Microsoft Academic Search

Here, we report the aquaporin 2 (AQP2) mutational analysis of a patient with nephrogenic diabetes insipidus heterozygote due to two novel missense mutations. Direct sequencing of DNA in the male patient revealed that he was compound heterozygote for two mutations in the AQP2 gene: a thymine-to-adenine transversion at position 450 (c.450T>A) in exon 2 and a guanine-to-thymine at nucleotide position

Achille Iolascon; Veruska Aglio; Grazia Tamma; Maria D’Apolito; Francesco Addabbo; Giuseppe Procino; Maria Carmela Simonetti; Giovanni Montini; Loreto Gesualdo; Erik W. Debler; Maria Svelto; Giovanna Valenti

2007-01-01

294

Detection of a New TIGR Gene Mutation in a Japanese Family With Primary Open Angle Glaucoma  

Microsoft Academic Search

Purpose: To describe a new mutation of the trabecular meshwork-inducible glucocorticoid response protein (TIGR) gene in a Japanese patient with familial primary open angle glaucoma (POAG).Methods: Standard ocular examinations were performed on the 44-year-old patient, his sister, and mother. DNA sequencing was used to identify the mutation. We also developed a DNA diagnostic method for detecting this missense mutation by

Akiko Yokoyama; Nobuhisa Nao-i; Yukari Date; Masamitu Nakazato; Hideki Chumann; Etsuo Chihara; Atsushi Sawada; Shigeru Matsukura

1999-01-01

295

Two Novel Missense Mutations in the Connexin 26 Gene in Turkish Patients with Nonsyndromic Hearing Loss  

Microsoft Academic Search

Most nonsyndromic hearing losses are caused by mutations in the GJB2 gene, and studies have revealed that the forms and frequencies of these mutations are largely dependent on ethnic origin.\\u000a In the present study, we aimed to characterize the mutation profiles of 151 patients with hearing loss in Turkey. The entire\\u000a coding region of the GJB2 was directly sequenced in

Akin Yilmaz; Sevda Menevse; Yildirim Bayazit; Recep Karamert; Volkan Ergin; Adnan Menevse

2010-01-01

296

[Mutations of noncollagen genes in osteogenesis imperfecta--implications of the gene products in collagen biosynthesis and pathogenesis of disease].  

PubMed

 Recent investigations revealed that the "brittle bone" phenotype in osteogenesis imperfecta (OI) is caused not only by dominant mutations in collagen type I genes, but also by recessively inherited mutations in genes responsible for the post-translational processing of type I procollagen as well as for bone formation. The phenotype of patients with mutations in noncollagen genes overlaps with very severe type III and lethal type II OI caused by mutations in collagen genes. Mutations in genes that encode proteins involved in collagen prolyl 3-hydroxylation (P3H1/CRTAP/CyPB) eliminated Pro986 hydroxylation and caused an increase in modification of collagen helix by prolyl 4-hydroxylase and lysyl hydroxylase. However, the importance of these disturbances in the disease pathomechanism is not known. Loss of complex proteins' function as collagen chaperones may dominate the disease mechanism. The latest findings added to the spectrum of OI-causing and collagen-influencing factors other chaperones (HSP47 and FKBP65) and protein BMP-1, which emphasizes the complexity of collagen folding and secretion as well as their importance in bone formation. Furthermore, mutations in genes encoding transcription factor SP7/Osterix and pigment epithelium-derived factor (PEDF) constitute a novel mechanism for OI, which is independent of changes in biosynthesis and processing of collagen. PMID:22706122

Galicka, Anna

2012-06-14

297

Differences in the evolutionary history of disease genes affected by dominant or recessive mutations  

Microsoft Academic Search

BACKGROUND: Global analyses of human disease genes by computational methods have yielded important advances in the understanding of human diseases. Generally these studies have treated the group of disease genes uniformly, thus ignoring the type of disease-causing mutations (dominant or recessive). In this report we present a comprehensive study of the evolutionary history of autosomal disease genes separated by mode

Simon J Furney; M Mar Albŕ; Núria López-Bigas

2006-01-01

298

Consequences of Marfan mutations to expression of fibrillin gene and to the structure of microfibrils  

SciTech Connect

Marfan syndrome (MFS) is a dominantly inherited connective tissue disorder which is caused by mutations in the fibrillin-1 gene (FBN1). Over 40 family-specific FBN1 mutations have been identified. We have characterized 18 different heterozygous mutations including amino acid substitutions, premature stop, and splicing defects leading to deletions or one insertion, and one compound heterozygote with two differently mutated FBN1 alleles inherited from his affected parents. To unravel the consequences of FBN1 mutations to the transcription of FBN1 gene, we have measured the steady state levels of mRNA transcribed from the normal and mutated alleles. The missense mutations do not affect the transcription of the allele while the nonsense mutation leads to lower steady state amount of mutated allele. For the dissection of molecular pathogenesis of FBN1 mutations we have performed rotary shadowing of the microfibrils produced by the cell cultures from MFS patients. The cells from the neonatal patients with established mutations produced only disorganized fibrillin aggregates but no clearly defined microfibrils could be detected, suggesting a major role of this gene region coding for exons 24-26 in stabilization and organization of the bead structure of microfibrils. From the cells of a rare compound heterozygote case carrying two different mutations, no detectable microfibrils could be detected whereas the cells of his parents with heterozygous mutations were able to form identifiable but disorganized microfibrils. In the cells of an MFS case caused by a premature stop removing the C-terminus of fibrillin, the microfibril assembly takes place but the appropriate packing of the microfibrils is disturbed suggesting that C-terminae are actually located within the interbead domain of the microfibrils.

Peltonen, L.; Karttunen, L.; Rantamaeki, T. [NPHI, Helsinki (Finland)] [and others

1994-09-01

299

Evolutionary pattern of mutation in the factor IX genes of great apes: How does it compare to the pattern of recent germline mutation in patients with hemophilia B?  

Microsoft Academic Search

Most mutations causing hemophilia B have arisen within the past 150 years. By correcting for multiple biases, the underlying rates of spontaneous germline mutation have been estimated in the factor IX gene. From these rates, an underlying pattern of mutation has emerged. To determine if this pattern compares to a underlying pattern found in the great apes, sequence changes were

L. H. Grouse; R. P. Ketterling; S. S. Sommer

1994-01-01

300

Mutation detection in the aspartoacylase gene in 17 patients with Canavan disease: four new mutations in the non-Jewish population  

Microsoft Academic Search

Canavan disease is a severe progressive autosomal recessive disorder, which is characterised by spongy degeneration of the brain. The disease is caused by mutations in the aspartoacylase gene. Two different mutations were reported on 98% of the alleles of Ashkenazi Jewish patients, in which population the disease is highly prevalent. In non-Jewish patients of European origin, one mutation (914C >

Erik A Sistermans; René FM de Coo; Hetty M van Beerendonk; Bwee Tien Poll-The; Wim J Kleijer; Bernard A van Oost

2000-01-01

301

p53 gene mutation analysis in tumors of patients exposed to alpha-particles.  

PubMed

The p53 gene was examined for point mutations in archived, alpha-radiation-associated lung and liver cancers. Lung tumors of 50 uranium miners in Germany were screened by restriction fragment length analysis for the putative hotspot mutation at codon 249 (Arg-->Met) previously detected in a significant fraction of miners from the Colorado Plateau, USA. This mutation has been proposed as a marker of radon exposure. None of the tumors we examined harbored the hotspot mutation. Five of the 50 tumors, however, did indeed harbor exon 7 mutations, as determined by subsequent mutation analysis of exon 7. These mutations were dispersed among various codons and may be attributable to heavy tobacco smoking in this cohort. In support of this interpretation, we found no mutations in exons 5-8 of the p53 gene in 13 iatrogenic liver cancers induced by injection of Thorotrast, an alpha-emitting radiocontrast agent. We propose that if the p53 tumor suppressor gene is a target for the carcinogenic action of alpha-particle radiation, loss of suppressor function may occur preferentially by mechanisms such as intrachromosomal deletions, rather than by base substitution mutations. PMID:9067550

Hollstein, M; Bartsch, H; Wesch, H; Kure, E H; Mustonen, R; Mühlbauer, K R; Spiethoff, A; Wegener, K; Wiethege, T; Müller, K M

1997-03-01

302

Recessive mutations in the INS gene result in neonatal diabetes through reduced insulin biosynthesis  

PubMed Central

Heterozygous coding mutations in the INS gene that encodes preproinsulin were recently shown to be an important cause of permanent neonatal diabetes. These dominantly acting mutations prevent normal folding of proinsulin, which leads to beta-cell death through endoplasmic reticulum stress and apoptosis. We now report 10 different recessive INS mutations in 15 probands with neonatal diabetes. Functional studies showed that recessive mutations resulted in diabetes because of decreased insulin biosynthesis through distinct mechanisms, including gene deletion, lack of the translation initiation signal, and altered mRNA stability because of the disruption of a polyadenylation signal. A subset of recessive mutations caused abnormal INS transcription, including the deletion of the C1 and E1 cis regulatory elements, or three different single base-pair substitutions in a CC dinucleotide sequence located between E1 and A1 elements. In keeping with an earlier and more severe beta-cell defect, patients with recessive INS mutations had a lower birth weight (?3.2 SD score vs. ?2.0 SD score) and were diagnosed earlier (median 1 week vs. 10 weeks) compared to those with dominant INS mutations. Mutations in the insulin gene can therefore result in neonatal diabetes as a result of two contrasting pathogenic mechanisms. Moreover, the recessively inherited mutations provide a genetic demonstration of the essential role of multiple sequence elements that regulate the biosynthesis of insulin in man.

Garin, Intza; Edghill, Emma L.; Akerman, Ildem; Rubio-Cabezas, Oscar; Rica, Itxaso; Locke, Jonathan M.; Maestro, Miguel Angel; Alshaikh, Adnan; Bundak, Ruveyde; del Castillo, Gabriel; Deeb, Asma; Deiss, Dorothee; Fernandez, Juan M.; Godbole, Koumudi; Hussain, Khalid; O'Connell, Michele; Klupa, Thomasz; Kolouskova, Stanislava; Mohsin, Fauzia; Perlman, Kusiel; Sumnik, Zdenek; Rial, Jose M.; Ugarte, Estibaliz; Vasanthi, Thiruvengadam; Johnstone, Karen; Flanagan, Sarah E.; Martinez, Rosa; Castano, Carlos; Patch, Ann-Marie; Fernandez-Rebollo, Eduardo; Raile, Klemens; Morgan, Noel; Harries, Lorna W.; Castano, Luis; Ellard, Sian; Ferrer, Jorge; de Nanclares, Guiomar Perez; Hattersley, Andrew T.

2010-01-01

303

Mutations in planar cell polarity gene SCRIB are associated with spina bifida.  

PubMed

Neural tube defects (NTDs) (OMIM #182940) including anencephaly, spina bifida and craniorachischisis, are severe congenital malformations that affect 0.5-1 in 1,000 live births in the United States, with varying prevalence around the world. Mutations in planar cell polarity (PCP) genes are believed to cause a variety of NTDs in both mice and humans. SCRIB is a PCP-associated gene. Mice that are homozygous for the Scrib p.I285K and circletail (Crc) mutations, present with the most severe form of NTDs, namely craniorachischisis. A recent study reported that mutations in SCRIB were associated with craniorachischisis in humans, but whether SCRIB mutations contribute to increased spina bifida risk is still unknown. We sequenced the SCRIB gene in 192 infants with spina bifida and 190 healthy controls. Among the spina bifida patients, we identified five novel missense mutations that were predicted-to-be-deleterious by the PolyPhen software. Of these five mutations, three of them (p.P1043L, p.P1332L, p.L1520R) significantly affected the subcellular localization of SCRIB. In addition, we demonstrated that the craniorachischisis mouse line-90 mutation I285K, also affected SCRIB subcellular localization. In contrast, only one novel missense mutation (p.A1257T) was detected in control samples, and it was predicted to be benign. This study demonstrated that rare deleterious mutations of SCRIB may contribute to the multifactorial risk for human spina bifida. PMID:23922697

Lei, Yunping; Zhu, Huiping; Duhon, Cody; Yang, Wei; Ross, M Elizabeth; Shaw, Gary M; Finnell, Richard H

2013-07-26

304

An analysis of substitution, deletion and insertion mutations in cancer genes  

PubMed Central

Cancer-associated mutations in cancer genes constitute a diverse set of mutations associated with the disease. To gain insight into features of the set, substitution, deletion and insertion mutations were analysed at the nucleotide level, from the COSMIC database. The most frequent substitutions were c?t, g?a, g?t, and the most frequent codon changes were to termination codons. Deletions more than insertions, FS (frameshift) indels more than I-F (in-frame) ones, and single-nucleotide indels, were frequent. FS indels cause loss of significant fractions of proteins. The 5?-cut in FS deletions, and 5?-ligation in FS insertions, often occur between pairs of identical bases. Interestingly, the cut-site and 3?-ligation in insertions, and 3?-cut and join-pair in deletions, were each found to be the same significantly often (p?mutations. Tumor suppressors undergo larger numbers of mutations, especially disruptive ones, over the entire protein length, to inactivate two alleles. Proto-oncogenes undergo fewer, less-disruptive mutations, in selected protein regions, to activate a single allele. Finally, catalogues, in ranked order, of genes mutated in each cancer, and cancers in which each gene is mutated, were created. The study highlights the nucleotide level preferences and disruptive nature of cancer mutations.

Iengar, Prathima

2012-01-01

305

Mutations in Planar Cell Polarity Gene SCRIB Are Associated with Spina Bifida  

PubMed Central

Neural tube defects (NTDs) (OMIM #182940) including anencephaly, spina bifida and craniorachischisis, are severe congenital malformations that affect 0.5–1 in 1,000 live births in the United States, with varying prevalence around the world. Mutations in planar cell polarity (PCP) genes are believed to cause a variety of NTDs in both mice and humans. SCRIB is a PCP-associated gene. Mice that are homozygous for the Scrib p.I285K and circletail (Crc) mutations, present with the most severe form of NTDs, namely craniorachischisis. A recent study reported that mutations in SCRIB were associated with craniorachischisis in humans, but whether SCRIB mutations contribute to increased spina bifida risk is still unknown. We sequenced the SCRIB gene in 192 infants with spina bifida and 190 healthy controls. Among the spina bifida patients, we identified five novel missense mutations that were predicted-to-be-deleterious by the PolyPhen software. Of these five mutations, three of them (p.P1043L, p.P1332L, p.L1520R) significantly affected the subcellular localization of SCRIB. In addition, we demonstrated that the craniorachischisis mouse line-90 mutation I285K, also affected SCRIB subcellular localization. In contrast, only one novel missense mutation (p.A1257T) was detected in control samples, and it was predicted to be benign. This study demonstrated that rare deleterious mutations of SCRIB may contribute to the multifactorial risk for human spina bifida.

Lei, Yunping; Zhu, Huiping; Duhon, Cody; Yang, Wei; Ross, M. Elizabeth; Shaw, Gary M.; Finnell, Richard H.

2013-01-01

306

Further evidence of mutational heterogeneity of the XPC gene in Tunisian families: a spectrum of private and ethnic specific mutations.  

PubMed

Xeroderma Pigmentosum (XP) is a rare recessive autosomal cancer prone disease, characterized by UV hypersensitivity and early appearance of cutaneous and ocular malignancies. We investigated four unrelated patients suspected to be XP-C. To confirm linkage to XPC gene, genotyping and direct sequencing of XPC gene were performed. Pathogenic effect of novel mutations was confirmed by reverse Transciptase PCR. Mutation screening revealed the presence of two novel mutations g.18246G>A and g.18810G>T in the XPC gene (NG_011763.1). The first is present in one patient XP50NEF, but the second is present in three unrelated patients (XP16KEB, XP28SFA, and XP45GB). These 3 patients are from three different cities of Southern Tunisia and bear the same haplotype, suggesting a founder effect. Reverse Transciptase PCR revealed the absence of the XPC mRNA. In Tunisia, as observed in an other severe genodermatosis, the mutational spectrum of XP-C group seems to be homogeneous with some clusters of heterogeneity that should be taken into account to improve molecular diagnosis of this disease. PMID:23984341

Ben Rekaya, Mariem; Jerbi, Manel; Messaoud, Olfa; Ben Brick, Ahlem Sabrine; Zghal, Mohamed; Mbarek, Chiraz; Chadli-Debbiche, Ashraf; Jones, Meriem; Mokni, Mourad; Boussen, Hamouda; Boubaker, Mohamed Samir; Fazaa, Becima; Yacoub-Youssef, Houda; Abdelhak, Sonia

2013-07-25

307

Further Evidence of Mutational Heterogeneity of the XPC Gene in Tunisian Families: A Spectrum of Private and Ethnic Specific Mutations  

PubMed Central

Xeroderma Pigmentosum (XP) is a rare recessive autosomal cancer prone disease, characterized by UV hypersensitivity and early appearance of cutaneous and ocular malignancies. We investigated four unrelated patients suspected to be XP-C. To confirm linkage to XPC gene, genotyping and direct sequencing of XPC gene were performed. Pathogenic effect of novel mutations was confirmed by reverse Transciptase PCR. Mutation screening revealed the presence of two novel mutations g.18246G>A and g.18810G>T in the XPC gene (NG_011763.1). The first is present in one patient XP50NEF, but the second is present in three unrelated patients (XP16KEB, XP28SFA, and XP45GB). These 3 patients are from three different cities of Southern Tunisia and bear the same haplotype, suggesting a founder effect. Reverse Transciptase PCR revealed the absence of the XPC mRNA. In Tunisia, as observed in an other severe genodermatosis, the mutational spectrum of XP-C group seems to be homogeneous with some clusters of heterogeneity that should be taken into account to improve molecular diagnosis of this disease.

Ben Rekaya, Mariem; Jerbi, Manel; Messaoud, Olfa; Ben Brick, Ahlem Sabrine; Zghal, Mohamed; Mbarek, Chiraz; Chadli-Debbiche, Ashraf; Mokni, Mourad; Boussen, Hamouda; Boubaker, Mohamed Samir; Fazaa, Becima; Yacoub-Youssef, Houda; Abdelhak, Sonia

2013-01-01

308

Founder mutations in the lipase h gene in families with autosomal recessive woolly hair/hypotrichosis.  

PubMed

Autosomal-recessive woolly hair (ARWH)/hypotrichosis is a hereditary hair disorder which is characterized by tightly curled hair and is associated with sparse hair. ARWH can be caused by mutations in the P2RY5 or lipase H (LIPH) gene. Disruption of either gene results in phenotypes with features of both wooly hair (WH) and hypotrichosis. In this study, we identified two Guyanese families with ARWH. Both families are of recent Indian descent. Mutation analysis resulted in the identification of mutations in the LIPH gene in both families. Affected individuals in the first family carry compound heterozygous mutations Ex7_8del and 1303_1309dupGAAAACG in the LIPH gene, while those in the second family have a homozygous mutation 659_660delTA in the LIPH gene. The mutations Ex7_8del and 659_660delTA were identified earlier in several Pakistani families with ARWH. Haplotype analysis using microsatellite markers close to the LIPH gene defined a founder haplotype shared in families from Pakistan and Guyana. Proteomic analysis of hair shaft samples from one of the families revealed no substantial changes among the proteins identified, indicating that the syndrome does not involve global alterations in protein expression. Our results further suggest a crucial role of LIPH gene in hair growth. PMID:19262606

Shimomura, Yutaka; Wajid, Muhammad; Zlotogorski, Abraham; Lee, Young-Jin; Rice, Robert H; Christiano, Angela M

2009-03-05

309

UV and Skin Cancer: Specific p53 Gene Mutation in Normal Skin as a Biologically Relevant Exposure Measurement  

Microsoft Academic Search

Many human skin tumors contain mutated p53 genes that probably result from UV exposure. To investigate the link between UV exposure and p53 gene mutation, we developed two methods to detect presumptive UV-specific p53 gene mutations in UV-exposed normal skin. The methods are based on mutant allele-specific PCRs and ligase chain reactions and designed to detect CC to TT mutations

Hisayoshi Nakazawa; Dallas English; Peter L. Randell; Keiko Nakazawa; Nicole Martel; Bruce K. Armstrong; Hiroshi Yamasaki

1994-01-01

310

Screening of 38 genes identifies mutations in 62% of families with nonsyndromic deafness in Turkey.  

PubMed

More than 60% of prelingual deafness is genetic in origin, and of these up to 95% are monogenic autosomal recessive traits. Causal mutations have been identified in 1 of 38 different genes in a subset of patients with nonsyndromic autosomal recessive deafness. In this study, we screened 49 unrelated Turkish families with at least three affected children born to consanguineous parents. Probands from all families were negative for mutations in the GJB2 gene, two large deletions in the GJB6 gene, and the 1555A>G substitution in the mitochondrial DNA MTRNR1 gene. Each family was subsequently screened via autozygosity mapping with genomewide single-nucleotide polymorphism arrays. If the phenotype cosegregated with a haplotype flanking one of the 38 genes, mutation analysis of the gene was performed. We identified 22 different autozygous mutations in 11 genes, other than GJB2, in 26 of 49 families, which overall explains deafness in 62% of families. Relative frequencies of genes following GJB2 were MYO15A (9.9%), TMIE (6.6%), TMC1 (6.6%), OTOF (5.0%), CDH23 (3.3%), MYO7A (3.3%), SLC26A4 (1.7%), PCDH15 (1.7%), LRTOMT (1.7%), SERPINB6 (1.7%), and TMPRSS3 (1.7%). Nineteen of 22 mutations are reported for the first time in this study. Unknown rare genes for deafness appear to be present in the remaining 23 families. PMID:21117948

Duman, Duygu; Sirmaci, Asli; Cengiz, F Basak; Ozdag, Hilal; Tekin, Mustafa

2010-11-30

311

Gene expression profiling and candidate gene resequencing identifies pathways and mutations important for malignant transformation caused by leukemogenic fusion genes.  

PubMed

NUP98-HOXD13 (NHD13) and CALM-AF10 (CA10) are oncogenic fusion proteins produced by recurrent chromosomal translocations in patients with acute myeloid leukemia (AML). Transgenic mice that express these fusions develop AML with a long latency and incomplete penetrance, suggesting that collaborating genetic events are required for leukemic transformation. We employed genetic techniques to identify both preleukemic abnormalities in healthy transgenic mice as well as collaborating events leading to leukemic transformation. Candidate gene resequencing revealed that 6 of 27 (22%) CA10 AMLs spontaneously acquired a Ras pathway mutation and 8 of 27 (30%) acquired an Flt3 mutation. Two CA10 AMLs acquired an Flt3 internal-tandem duplication, demonstrating that these mutations can be acquired in murine as well as human AML. Gene expression profiles revealed a marked upregulation of Hox genes, particularly Hoxa5, Hoxa9, and Hoxa10 in both NHD13 and CA10 mice. Furthermore, mir196b, which is embedded within the Hoxa locus, was overexpressed in both CA10 and NHD13 samples. In contrast, the Hox cofactors Meis1 and Pbx3 were differentially expressed; Meis1 was increased in CA10 AMLs but not NHD13 AMLs, whereas Pbx3 was consistently increased in NHD13 but not CA10 AMLs. Silencing of Pbx3 in NHD13 cells led to decreased proliferation, increased apoptosis, and decreased colony formation in vitro, suggesting a previously unexpected role for Pbx3 in leukemic transformation. PMID:22885519

Novak, Rachel L; Harper, David P; Caudell, David; Slape, Christopher; Beachy, Sarah H; Aplan, Peter D

2012-08-08

312

High Incidence of Hemochromatosis Gene Mutations in the Myelodysplastic Syndrome: The Budapest Study on 50 Patients  

Microsoft Academic Search

Genotypic testing of nonselected patients with the myelodysplastic syndrome (MDS) for the C282Y and H63D mutations of the HFE gene responsible for hereditary hemochromatosis revealed a significantly increased frequency of these mutations when compared to healthy blood donors reflecting the average population. Among the 50 patients examined [26 refractory anemia (RA), 9 refractory anemia with ring sideroblasts (RARS), 2 refractory

Judit Várkonyi; Gábor Tarkovács; István Karádi; Hajnalka Andrikovics; Ferenc Varga; Fatime Varga; Judit Demeter; Attila Tordai

2003-01-01

313

Familial Congenital Hypothyroidism Caused by Abnormal and Bioinactive TSH due to Mutations in the ?-Subunit Gene  

Microsoft Academic Search

Hereditary TSH deficiency is a rare autosomal recessive disease described in inbred Japanese families and in Greek and Brazilian kindreds. The TSH-?-subunit gene has been shown to be the site of mutations that will give rise to truncated proteins that cannot dimerize with the ? subunit or, alternatively, will produce a mutated TSH that is present in the circulation of

Geraldo Medeiros-Neto; Luiz de Lacerda; Fredric E. Wondisford

1997-01-01

314

A mutation in CTSK gene in an autosomal recessive pycnodysostosis family of Pakistani origin  

Microsoft Academic Search

BACKGROUND: Pycnodysostosis is a rare autosomal recessive skeletal dysplasia characterized by short stature, osteosclerosis, acro-osteolysis, frequent fractures and skull deformities. Mutations in the gene encoding cathepsin K (CTSK), a lysosomal cysteine protease, have been found to be responsible for this disease. OBJECTIVES: To identify pathogenic mutation in a consanguineous Pakistani family with 3 affected individuals demonstrating autosomal recessive pycnodysostosis. METHODS:

Muhammad Naeem; Sabeen Sheikh; Wasim Ahmad

2009-01-01

315

Chemical treatment enhances skipping of a mutated exon in the dystrophin gene  

Microsoft Academic Search

Duchenne muscular dystrophy (DMD) is a fatal muscle wasting disease caused by a loss of the dystrophin protein. Control of dystrophin mRNA splicing to convert severe DMD to a milder phenotype is attracting much attention. Here we report a dystrophinopathy patient who has a point mutation in exon 31 of the dystrophin gene. Although the mutation generates a stop codon,

Atsushi Nishida; Naoyuki Kataoka; Yasuhiro Takeshima; Mariko Yagi; Hiroyuki Awano; Mitsunori Ota; Kyoko Itoh; Masatoshi Hagiwara; Masafumi Matsuo

2011-01-01

316

Mutational hot spot in the p53 gene in human hepatocellular carcinomas  

Microsoft Academic Search

HUMAN hepatocellular carcinomas (HCC) from patients in Qidong, an area of high incidence in China, in which both hepatitis B virus and aflatoxin B1 are risk factors1, were analysed for mutations in p53, a putative tumour-suppressor gene. Eight of the 16 HCC had a point mutation at the third base position of codon 249. The G --> T transversion in

I. C. Hsu; R. A. Metcalf; T. Sun; J. A. Welsh; N. J. Wang; C. C. Harris

1991-01-01

317

Frequency and clinical characteristics of dilated cardiomyopathy caused by desmin gene mutation in a Japanese population  

Microsoft Academic Search

Aims Dilated cardiomyopathy is partly caused by a muta- tion of some cytoskeletal or nuclear envelope proteins. It has been confirmed recently that a missense mutation of the gene encoding desmin, a cytoskeletal protein, can cause dilated cardiomyopathy. This study was aimed at elucidat- ing the frequency and clinical characteristics of dilated cardiomyopathy caused by desmin mutation. Methods and Results

Y. Miyamoto; H. Akita; N. Shiga; E. Takai; C. Iwai; K. Mizutani; H. Kawai; A. Takarada; M. Yokoyama

2001-01-01

318

Clinical and Biological Features Associated With Epidermal Growth Factor Receptor Gene Mutations in Lung Cancers  

Microsoft Academic Search

Background: Mutations in the tyrosine kinase (TK) domain of the epidermal growth factor receptor (EGFR) gene in lung cancers are associated with increased sensitivity of these can- cers to drugs that inhibit EGFR kinase activity. However, the role of such mutations in the pathogenesis of lung cancers is unclear. Methods: We sequenced exons 18 - 21 of the EGFR TK

Hisayuki Shigematsu; Li Lin; Takao Takahashi; Masaharu Nomura; Makoto Suzuki; Ignacio I. Wistuba; Kwun M. Fong; Huei Lee; Shinichi Toyooka; Nobuyoshi Shimizu; Takehiko Fujisawa; Ziding Feng; Jack A. Roth; Joachim Herz; John D. Minna; Adi F. Gazdar

319

Deleting a Single Protein Restores Critical DNA Repair Process in Mice with BRCA1 Gene Mutations  

Cancer.gov

By eliminating a single protein, researchers restored a critical DNA repair process that is deficient in mice with mutations in the BRCA1 breast cancer susceptibility gene, thereby dramatically reducing the risk of cancer in these mice. These results suggest that it may one day be possible to restore the same DNA repair process and reduce cancer risk in women with BRCA1 mutations.

320

Mutations in short stature homeobox containing gene ( SHOX ) in dyschondrosteosis but not in hypochondroplasia  

Microsoft Academic Search

Dyschondrosteosis (DCO) and hypochondroplasia (HCH) are common skeletal dysplasias characterized by disproportionate short stature. The diagnosis of these conditions might be difficult to establish especially in early childhood. Point mutations and deletions of the short stature homeobox containing gene (SHOX) are detected in DCO and idiopathic short stature with some rhizomelic body disproportion, whereas mutations in the fibroblast growth factor

Giedre Grigelioniene; Ole Eklöf; Sten Anders Ivarsson; Otto Westphal; Lo Neumeyer; Darek Kedra; Jan Dumanski; Lars Hagenäs

2000-01-01

321

Mutations in the human SIX3 gene in holoprosencephaly are loss of function  

Microsoft Academic Search

Holoprosencephaly (HPE) is the most common developmental anomaly of the human forebrain; however, the genetics of this heterogeneous and etiologically complex malformation is incompletely understood. Heterozygous mutations in SIX3, a transcription factor gene expressed in the anterior forebrain and eyes during early vertebrate development, have been frequently detected in human HPE cases. However, only a few mutations have been investigated

Sabina Domene ´; Erich Roessler; Kenia B. El-Jaick; Mirit Snir; Jamie L. Brown; Jorge I. Velez; Sherri Bale; Felicitas Lacbawan; Maximilian Muenke; Benjamin Feldman

2008-01-01

322

Mutations in the cationic trypsinogen gene are associated with recurrent acute and chronic pancreatitis  

Microsoft Academic Search

BACKGROUND & AIMS: We recently identified a single R117H mutation in the cationic trypsinogen gene in several kindreds with an inherited form of acute and chronic pancreatitis (HP1), providing strong evidence that trypsin plays a central role in premature zymogen activation and pancreatitis. However, not all families studied have this mutation. The aim of this study was to determine the

M. C. Gorry; D. Gabbaizedeh; W. Furey; L. K. Gates; RA Preston; C. E. Aston; Y Zhang; C Ulrich; GD Ehrlich; DC Whitcomb

1997-01-01

323

Mutation Patterns of 16 Genes in Primary and Secondary Acute Myeloid Leukemia (AML) with Normal Cytogenetics  

PubMed Central

Acute myeloid leukemia patients with normal cytogenetics (CN-AML) account for almost half of AML cases. We aimed to study the frequency and relationship of a wide range of genes previously reported as mutated in AML (ASXL1, NPM1, FLT3, TET2, IDH1/2, RUNX1, DNMT3A, NRAS, JAK2, WT1, CBL, SF3B1, TP53, KRAS and MPL) in a series of 84 CN-AML cases. The most frequently mutated genes in primary cases were NPM1 (60.8%) and FLT3 (50.0%), and in secondary cases ASXL1 (48.5%) and TET2 (30.3%). We showed that 85% of CN-AML patients have mutations in at least one of ASXL1, NPM1, FLT3, TET2, IDH1/2 and/or RUNX1. Serial samples from 19 MDS/CMML cases that progressed to AML were analyzed for ASXL1/TET2/IDH1/2 mutations; seventeen cases presented mutations of at least one of these genes. However, there was no consistent pattern in mutation acquisition during disease progression. This report concerns the analysis of the largest number of gene mutations in CN-AML studied to date, and provides insight into the mutational profile of CN-AML.

Fernandez-Mercado, Marta; Yip, Bon Ham; Pellagatti, Andrea; Davies, Carwyn; Larrayoz, Maria Jose; Kondo, Toshinori; Perez, Cristina; Killick, Sally; McDonald, Emma-Jane; Odero, Maria Dolores; Agirre, Xabier; Prosper, Felipe; Calasanz, Maria Jose; Wainscoat, James S.; Boultwood, Jacqueline

2012-01-01

324

Androgen Receptor Gene Mutations are Rarely Associated with Isolated Penile Hypospadias  

Microsoft Academic Search

PurposeHypospadias has no known single etiology but it has been linked to androgen insensitivity caused by mutations of the androgen receptor gene. The purpose of this study was to search for such mutations in cases of various degrees of isolated hypospadias to determine whether such an association exists and, if so, with any particular anatomical subgroup.

Richard W. Sutherland; John S. Wiener; Joseph P. Hicks; Marco Marcelli; Edmond T. Gonzales; David R. Roth; Dolores J. Lamb

1996-01-01

325

Spectrum of mutations in the HFE gene implicated in haemochromatosis and porphyria  

Microsoft Academic Search

Mutation analysis was performed on DNA samples of 965 individuals from four different ethnic groups in South Africa, in an attempt to determine the spectrum of sequence variants in the haemochroma- tosis (HFE) gene. This population screening approach, utilizing a combined heteroduplex and sin- gle-strand conformation polymorphism (HEX-SSCP) method, revealed three previously described and four novel missense mutations. Novel variants

J. de Villiers; Renate Hillermann; Maritha J. Kotze

1999-01-01

326

Development of a multiplex ARMS test for mutations in the HFE gene associated with hereditary haemochromatosis  

Microsoft Academic Search

Genetic testing for hereditary haemochromatosis is likely to be a significant workload for diagnostic laboratories. The C282Y and H63D mutations in the HFE gene associated with hereditary haemochromatosis have previously been detected using a number of methods including alterations in the restriction digest pattern of polymerase chain reaction (PCR) amplified products. An amplification refractory mutation system (ARMS) has been developed

D. Baty; A. Terron Kwiatkowski; D. Mechan; A. Harris; M. J. Pippard; D. Goudie

1998-01-01

327

Assessing the underlying pattern f human germline mutations: lessons from the factor IX gene  

Microsoft Academic Search

Germline mutations cause or predispose to most diseases. Hemophilia B is a useful model for studying the underlying pattern of recent germline muta- tions in humans because the observed pattern of muta- tion in factor IX more closely reflects the underlying pat- tern of mutation than the observed pattern for many other genes. In addition, it is possible to identify

STEVE S. SOMMER

328

Mitochondrial gene mutation is a significant predisposing factor in aminoglycoside ototoxicity  

Microsoft Academic Search

Purpose: Aminoglycoside-induced deafness caused by mutations in the mitochondrial 12S ribosomal RNA gene has been described in a number of Asian patients. The purpose of the current study is to analyze ethnically diverse patients in the United States with hearing loss after aminoglycoside exposure for presence or absence of these mitochondrial DNA mutations, and establish the frequency and clinical presentation

Nathan Fischel-Ghodsian; Toni R. Prezant; William E. Chaltraw; Kimberly A. Wendt; Ralph A. Nelson; Kathleen S. Arnos; Rena E. Falk

1997-01-01

329

Mutational analysis of EGFR and K-RAS genes in lung adenocarcinomas  

Microsoft Academic Search

Both epidermal growth factor receptor (EGFR) and RAS gene mutations contribute to the development of non-small cell lung cancer (NSCLC). Because RAS is one of the downstream molecules in the EGFR signal transduction, the association between the somatic mutations of EGFR and RAS may be important in the pathogenesis of NSCLC . However, to date, such data are lacking. In

Young Hwa Soung; Jong Woo Lee; Su Young Kim; Si Hyung Seo; Won Sang Park; Suk Woo Nam; Sang Yong Song; Joung Ho Han; Cheol Keun Park; Jung Young Lee; Nam Jin Yoo; Sug Hyung Lee

2005-01-01

330

Mutations and a polymorphism in the factor VIII gene discovered by denaturing gradient gel electrophoresis  

SciTech Connect

Hemophilia A results from mutations in the gene coding for coagulation factor VIII. The authors gradient gel electrophoresis to screen for mutations in the region of the factor VIII gene coding for the first acidic domain. Amplification primers were designed employing the MELTMAP computer program to optimize the ability to detect mutations. Screening of amplified DNA from 228 unselected hemophilia A patients revealed two mutations and one polymorphism. Rescreening the same population by making heteroduplexes between amplified patient and control samples prior to electrophoresis revealed one additional mutation. The mutations include two missense and one 4-base-pair deletion, and each mutation was found in patients with severe hemophilia. The polymorphism, located adjacent to the adenine branch site in intron 7, is useful for genetic prediction in some cases where the Bcl I and Xba I polymorphisms are uninformative. These results suggest that DNA amplification and denaturing gradient gel electrophoresis should be an excellent strategy for identifying mutations and polymorphisms in defined regions of the factor VIII gene and other large genes.

Kogan, S.; Gitschier, J. (Univ. of California, San Francisco (USA))

1990-03-01

331

A NATURALLY OCCURRING EPIGENETIC MUTATION IN AN SBP-BOX GENE INHIBITS TOMATO FRUIT RIPENING  

Technology Transfer Automated Retrieval System (TEKTRAN)

A major player in the regulatory network controlling fruit ripening is likely to be the gene at the tomato Colorless non-ripening (Cnr) locus 1,2. The Cnr mutation results in colorless fruits with a significant loss of cell to cell adhesion. The nature of the mutation and the identity of the Cnr g...

332

Low frequency of NRAS and KRAS2 gene mutations in childhood myelodysplastic syndromes  

Microsoft Academic Search

In children, myelodysplastic syndromes (MDS) represent less then 10% of all hematological malignancies; consequently, molecular genetic studies dealing with this group of patients are scarce. We have analyzed 35 archival bone marrow samples of children with MDS for the presence of mutations in the first and second exons of the NRAS and KRAS2 genes. Mutations were detected with single-strand conformation

Biljana Jekic; Ivana Novakovic; Ljiljana Lukovic; Milos Kuzmanovic; Branka Popovic; Irena Pastar; Jelena Milasin; Gordana Bunjevacki; Vera Bunjevacki

2004-01-01

333

Different ras gene mutational frequencies in thyroid papillary carcinomas in Japan and Thailand  

Microsoft Academic Search

The incidence and pattern of ras oncogene mutations in human malignancies demonstrate geographic and racial differences. For example, specificity of alterations is found in cholangiocellular carcinomas in Thai patients with a different etiology from those in Japanese patients. In the present study, a comparison of ras gene mutations in thyroid papillary carcinomas from Japanese and Thai patients was performed using

Hiroaki Naito; Chawalit Pairojkul; Yoshiteru Kitahori; Katsunari Yane; Hiroshi Miyahara; Noboru Konishi; Takashi Matsunaga; Yoshio Hiasa

1998-01-01

334

Mutations of CD40 gene cause an autosomal recessive form of immunodeficiency with hyper IgM  

PubMed Central

CD40 is a member of the tumor necrosis factor receptor superfamily, expressed on a wide range of cell types including B cells, macrophages, and dendritic cells. CD40 is the receptor for CD40 ligand (CD40L), a molecule predominantly expressed by activated CD4+ T cells. CD40/CD40L interaction induces the formation of memory B lymphocytes and promotes Ig isotype switching, as demonstrated in mice knocked-out for either CD40L or CD40 gene, and in patients with X-linked hyper IgM syndrome, a disease caused by CD40L/TNFSF5 gene mutations. In the present study, we have identified three patients with an autosomal recessive form of hyper IgM who fail to express CD40 on the cell surface. Sequence analysis of CD40 genomic DNA showed that one patient carried a homozygous silent mutation at the fifth base pair position of exon 5, involving an exonic splicing enhancer and leading to exon skipping and premature termination; the other two patients showed a homozygous point mutation in exon 3, resulting in a cysteine to arginine substitution. These findings show that mutations of the CD40 gene cause an autosomal recessive form of hyper IgM, which is immunologically and clinically undistinguishable from the X-linked form.

Ferrari, Simona; Giliani, Silvia; Insalaco, Antonella; Al-Ghonaium, Abdulaziz; Soresina, Anna R.; Loubser, Michael; Avanzini, Maria A.; Marconi, Massimo; Badolato, Raffaele; Ugazio, Alberto G.; Levy, Yves; Catalan, Nadia; Durandy, Anne; Tbakhi, Abdelghani; Notarangelo, Luigi D.; Plebani, Alessandro

2001-01-01

335

Mutations of CD40 gene cause an autosomal recessive form of immunodeficiency with hyper IgM.  

PubMed

CD40 is a member of the tumor necrosis factor receptor superfamily, expressed on a wide range of cell types including B cells, macrophages, and dendritic cells. CD40 is the receptor for CD40 ligand (CD40L), a molecule predominantly expressed by activated CD4(+) T cells. CD40/CD40L interaction induces the formation of memory B lymphocytes and promotes Ig isotype switching, as demonstrated in mice knocked-out for either CD40L or CD40 gene, and in patients with X-linked hyper IgM syndrome, a disease caused by CD40L/TNFSF5 gene mutations. In the present study, we have identified three patients with an autosomal recessive form of hyper IgM who fail to express CD40 on the cell surface. Sequence analysis of CD40 genomic DNA showed that one patient carried a homozygous silent mutation at the fifth base pair position of exon 5, involving an exonic splicing enhancer and leading to exon skipping and premature termination; the other two patients showed a homozygous point mutation in exon 3, resulting in a cysteine to arginine substitution. These findings show that mutations of the CD40 gene cause an autosomal recessive form of hyper IgM, which is immunologically and clinically undistinguishable from the X-linked form. PMID:11675497

Ferrari, S; Giliani, S; Insalaco, A; Al-Ghonaium, A; Soresina, A R; Loubser, M; Avanzini, M A; Marconi, M; Badolato, R; Ugazio, A G; Levy, Y; Catalan, N; Durandy, A; Tbakhi, A; Notarangelo, L D; Plebani, A

2001-10-23

336

Osteopoikilosis and multiple exostoses caused by novel mutations in LEMD3 and EXT1 genes respectively - coincidence within one family  

PubMed Central

Background Osteopoikilosis is a rare autosomal dominant genetic disorder, characterised by the occurrence of the hyperostotic spots preferentially localized in the epiphyses and metaphyses of the long bones, and in the carpal and tarsal bones [1]. Heterozygous LEMD3 gene mutations were shown to be the primary cause of the disease [2]. Association of the primarily asymptomatic osteopokilosis with connective tissue nevi of the skin is categorized as Buschke-Ollendorff syndrome (BOS) [3]. Additionally, osteopoikilosis can coincide with melorheostosis (MRO), a more severe bone disease characterised by the ectopic bone formation on the periosteal and endosteal surface of the long bones [4-6]. However, not all MRO affected individuals carry germ-line LEMD3 mutations [7]. Thus, the genetic cause of MRO remains unknown. Here we describe a familial case of osteopoikilosis in which a novel heterozygous LEMD3 mutation coincides with a novel mutation in EXT1, a gene involved in aetiology of multiple exostosis syndrome. The patients affected with both LEMD3 and EXT1 gene mutations displayed typical features of the osteopoikilosis. There were no additional skeletal manifestations detected however, various non-skeletal pathologies coincided in this group. Methods We investigated LEMD3 and EXT1 in the three-generation family from Poland, with 5 patients affected with osteopoikilosis and one child affected with multiple exostoses. Results We found a novel c.2203C > T (p.R735X) mutation in exon 9 of LEMD3, resulting in a premature stop codon at amino acid position 735. The mutation co-segregates with the osteopoikilosis phenotype and was not found in 200 ethnically matched controls. Another new substitution G > A was found in EXT1 gene at position 1732 (cDNA) in Exon 9 (p.A578T) in three out of five osteopoikilosis affected family members. Evolutionary conservation of the affected amino acid suggested possible functional relevance, however no additional skeletal manifestations were observed other then those specific for osteopoikilosis. Finally in one member of the family we found a splice site mutation in the EXT1 gene intron 5 (IVS5-2 A > G) resulting in the deletion of 9 bp of cDNA encoding three evolutionarily conserved amino acid residues. This child patient suffered from a severe form of exostoses, thus a causal relationship can be postulated. Conclusions We identified a new mutation in LEMD3 gene, accounting for the familial case of osteopoikilosis. In the same family we identified two novel EXT1 gene mutations. One of them A598T co-incided with the LEMD3 mutation. Co-incidence of LEMD3 and EXT1 gene mutations was not associated with a more severe skeletal phenotype in those patients.

2010-01-01

337

Nonsense mutations in the human. beta. -globin gene affect mRNA metabolism  

SciTech Connect

A number of premature translation termination mutations (nonsense mutations) have been described in the human {alpha}- and {beta}-globin genes. Studies on mRNA isolated from patients with {beta}{sup 0}-thalassemia have shown that for both the {beta}-17 and the {beta}-39 mutations less than normal levels of {beta}-globin mRNA accumulate in peripheral blood cells. (The codon at which the mutation occurs designates the name of the mutation; there are 146 codons in human {beta}-globin mRNA). In vitro studies using the cloned {beta}-39 gene have reproduced this effect in a heterologous transfection system and have suggested that the defect resides in intranuclear metabolism. The authors have asked if this phenomenon of decreased mRNA accumulation is a general property of nonsense mutations and if the effect depends on the location or the type of mutation. Toward this end, they have studied the effect of five nonsense mutations and two missense mutations on the expression of human {beta}-globin mRNA in a heterologous transfection system. In all cases studied, the presence of a translation termination codon correlates with a decrease in the steady-state level of mRNA. The data suggest that the metabolism of a mammalian mRNA is affected by the presence of a mutation that affects translation.

Baserga, S.J.; Benz, E.J. Jr. (Yale Univ., New Haven, CT (USA))

1988-04-01

338

Functional characterization of mutations in the myosin Vb gene associated with microvillus inclusion disease  

PubMed Central

Objectives Microvillus inclusion disease (MVID) is a rare autosomal recessive enteropathy characterized by intractable diarrhea and malabsorption. Recently, various MYO5B gene mutations have been identified in MVID patients. Interestingly, several MVID patients showed only a MYO5B mutation in one allele (heterozygous) or no mutations in the MYO5B gene, illustrating the need to further functionally characterize the cell biological effects of the MYO5B mutations. Methods The genomic DNA of nine patients diagnosed with microvillus inclusion disease was screened for MYO5B mutations, and qPCR and immunohistochemistry on the material of two patients was performed to investigate resultant cellular consequences. Results We demonstrate for the first time that MYO5B mutations can be correlated with altered myosin Vb mRNA expression and with an aberrant subcellular distribution of the myosin Vb protein. Moreover, we demonstrate that the typical and myosin Vb–controlled accumulation of rab11a-and FIP5-positive recycling endosomes in the apical cytoplasm of the cells is abolished in MVID enterocytes, which is indicative for altered myosin Vb function. Also, we report 8 novel MYO5B mutations in 9 MVID patients of various etnic backgrounds, including compound heterozygous mutations. Conclusions Our functional analysis indicate that MYO5B mutations can be correlated with an aberrant subcellular distribution of the myosin Vb protein and apical recycling endosomes which, together with the additional compound heterozygous mutations, significantly strengthen the link between MYO5B and MVID.

Szperl, Agata M.; Golachowska, Magdalena R.; Bruinenberg, Marcel; Prekeris, Rytis; Thunnissen, Andy-Mark W. H.; Karrenbeld, Arend; Dijkstra, Gerard; Hoekstra, Dick; Mercer, David; Ksiazyk, Janusz; Wijmenga, Cisca; Wapenaar, Martin C.; Rings, Edmond H. H. M.; van IJzendoorn, Sven C. D.

2010-01-01

339

Gene Mutation May Double Rate of Brain Tissue Lost to Alzheimer's  

MedlinePLUS

... enable JavaScript. Gene Mutation May Double Rate of Brain Tissue Lost to Alzheimer's 1 percent of people ... Alzheimer's disease have double the rate of debilitating brain-tissue loss, a new study finds. People with ...

340

Germline Mutations of the Paired-Like Homeobox 2B (PHOX2B) Gene in Neuroblastoma  

PubMed Central

Neuroblastoma (NB) is a frequent pediatric tumor for which recurrent somatic rearrangements are known. Germline mutations of predisposing gene(s) are suspected on the basis of rare familial cases and the association of NB with other genetically determined congenital malformations of neural crest–derived cells—namely, Hirschsprung disease (HSCR) and/or congenital central hypoventilation syndrome (CCHS). We recently identified the paired–like homeobox 2B (PHOX2B) gene as the major disease-causing gene in isolated and syndromic CCHS, which prompted us to regard it as a candidate gene in NB. Here, we report on germline mutations of PHOX2B in both a familial case of NB and a patient with the HSCR-NB association. PHOX2B, therefore, stands as the first gene for which germline mutations predispose to NB.

Trochet, Delphine; Bourdeaut, Franck; Janoueix-Lerosey, Isabelle; Deville, Anne; de Pontual, Loic; Schleiermacher, Gudrun; Coze, Carole; Philip, Nicole; Frebourg, Thierry; Munnich, Arnold; Lyonnet, Stanislas; Delattre, Olivier; Amiel, Jeanne

2004-01-01

341

Germline mutations of the paired-like homeobox 2B (PHOX2B) gene in neuroblastoma.  

PubMed

Neuroblastoma (NB) is a frequent pediatric tumor for which recurrent somatic rearrangements are known. Germline mutations of predisposing gene(s) are suspected on the basis of rare familial cases and the association of NB with other genetically determined congenital malformations of neural crest-derived cells--namely, Hirschsprung disease (HSCR) and/or congenital central hypoventilation syndrome (CCHS). We recently identified the paired-like homeobox 2B (PHOX2B) gene as the major disease-causing gene in isolated and syndromic CCHS, which prompted us to regard it as a candidate gene in NB. Here, we report on germline mutations of PHOX2B in both a familial case of NB and a patient with the HSCR-NB association. PHOX2B, therefore, stands as the first gene for which germline mutations predispose to NB. PMID:15024693

Trochet, Delphine; Bourdeaut, Franck; Janoueix-Lerosey, Isabelle; Deville, Anne; de Pontual, Loďc; Schleiermacher, Gudrun; Coze, Carole; Philip, Nicole; Frébourg, Thierry; Munnich, Arnold; Lyonnet, Stanislas; Delattre, Olivier; Amiel, Jeanne

2004-03-11

342

AID?Initiated Purposeful Mutations in Immunoglobulin Genes  

Microsoft Academic Search

Exposure brings risk to all living organisms. Using a remarkably effective strategy, higher vertebrates mitigate risk by mounting a complex and sophisticated immune response to counter the potentially toxic invasion by a virtually limitless army of chemical and biological antagonists. Mutations are almost always deleterious, but in the case of antibody diversification there are mutations occurring at hugely elevated rates

Myron F. Goodman; Matthew D. Scharff; Floyd E. Romesberg

2007-01-01

343

PDGFR? Gene Mutation and Protein Expression in Gastrointestinal Stromal Tumors  

Microsoft Academic Search

Objective: Mutation of the PDGFR? is a potential candidate in the pathogenesis of KIT wild-type gastrointestinal tumors (GISTs). In this study, we evaluated the prevalence of PDGFR? mutations and corresponding protein expression in GISTs, to determine their usefulness in obtaining a prognosis. Methods: Genomic DNA was extracted from paraffin-embedded tumor tissues from 194 GISTs. Exons 12, 14 and 18 of

Heung Moon Chang; Min-Hee Ryu; Hyoungnam Lee; Se Jin Jang; Jae-Lyun Lee; Tae Won Kim; Jeong Hwan Yook; Sung Tae Oh; Byung Sik Kim; Jung Shin Lee; Yoon-Koo Kang

2008-01-01

344

Molecular basis of albinism: mutations and polymorphisms of pigmentation genes associated with albinism.  

PubMed

Albinism, caused by a deficiency of melanin pigment in the skin, hair, and eye (oculocutaneous albinism [OCA]), or primarily in the eye (ocular albinism [OA]), results from mutations in genes involved in the biosynthesis of melanin pigment. The lack of melanin pigment in the developing eye leads to fovea hypoplasia and abnormal routing of the optic nerves. These changes are responsible for the nystagmus, strabismus, and reduced visual acuity common to all types of albinism. Mutations in six genes have been reported to be responsible for different types of oculocutaneous and ocular albinism, including the tyrosinase gene (TYR) and OCA1 (MIM# 203100), the OCA2 gene and OCA2 (MIM# 203200), the tyrosinase-related protein-1 gene (TYRP1) and OCA3 (MIM# 203290), the HPS gene and Hermansky-Pudlak syndrome (MIM# 203300), the CHS gene (CHS1), and Chediak-Higashi syndrome (MIM# 214500), and the X-linked ocular albinism gene and OA1 (MIM#300500). The function of only two of the gene products is known tyrosinase and tyrosinase-related protein-1 both of which are enzymes in the melanin biosynthetic pathway. Continued mutational analysis coupled with function/structure studies should aid our understanding of the function of the remaining genes and their role in albinism. Mutation and polymorphism data on these genes are available from the International Albinism Center Albinism Database web site (http://www.cbc.umn.edu/tad). PMID:10094567

Oetting, W S; King, R A

1999-01-01

345

A Dominant Mutation in the Chlamydomonas Reinhardtii Nuclear Gene Sim30 Suppresses Translational Defects Caused by Initiation Codon Mutations in Chloroplast Genes  

PubMed Central

A suppressor of a translation initiation defect caused by an AUG to AUU mutation in the Chlamydomonas reinhardtii chloroplast petD gene was isolated, defining a nuclear locus that we have named SIM30. A dominant mutant allele at this locus, sim30-1d, was found to increase the translation initiation rate of the mutant petD mRNA. sim30-1d was also able to suppress the translational defect caused by an AUG to AUC mutation in the petD gene, and an AUG to AUU mutation in the chloroplast petA gene. We therefore suggest that the SIM30 gene may encode a general chloroplast translation factor. The ability of sim30-1d to suppress the petD AUG to AUU mutation is diminished in the presence of one or more antibiotic resistance markers located within the 16S and 23S rRNAs, suggesting that the activity of the sim30-1d gene product in translation initiation may involve interaction with ribosomal subunits.

Chen, X.; Simpson, C. L.; Kindle, K. L.; Stern, D. B.

1997-01-01

346

THE G209A MUTATION IN THE ? ? ? ?-SYNUCLEIN GENE IN BRAZILIAN FAMILIES WITH PARKINSON'S DISEASE  

Microsoft Academic Search

A missense G209A mutation of the alpha-synuclein gene was recently described in a large Contursi kindred with Parkinson's disease (PD). The objective of this study is to determine if the mutation G209A of the alpha-synuclein gene was present in 10 Brazilian families with PD. PD patients were recruited from movement disorders clinics of Brazil. A family history with two or

Hélio A. G. Teive; Salmo Raskin; Fábio M. Iwamoto; Francisco M. B. Germiniani; Maria H. H. Baran; Lineu C. Werneck; Nasser Allan; Elizabeth Quagliato; Elisabeth Leroy; Susan E. Ide; Mihael H. Polymeropoulos

347

Seven novel mutations of the PKD2 gene in families with autosomal dominant polycystic kidney disease  

Microsoft Academic Search

Seven novel mutations of thePKD2gene in families with autosomal dominant polycystic kidney disease.BackgroundAutosomal dominant polycystic kidney disease (ADPKD) is genetically heterogeneous, with at least three chromosomal loci accounting for the disease. Mutations in the PKD2 gene on the long arm of chromosome 4 are expected to be responsible for approximately 15% of cases of ADPKD.MethodsWe report a systematic screening for

Roser Torra; Miguel Viribay; Dolores Tellería; Cčlia Badenas; Michael Watson; Peter Harris; Alejandro Darnell; José L San Millán

1999-01-01

348

Mutation analysis of the spastin gene (SPG4) in patients with hereditary spastic paraparesis  

Microsoft Academic Search

BACKGROUNDHereditary spastic paraparesis is a genetically heterogeneous condition. Recently, mutations in the spastin gene were reported in families linked to the common SPG4 locus on chromosome 2p21-22.OBJECTIVESTo study a population of patients with hereditary spastic paraparesis for mutations in the spastin gene (SPG4) on chromosome 2p21-22.METHODSDNA from 32 patients (12 from families known to be linked to SPG4) was analysed

J C Lindsey; M E Lusher; C J McDermott; K D White; E Reid; D C Rubinsztein; R Bashir; J Hazan; P J Shaw; K M D Bushby

2000-01-01

349

Mutational analysis of the RPGRIP1L gene in patients with Joubert syndrome and nephronophthisis  

Microsoft Academic Search

Joubert syndrome (JS) is an autosomal recessive disorder, consisting of mental retardation, cerebellar vermis aplasia, an irregular breathing pattern, and retinal degeneration. Nephronophthisis (NPHP) is found in 17–27% of these patients, which was designated JS type B. Mutations in four separate genes (AHI1, NPHP1, CEP290\\/NPHP6, and MKS3) are linked to JS. However, missense mutations in a new ciliary gene (RPGRIP1L)

M T F Wolf; S Saunier; J F O'Toole; N Wanner; T Groshong; M Attanasio; R Salomon; T Stallmach; J A Sayer; R Waldherr; M Griebel; J Oh; T J Neuhaus; U Josefiak; C Antignac; E A Otto; F Hildebrandt

2007-01-01

350

HFE Gene Mutation, Chronic Liver Disease, and Iron Overload In Turkey  

Microsoft Academic Search

We aimed to determine the relationships between iron overload and HFE gene mutation in chronic liver disease in Turkey. One\\u000a hundred thirteen chronic liver disease patients and 138 healthy controls were evaluated regarding their clinical, biochemical,\\u000a and genetic parameters. Each group was divided into two subgroups according to transferrin saturation (TS) (45% and >45%).\\u000a HFE gene mutation was analyzed by

Oya Yönal; Özden Hat?rnaz; Filiz Akyüz; Ugur Özbek; Kadir Demir; Sabahattin Kaymakoglu; Atilla Ökten; Zeynel Mungan

2007-01-01

351

Prevalence of HFE (hemochromatosis gene) mutations in unselected male patients with type 2 diabetes  

Microsoft Academic Search

To assess the prevalence of mutations in the HFE (hemochromatosis) gene in unselected male patients with type 2 diabetes, we examined 220 white men without known diabetes and 220 age-matched white men with type 2 diabetes for mutations in the HFE gene. Nucleotide 845 (C282Y) and 187(H63D) alleles were amplified by polymerase chain reaction (PCR) with lymphocyte DNA. The PCR

Michael J Sampson; Tracey Williams; Philip J Heyburn; Richard H Greenwood; Rosemary C Temple; Jennie Z Wimperis; Barbara A Jennings; Gavin A Willis

2000-01-01

352

Translational Polarity of a Mutation in the Initiator AUG Codon of the X cl Gene  

Microsoft Academic Search

A P-cI-lac2 fusion inserted into the 62 region of bacteriophage X was used to isolate mutations affecting expression of both the X cI gene and the lac2 gene. One such mutation, a change in the CI initiator codon from AUG to AUA, reduces immunity of a X prophage to superinfection, and causes a 60-70% reduction in &galactosidase synthesis, even when

Gary N. Gussin; Susan Brown; Karen Matz

1987-01-01

353

Mutations of the Btk gene in 12 unrelated families with X-linked agammaglobulinemia in Japan  

Microsoft Academic Search

Alterations of the Bruton's tyrosine kinase(Btk) gene are responsible for X-linked agammaglobulinemia (XLA). Although mutations in various regions were reported mainly in the Caucasian population, correlation between the locations of mutation and the clinical phenotypes remains unclear. We report 12 abnormalities of theBtk gene found in 12 unrelated families out of 14 XLA families in Japan and their clinical features.

Shigetoshi Kobayashi; Tsutomu Iwata; Makiko Saito; Ryu Iwasaki; Hiroshi Matsumoto; Shinichi Naritaka; Yoichi Kono; Yasuhide Hayashi

1996-01-01

354

Mutations of the Btk gene in 12 unrelated families with X-linked agammaglobulinemia in Japan  

Microsoft Academic Search

Alterations of the Bruton’s tyrosine kinase (Btk) gene are responsible for X-linked agammaglobulinemia (XLA). Although mutations in various regions were reported mainly in\\u000a the Caucasian population, correlation between the locations of mutation and the clinical phenotypes remains unclear. We report\\u000a 12 abnormalities of the Btk gene found in 12 unrelated families out of 14 XLA families in Japan and their

Shigetoshi Kobayashi; Tsutomu Iwata; Makiko Saito; Ryu Iwasaki; Hiroshi Matsumoto; Shinichi Naritaka; Yoichi Kono; Yasuhide Hayashi

1996-01-01

355

High frequency hearing loss correlated with mutations in the GJB2 gene  

Microsoft Academic Search

Genetic hearing impairment affects approximately 1\\/2000 live births. Mutations in one gene, GJB2, coding for connexin 26 cause 10%-20% of all genetic sensorineural hearing loss. Mutation analysis in the GJB2 gene and audiology were performed on 106 families presenting with at least one child with congenital hearing loss. The families were recruited from a hospital-based multi-disciplinary clinic, which functions to

Stephen A Wilcox; Kerryn Saunders; Amelia H Osborn; Angela Arnold; Julia Wunderlich; Therese Kelly; Veronica Collins; Leah J Wilcox; RJ McKinlay Gardner; Maria Kamarinos; Barbara Cone-Wesson; Robert Williamson; Hans-Henrik M. Dahl

2000-01-01

356

Transcription Termination Factor Rho Activity is Altered in Escherichia coli with suA Gene Mutations  

Microsoft Academic Search

Rho factor has been purified from a strain of E. coli containing the Su78 mutation in the suA gene and assayed in another strain with an amber mutation in the suA gene. The rho from the Su78 mutant strain is present in normal amounts but has altered termination function; it does not terminate transcription at some sites that are recognized

John P. Richardson; Christopher Grimley; Carolyn Lowery

1975-01-01

357

Novel Somatic Mutations to PI3K Pathway Genes in Metastatic Melanoma  

PubMed Central

Background BRAFV600 inhibitors have offered a new gateway for better treatment of metastatic melanoma. However, the overall efficacy of BRAFV600 inhibitors has been lower than expected in clinical trials, and many patients have shown resistance to the drug’s effect. We hypothesized that somatic mutations in the Phosphoinositide 3-Kinase (PI3K) pathway, which promotes proliferation and survival, may coincide with BRAFV600 mutations and contribute to chemotherapeutic resistance. Methods We performed a somatic mutation profiling study using the 454 FLX pyrosequencing platform in order to identify candidate cancer genes within the MAPK and PI3K pathways of melanoma patients. Somatic mutations of theses candidate cancer genes were then confirmed using Sanger sequencing. Results As expected, BRAFV600 mutations were seen in 51% of the melanomas, whereas NRAS mutations were seen in 19% of the melanomas. However, PI3K pathway mutations, though more heterogeneous, were present in 41% of the melanoma, with PTEN being the highest mutated PI3K gene in melanomas (22%). Interestingly, several novel PI3K pathway mutations were discovered in MTOR, IRS4, PIK3R1, PIK3R4, PIK3R5, and NFKB1. PI3K pathway mutations co-occurred with BRAFV600 mutations in 17% of the tumors and co-occurred with 9% of NRAS mutant tumors, implying cooperativity between these pathways in terms of melanoma progression. Conclusions These novel PI3K pathway somatic mutations could provide alternative survival and proliferative pathways for metastatic melanoma cells. They therefore may be potential chemotherapeutic targets for melanoma patients who exhibit resistance to BRAFV600 inhibitors.

Ramasamy, Poornema; Leskoske, Kristin; Oroian, Dora; Birtwistle, Marc R.; Buckhaults, Phillip J.

2012-01-01

358

Dystrophin Gene Mutation Location and the Risk of Cognitive Impairment in Duchenne Muscular Dystrophy  

PubMed Central

Background A significant component of the variation in cognitive disability that is observed in Duchenne muscular dystrophy (DMD) is known to be under genetic regulation. In this study we report correlations between standardised measures of intelligence and mutational class, mutation size, mutation location and the involvement of dystrophin isoforms. Methods and Results Sixty two male subjects were recruited as part of a study of the cognitive spectrum in boys with DMD conducted at the Sydney Children's Hospital (SCH). All 62 children received neuropsychological testing from a single clinical psychologist and had a defined dystrophin gene (DMD) mutation; including DMD gene deletions, duplications and DNA point mutations. Full Scale Intelligence Quotients (FSIQ) in unrelated subjects with the same mutation were found to be highly correlated (r?=?0.83, p?=?0.0008), in contrast to results in previous publications. In 58 cases (94%) it was possible to definitively assign a mutation as affecting one or more dystrophin isoforms. A strong association between the risk of cognitive disability and the involvement of groups of DMD isoforms was found. In particular, improvements in the correlation of FSIQ with mutation location were identified when a new classification system for mutations affecting the Dp140 isoform was implemented. Significance These data represent one of the largest studies of FSIQ and mutational data in DMD patients and is among the first to report on a DMD cohort which has had both comprehensive mutational analysis and FSIQ testing through a single referral centre. The correlation between FSIQ results with the location of the dystrophin gene mutation suggests that the risk of cognitive deficit is a result of the cumulative loss of central nervous system (CNS) expressed dystrophin isoforms, and that correct classification of isoform involvement results in improved estimates of risk.

Maroulis, Sarah; Gilissen, Christian; Pedersen, Robyn L.; Mowat, David R.; Johnston, Heather M.; Buckley, Michael F.

2010-01-01

359

The pattern of spontaneous germ-line mutation: relative rates of mutation at or near CpG dinucleotides in the factor IX gene  

Microsoft Academic Search

Mutations at CpG dinucleotides were delineated in the factor IX gene of 38 hemophilia B patients. When transitions at CpG were considered with those previously reported by us and those compiled in the factor IX mutation database, the following patterns emerged. Many CpG sites were mutated with high frequency, while two CpG sites were infrequently mutated (R29?Q and R116? TGA).

Cynthia D. K. Bottema; Rhett P. Ketterling; Erica Vielhaber; Hong-Sup Yoon; Bobbie Gostout; David P. Jacobson; Amy Shapiro; Steve S. Sommer

1993-01-01

360

A Sporadic Case of Mal de Meleda Caused by Gene Mutation in SLURP-1 in Korea  

PubMed Central

Mal de Meleda (MDM), also known as keratoderma palmoplantaris transgrediens, is a rare inherited form of palmoplantar keratoderma. It is characterized by erythema and hyperkeratosis of the palms and soles, extending to the dorsal aspects of the hands and feet. A 15-year-old Korean female presented with sharply demarcated hyperkeratotic plaques on the palms and soles, which extended to the dorsal surfaces of the hands and feet, in a "glove-and-socks" distribution. The histopathologic study showed marked hyperkeratosis, acanthosis, and normogranulosis, without epidermolysis. Her genetic study detected compound heterozygous mutation in exon 3 of the ARS gene encoding SLURP-1. Family history did not reveal any other affected members and no consanguineous relationship was found. In view of these findings, we diagnosed this case as the first reported sporadic case of MDM in Korea, the farthest location from the endemic island of Meleda.

Oh, Young Jae; Lee, Ha Eun; Ro, Young Suck; Yu, Hee Joon

2011-01-01

361

Patterns of Epistasis between Beneficial Mutations in an Antibiotic Resistance Gene  

PubMed Central

Understanding epistasis is central to biology. For instance, epistatic interactions determine the topography of the fitness landscape and affect the dynamics and determinism of adaptation. However, few empirical data are available, and comparing results is complicated by confounding variation in the system and the type of mutations used. Here, we take a systematic approach by quantifying epistasis in two sets of four beneficial mutations in the antibiotic resistance enzyme TEM-1 ?-lactamase. Mutations in these sets have either large or small effects on cefotaxime resistance when present as single mutations. By quantifying the epistasis and ruggedness in both landscapes, we find two general patterns. First, resistance is maximal for combinations of two mutations in both fitness landscapes and declines when more mutations are added due to abundant sign epistasis and a pattern of diminishing returns with genotype resistance. Second, large-effect mutations interact more strongly than small-effect mutations, suggesting that the effect size of mutations may be an organizing principle in understanding patterns of epistasis. By fitting the data to simple phenotype resistance models, we show that this pattern may be explained by the nonlinear dependence of resistance on enzyme stability and an unknown phenotype when mutations have antagonistically pleiotropic effects. The comparison to a previously published set of mutations in the same gene with a joint benefit further shows that the enzyme's fitness landscape is locally rugged but does contain adaptive pathways that lead to high resistance.

Schenk, Martijn F.; Szendro, Ivan G.; Salverda, Merijn L.M.; Krug, Joachim; de Visser, J. Arjan G.M.

2013-01-01

362

Herlitz Junctional Epidermolysis Bullosa: Novel and Recurrent Mutations in the LAMB3 Gene and the Population Carrier Frequency  

Microsoft Academic Search

SummaryHerlitz junctional epidermolysis bullosa is a heritable bullous disease caused by mutations found primarily in the ?3 chain of laminin 5 (LAMB3). In this study, we examined the LAMB3 gene for mutations in 22 Herlitz junctional epidermolysis bullosa families, and identified 15 distinct mutations, eight of them previously unreported, bringing the total number of distinct Herlitz junctional epidermolysis bullosa mutations

Aoi Nakano; Ellen Pfendner; Leena Pulkkinen; Isao Hashimoto; Jouni Uitto

2000-01-01

363

Gain-of-function mutations of platelet-derived growth factor receptor ? gene in gastrointestinal stromal tumors  

Microsoft Academic Search

Background & Aims: Most gastrointestinal stromal tumors (GISTs) have gain-of-function mutations of c-kit receptor tyrosine kinase (KIT) gene, but some GISTs do not. We investigated the cause of GISTs without KIT mutations. Because GISTs apparently expressed platelet-derived growth factor receptor (PDGFR) ?, we examined whether GISTs without KIT mutations had a mutation of PDGFR ?. Methods: Whole coding region of

Seiichi Hirota; Akiko Ohashi; Toshirou Nishida; Koji Isozaki; Kazuo Kinoshita; Yasuhisa Shinomura; Yukihiko Kitamura

2003-01-01

364

A novel HAX1 gene mutation in severe congenital neutropenia (SCN) associated with neurological manifestations.  

PubMed

Autosomal recessive severe congenital neutropenia (SCN) results from a maturation arrest of granulopoiesis at the level of promyelocytes and apoptosis of myeloid cells. In SCN patients, mutations have been described in the HAX1 gene. Most of the SCN patients who carry nonsense mutations that are common to both transcript variants of the HAX1 gene also exhibit neurological deficits. This study describes an SCN patient with neurological manifestations including daily episodes of atonic seizures, learning disabilities, and developmental delay. Sequencing of the HAX1 gene of this SCN patient identified a novel nonsense c.463_464insC homozygous mutation in exon 3, which is common to both transcript variants of the gene. This mutation encodes for a p.Gln155ProfsX14 change and causes premature truncation of the HAX1 protein. Neutrophils isolated from the patient exhibited spontaneous apoptosis and loss of inner mitochondrial membrane potential, which were further enhanced upon treatment with hydrogen peroxide. This study adds to the spectrum of novel HAX1 gene mutations and disease manifestations in ethnically distinct SCN patients. Our report describes the only nonsense mutation in the HAX1 gene present in SCN patients of Arab origin. PMID:20182745

Faiyaz-Ul-Haque, Muhammad; Al-Jefri, Abdullah; Al-Dayel, Fouad; Bhuiyan, Jalaluddin A K M; Abalkhail, Hala A; Al-Nounou, Randa; Al-Abdullatif, Ahmed; Pulicat, Monogaran S; Gaafar, Ameera; Alaiya, Ayodele A; Peltekova, Iskra; Zaidi, Syed H E

2010-02-25

365

Screening for germline mutations in the neurofibromatosis type 2 (NF2) gene in NF2 patients  

SciTech Connect

Neurofibromatosis type 2 (NF2) is an autosomal dominant disease with over 95% penetrance which predisposes gene carriers to develop multiple tumors of the central nervous system. The NF2 gene is a putative tumor suppressor gene which was previously mapped to the long arm of chromosome 22, and has recently been identified, using positional cloning techniques. The gene encodes a protein, schwannomin (SCH), which is highly homologous to the band 4.1 protein family. In an attempt to identify and characterize mutations which lead to the manifestation of the disease, we have used single strand conformation analysis (SSCA) to screen for germline mutations in all 17 exons of the NF2 gene in 59 unrelated NF2 patients, representing both familial and new mutations. A total of 27 migration abnormalities was found in 26 patients. Using direct sequencing analysis, the majority of these variants were found to result in nonsense, splice-site or frameshift mutations. Mutations identified in familial NF2 patients segregate in the family, and may prove to be useful tools for a simple and direct SSCA-based technique of presymptomatic or prenatal diagnosis in relatives of patients with NF2. This may be of particular importance in children of patients who have new mutations in the NF2 gene, where linkage analysis may not be feasible.

Andermann, A.A.; Ruttledge, M.H.; Rangaratnam, A. [McGill Univ. and Montreal General Hospital Research Institute, Quebec (Canada)] [and others

1994-09-01

366

Three cases of congenital adrenal hypoplasia with novel mutations in the (NROB1) DAX-1 gene.  

PubMed

Abnormalities in the DAX-1 gene (dosage-sensitive sex reversal-adrenal hypoplasia gene on the X chromosome) are a well-recognized cause of congenital adrenal hypoplasia. DAX-1 is expressed in the adrenal cortex, gonads, hypothalamus and anterior pituitary, which gives rise to the clinical features of this deletion. Presentations are varied but salt-wasting and/or hypoglycaemia are the most common in an infant, with late onset of hypogonadotrophic hypogonadism. Over 80 different mutations in this gene have been identified. We present three unrelated cases with variable clinical presentations, all with novel mutations in the DAX-1 gene. PMID:18941128

Wheeler, B; George, P M; Mackenzie, K; Hunt, P; Potter, H C; Florkowski, C M

2008-11-01

367

Mutations in genes involved in nonsense mediated decay ameliorate the phenotype of sel-12 mutants with amber stop mutations in Caenorhabditis elegans  

Microsoft Academic Search

BACKGROUND: Presenilin proteins are part of a complex of proteins that can cleave many type I transmembrane proteins, including Notch Receptors and the Amyloid Precursor Protein, in the middle of the transmembrane domain. Dominant mutations in the human presenilin genes PS1 and PS2 lead to Familial Alzheimer's disease. Mutations in the Caenorhabditis elegans sel-12 presenilin gene cause a highly penetrant

Alisson M Gontijo; Sylvie Aubert; Ingele Roelens; Bernard Lakowski

2009-01-01

368

Human gene mutation database-a biomedical information and research resource.  

PubMed

Although 20 years have elapsed since the first single basepair substitution underlying an inherited disease in humans was characterised at the DNA level, the initiative has only recently been taken to establish central database resources for pathological genetic variants. Disease-associated gene lesions are currently collected and publicised by the Human Gene Mutation Database (HGMD) in Cardiff, locus-specific mutation databases, and to some extent also by the Genome Database (GDB) and Online Mendelian Inheritance in Man (OMIM). To date, HGMD represents the only comprehensive and publicly available database of gene lesions underlying human inherited disease. By July 1999, HGMD contained over 18,000 different mutations from some 900 human genes, the majority being single basepair substitutions. In addition to its potential as an information resource for clinicians and genetic counsellors, HGMD has allowed molecular geneticists to address a variety of biological questions through meta-analysis of the collated data. HGMD also promises to assist research workers in optimising mutation search strategies for a given gene. A questionnaire sent out to, and answered by, the editors of 20 key journals revealed that human genetics journals are increasingly reluctant to publish mutation reports. Electronic data submission and publication facilities are therefore urgently required. The World Wide Web (WWW) provides an excellent medium within which to combine the centralised management of basic mutation data, including rigorous quality control, with the possibility of publishing additional mutation-related information. In response to these needs, HGMD has both instituted a collaboration with Springer-Verlag GmbH, Heidelberg, to potentiate free online submission and electronic publication of human gene mutation data and developed links with the curators of locus-specific mutation databases. PMID:10612821

Krawczak, M; Ball, E V; Fenton, I; Stenson, P D; Abeysinghe, S; Thomas, N; Cooper, D N

2000-01-01

369

Point Mutations Effects on Charge Transport Properties of the Tumor-Suppressor Gene p53  

NASA Astrophysics Data System (ADS)

We report on a theoretical study of point mutations effects on charge transfer properties in the DNA sequence of the tumor-suppressor p53 gene. On the basis of effective tight-binding models which simulate hole propagation along the DNA, a statistical analysis of mutation-induced charge transfer modifications is performed. In contrast to non-cancerous mutations, mutation hotspots tend to result in significantly weaker changes of transmission properties. This suggests that charge transport could play a significant role for DNA-repairing deficiency yielding carcinogenesis.

Roemer, Rudolf A.; Shih, Chi-Tin; Roche, Stephan

2008-03-01

370

Genes critical for muscle development and function in Caenorhabditis elegans identified through lethal mutations  

PubMed Central

By taking advantage of a lethal phenotype characteristic of Caenorhabditis elegans embryos that fail to move, we have identified 13 genes required for muscle assembly and function and discovered a new lethal class of alleles for three previously known muscle-affecting genes. By staining mutant embryos for myosin and actin we have recognized five distinct classes of genes: mutations in four genes disrupt the assembly of thick and thin filaments into the myofilament lattice as well as the polarized location of these components to the sarcolemma. Mutations in another three genes also disrupt thick and thin filament assembly, but allow proper polarization of lattice components based on the myosin heavy chain isoform that we analyzed. Another two classes of genes are defined by mutations with principal effects on thick or thin filament assembly into the lattice, but not both. The final class includes three genes in which mutations cause relatively minor defects in lattice assembly. Failure of certain mutants to stain with antibodies to specific muscle cell antigens suggest that two genes associated with severe disruptions of myofilament lattice assembly may code for components of the basement membrane and the sarcolemma that are concentrated where dense bodies (Z- line analogs) and M-lines attach to the cell membrane. Similar evidence suggests that one of the genes associated with mild effects on lattice assembly may code for tropomyosin. Many of the newly identified genes are likely to play critical roles in muscle development and function.

1994-01-01

371

Haemochromatosis gene mutations in a clustered Italian population: evidence of high prevalence in people of Celtic ancestry  

Microsoft Academic Search

Hereditary haemochromatosis is an inherited disorder characterised by an excessive iron absorption from the diet and is associated with several HFE gene mutations. One hypothesis is that these genetic mutations originated in the Celtic populations. The aim of this study is to determine the frequency of HFE gene mutations in a clustered Italian population of Celtic ancestry (Cimbri, Asiago plateau).

Gabriele Pozzato; Francesca Zorat; Fabiana Nascimben; Michela Gregorutti; Consuelo Comar; Stefano Baracetti; Serena Vatta; Elena Bevilacqua; Anna Belgrano; Sergio Crovella; Antonio Amoroso

2001-01-01

372

Identification and molecular modelling of a novel familial mutation in the SRY gene implicated in the pure gonadal dysgenesis  

Microsoft Academic Search

SRY gene is responsible for initiating male sexual differentiation. The protein encoded by SRY contains a homeobox (HMG) domain, which is a DNA-binding domain. Mutations of the SRY gene are reported to be associated with XY pure gonadal dysgenesis. The majority of these are de novo mutations affecting only one individual in a family. Only a small subset of mutations

Giorgio Gimelli; Stefania Gimelli; Nazzareno Dimasi; Renata Bocciardi; Eliana Di Battista; Tiziano Pramparo; Orsetta Zuffardi

2007-01-01

373

Screening of the Bruton Tyrosine Kinase (BTK) Gene Mutations in 13 Iranian Patients with Presumed X-Linked Agammaglobulinemia  

Microsoft Academic Search

X-linked agammaglobulinemia (XLA) is an immunodeficiency caused by mutations in the Bruton tyrosine kinase (Btk) gene. In order to identify the mutations in Btk gene in Iranian patients with antibody deficiency, 13 male patients with an XLA phenotype from 11 unrelated families were enrolled as the subjects of investigation for Btk mutation analysis using PCR-SSCP followed by sequencing. Five different

Asghar Aghamohammadi; Nima Parvaneh; Hirokazu Kanegana; Mostafa Moin; Ali Akbar Amirzargar; Abolhassan Farhoudi; Zahra Pourpak; Masoud Movahedi; Mohammad Gharagozlou; Nima Rezaei; Takeshi Futatani; Toshio Miyawaki

374

Identification of Missense Mutations in Exon 16 of Factor VIII Gene in Mild and Moderate Cases With Hemophilia A  

Microsoft Academic Search

Hemophilia A is a bleeding disorder caused by heterogeneous mutations of the factor VIII gene. A total of 60 unique mutations have been identified in exon 16. The current study was done with the objective of detecting small mutations in exon 16 of factor VIII gene in Indian cases with hemophilia A and to further analyze structural and functional alterations

Nuzhat Jahan Faridi; Nuzhat Husain; Mohammad Imran Siddiqi; Praveen Kumar; R. N. K. Bamezai

2011-01-01

375

Novel missense mutations in the glycogen-branching enzyme gene in adult polyglucosan body disease.  

PubMed

We describe the first non-Ashkenazi patient with adult polyglucosan body disease and decreased glycogen-branching enzyme (GBE) activity in leukocytes. Gene analysis revealed compound heterozygosity for two novel missense mutations Arg515His and Arg524Gln in the GBE gene. Both missense mutations are predicted to impair GBE activity. This is the first identification of GBE mutations underlying adult polyglucosan body disease in a non-Ashkenazi family, and confirms that adult glycogen storage disease type IV can manifest clinically as adult polyglucosan body disease. PMID:10762170

Ziemssen, F; Sindern, E; Schröder, J M; Shin, Y S; Zange, J; Kilimann, M W; Malin, J P; Vorgerd, M

2000-04-01

376

Bilateral transverse sinus thrombosis secondary to a homozygous C677T MTHFR gene mutation.  

PubMed

We describe the case of a previously healthy young man who presented with headache, diplopia, nausea, vomiting, and bilateral papilledema. Magnetic resonance venography of the brain revealed thrombosis of the right transverse sinus. Blood tests showed elevated homocysteine levels, and coagulation studies revealed a homozygous C677T mutation and a heterozygous A1298C mutation of the methylenetetrahydrofolate reductase (MTHFR) gene. The patient had no other etiology for venous thrombosis. We recommend screening patients who present with sinus thrombosis for MTHFR gene mutations. PMID:18666857

Kanaan, Ziad M; Mahfouz, Rami; Taher, Ali; Sawaya, Raja A

2008-09-01

377

Deleterious Mutation in the Mitochondrial Arginyl-Transfer RNA Synthetase Gene Is Associated with Pontocerebellar Hypoplasia  

PubMed Central

Homozygosity mapping was performed in a consanguineous Sephardic Jewish family with three patients who presented with severe infantile encephalopathy associated with pontocerebellar hypoplasia and multiple mitochondrial respiratory-chain defects. This resulted in the identification of an intronic mutation in RARS2, the gene encoding mitochondrial arginine–transfer RNA (tRNA) synthetase. The mutation was associated with the production of an abnormally short RARS2 transcript and a marked reduction of the mitochondrial tRNAArg transcript in the patients’ fibroblasts. We speculate that missplicing mutations in mitochondrial aminoacyl-tRNA synthethase genes preferentially affect the brain because of a tissue-specific vulnerability of the splicing machinery.

Edvardson, Simon; Shaag, Avraham; Kolesnikova, Olga; Gomori, John Moshe; Tarassov, Ivan; Einbinder, Tom; Saada, Ann; Elpeleg, Orly

2007-01-01

378

Absence of BRAF gene mutation in non-melanoma skin tumors.  

PubMed

Basal cell carcinoma (BCC) is the most common skin cancer, and its incidence is increasing. It was proposed that the RAS oncogene significantly contributes to skin cancer development. Numerous BRAF mutations have been detected in melanoma biopsy specimens and cell lines. For the first time, in the present study, tumor biopsy specimens from 78 patients with BCC were screened for BRAF mutation within exons 11 and 15. Our results indicate that the BRAF gene does not appear to be frequently mutated in nonmelanoma skin tumors such as BCC. These data suggest that other gene alterations may cause tumor development. PMID:16687919

Libra, Massimo; Malaponte, Grazia; Bevelacqua, Valentina; Siciliano, Roberta; Castrogiovanni, Paola; Fulvi, Alberto; Micali, Giuseppe; Ligresti, Giovanni; Mazzarino, Maria C; Stivala, Franca; Travali, Salvatore; McCubrey, James A

2006-05-01

379

Characterization of six mutations in Exon 37 of neurofibromatosis type 1 gene  

SciTech Connect

Neurofibromatosis type 1 (NF1) is one of the most common inherited disorders, with an incidence of 1 in 3,000. We screened a total of 320 unrelated NF1 patients for mutations in exon 37 of the NF1 gene. Six independent mutations were identified, of which three are novel, and these include a recurrent nonsense mutation identified in 2 unrelated patients at codon 2281 (G2281X), a 1-bp insertion (6791 ins A) resulting in a change of TAG (tyrosine) to a TAA (stop codon), and a 3-bp deletion (6839 del TAC) which generated a frameshift. Another recurrent nonsense mutation, Y2264X, which was detected in 2 unrelated patients in this study, was also previously reported in 2 NF1 individuals. All the mutations were identified within a contiguous 49-bp sequence. Further studies are warranted to support the notion that this region of the gene contains highly mutable sequences. 17 refs., 2 figs., 1 tab.

Upadhyaya, M.; Osborn, M.; Maynard, J.; Harper, P. [Institute of Medical Genetics, Cardiff, Wales (United Kingdom)

1996-07-26

380

Homozygous variegate porphyria: a compound heterozygote with novel mutations in the protoporphyrinogen oxidase gene.  

PubMed

Homozygous variegate porphyria results from mutations in both alleles of the protoporphyrinogen oxidase (PPOX) gene. Our patient, a 36-year-old woman, has severe cutaneous manifestations. Her clinical and biochemical features are similar to the few other reported cases, including onset before 18 months of age, photosensitivity, absence of acute porphyric attacks, and elevated erythrocyte protoporphyrin. Mutation analysis of the PPOX gene revealed an in-frame 12 bp insert (c. 657-658 ins AAGGCCAGCGCC) encoding lysine-alanine-serine-alanine (KASA), and a G to A transition at the splice donor site of exon 11 (IVS 11-1 G-->A). Neither of these mutations has been reported previously. Our patient's mother has the splice site mutation and has had acute porphyric episodes. A maternal first cousin has the same mutation but no clinical manifestations. The medical and family history of our patient's father is uncertain. PMID:11298551

Palmer, R A; Elder, G H; Barrett, D F; Keohane, S G

2001-04-01

381

Mutation spectrum of dystrophin gene in malaysian patients with Duchenne/Becker muscular dystrophy.  

PubMed

We undertook the clinical feature examination and dystrophin analysis using multiplex ligation-dependent probe amplification (MLPA) and direct DNA sequencing of selected exons in a cohort of 35 Malaysian Duchenne/Becker muscular dystrophy (DMD/BMD) patients. We found 27 patients with deletions of one or more exons, 2 patients with one exon duplication, 2 patients with nucleotide deletion, and 4 patients with nonsense mutations (including 1 patient with two nonsense mutations in the same exon). Although most cases showed compliance to the reading frame rule, we found two unrelated DMD patients with an in-frame deletion of the gene. Two novel mutations have been detected in the Dystrophin gene and our results were compatible with other studies where the majority of the mutations (62.8%) are located in the distal hotspot. However, the frequency of the mutations in our patient varied as compared with those found in other populations. PMID:23438214

Rani, Abdul Qawee; Sasongko, Teguh Haryo; Sulong, Sarina; Bunyan, David; Salmi, Abdul Razak; Zilfalil, Bin Alwi; Matsuo, Masafumi; Zabidi-Hussin, Z A M H

2013-02-26

382

Unusual deep intronic mutations in the COL4A5 gene cause X linked Alport syndrome.  

PubMed

The X-linked form of Alport syndrome is caused by mutations in the COL4A5 gene in Xq22. This large multiexonic gene has, in the past, been difficult to screen, with several studies detecting only about 50% of mutations. We report three novel intronic mutations that may, in part, explain this poor success rate and demonstrate that single base changes deep within introns can, and do, cause disease: one mutation creates a new donor splice site within an intron resulting in the inclusion of a novel in-frame cryptic exon; a second mutation results in a new exon splice enhancer sequence (ESE) that promotes splicing of a cryptic exon containing a stop codon; a third patient exhibits exon skipping as a result of a base substitution within the polypyrimidine tract that precedes the acceptor splice site. All three cases would have been missed using an exon-by-exon DNA screening approach. PMID:12436246

King, Kathy; Flinter, Frances A; Nihalani, Vandana; Green, Peter M

2002-09-14

383

Germline FAS gene mutation in a case of ALPS and NLP Hodgkin lymphoma.  

PubMed

FAS germline mutations have been associated with the development of autoimmune lymphoproliferative syndrome (ALPS). Occurrence of Hodgkin lymphoma (HL) has been reported in 2 families with ALPS. In both families an uncle of the index patient developed HL. A 15-year-old boy with autoimmune thrombopenia, lymphadenopathy, and splenomegaly for 6 years was studied. In an axillary lymph node biopsy nodular lymphocyte predominant (NLP) HL was diagnosed; in the areas between the nodules a proliferation of double-negative blastic T cells were present, suggestive of ALPS. Analysis for the presence of a FAS gene mutation using the denaturing gradient gel electrophoresis technique indicated a mutation in exon 9. Direct sequence analysis revealed a mutation causing a substitution of arginine with glutamine at codon 234. Because ALPS and NLP HL are both highly infrequent conditions, the occurrence in at least 3 families suggests a causative relationship between germline FAS gene mutations and NLP HL. PMID:11830507

van den Berg, Anke; Maggio, Ewerton; Diepstra, Arjan; de Jong, Debora; van Krieken, Johan; Poppema, Sibrand

2002-02-15

384

Recombination as a Mechanism for Sporadic Mutation in the Surfactant Protein-C Gene  

PubMed Central

SUMMARY Objective To determine haplotype background of common mutations in the genes encoding surfactant proteins B and C (SFTPB and SFTPC) and to assess recombination in SFTPC. Study design Using comprehensive resequencing of SFTPC and SFTPB, we assessed linkage disequilibrium (LD) (D’), and computationally inferred haplotypes. We computed average recombination rates and Bayes factors (BFs) within SFTPC in a population cohort and near SFTPC (±50kb) in HapMap cohorts. We then biochemically confirmed haplotypes in families with sporadic SFTPC mutations (n=11) and in individuals with the common SFTPB mutation (121ins2, n=34). Results We detected strong evidence (weak LD and BFs > 1400) for an intragenic recombination hot spot in both genes. The 121ins2 SFTPB mutation occurred predominantly (89%) on 2 common haplotypes. In contrast, no consistent haplotypes were associated with mutated SFTPC alleles. Sporadic SFTPC mutations arose on the paternal allele in 4 of 5 families; the remaining child had evidence for somatic recombination on the mutated allele. Conclusions In contrast to SFTPB, disease alleles at SFTPC do not share a common haplotype background. Most sporadic mutations in SFTPC occurred on the paternal allele, but somatic recombination may be an important mechanism of mutation in SFTPC.

McBee, Amy D.; Wegner, Daniel J.; Carlson, Christopher S.; Wambach, Jennifer A.; Yang, Ping; Heins, Hillary B.; Saugstad, Ola D.; Trusgnich, Michelle A.; Watkins-Torry, Julie; Nogee, Lawrence M.; Henderson, Howard; Cole, F. Sessions; Hamvas, Aaron

2009-01-01

385

Novel and recurrent mutations in the tyrosinase gene and the P gene in the German albino population  

Microsoft Academic Search

Albinism is a heterogeneous group of genetic disorders resulting from deficiencies in pigmentation. Clinically, it is divided into ocular (OA) and oculocutaneous albinism (OCA). OCA involves lack of pigment in the skin, hair, and eyes and results from mutations in the tyrosinase gene or in the P gene. OA mainly affects pigmentation in the visual system and may be a

Lori A. Passmore; Barbara Kaesmann-Kellner; Bernhard H. F. Weber

1999-01-01

386

A Mutation in the Mitochondrial Fission Gene Dnm1l Leads to Cardiomyopathy  

PubMed Central

Mutations in a number of genes have been linked to inherited dilated cardiomyopathy (DCM). However, such mutations account for only a small proportion of the clinical cases emphasising the need for alternative discovery approaches to uncovering novel pathogenic mutations in hitherto unidentified pathways. Accordingly, as part of a large-scale N-ethyl-N-nitrosourea mutagenesis screen, we identified a mouse mutant, Python, which develops DCM. We demonstrate that the Python phenotype is attributable to a dominant fully penetrant mutation in the dynamin-1-like (Dnm1l) gene, which has been shown to be critical for mitochondrial fission. The C452F mutation is in a highly conserved region of the M domain of Dnm1l that alters protein interactions in a yeast two-hybrid system, suggesting that the mutation might alter intramolecular interactions within the Dnm1l monomer. Heterozygous Python fibroblasts exhibit abnormal mitochondria and peroxisomes. Homozygosity for the mutation results in the death of embryos midway though gestation. Heterozygous Python hearts show reduced levels of mitochondria enzyme complexes and suffer from cardiac ATP depletion. The resulting energy deficiency may contribute to cardiomyopathy. This is the first demonstration that a defect in a gene involved in mitochondrial remodelling can result in cardiomyopathy, showing that the function of this gene is needed for the maintenance of normal cellular function in a relatively tissue-specific manner. This disease model attests to the importance of mitochondrial remodelling in the heart; similar defects might underlie human heart muscle disease.

Ashrafian, Houman; Docherty, Louise; Leo, Vincenzo; Towlson, Christopher; Neilan, Monica; Steeples, Violetta; Lygate, Craig A.; Hough, Tertius; Townsend, Stuart; Williams, Debbie; Wells, Sara; Norris, Dominic; Glyn-Jones, Sarah; Land, John; Barbaric, Ivana; Lalanne, Zuzanne; Denny, Paul; Szumska, Dorota; Bhattacharya, Shoumo; Griffin, Julian L.; Hargreaves, Iain; Fernandez-Fuentes, Narcis; Cheeseman, Michael; Watkins, Hugh; Dear, T. Neil

2010-01-01

387

De novo mutations in histone-modifying genes in congenital heart disease.  

PubMed

Congenital heart disease (CHD) is the most frequent birth defect, affecting 0.8% of live births. Many cases occur sporadically and impair reproductive fitness, suggesting a role for de novo mutations. Here we compare the incidence of de novo mutations in 362 severe CHD cases and 264 controls by analysing exome sequencing of parent-offspring trios. CHD cases show a significant excess of protein-altering de novo mutations in genes expressed in the developing heart, with an odds ratio of 7.5 for damaging (premature termination, frameshift, splice site) mutations. Similar odds ratios are seen across the main classes of severe CHD. We find a marked excess of de novo mutations in genes involved in the production, removal or reading of histone 3 lysine 4 (H3K4) methylation, or ubiquitination of H2BK120, which is required for H3K4 methylation. There are also two de novo mutations in SMAD2, which regulates H3K27 methylation in the embryonic left-right organizer. The combination of both activating (H3K4 methylation) and inactivating (H3K27 methylation) chromatin marks characterizes 'poised' promoters and enhancers, which regulate expression of key developmental genes. These findings implicate de novo point mutations in several hundreds of genes that collectively contribute to approximately 10% of severe CHD. PMID:23665959

Zaidi, Samir; Choi, Murim; Wakimoto, Hiroko; Ma, Lijiang; Jiang, Jianming; Overton, John D; Romano-Adesman, Angela; Bjornson, Robert D; Breitbart, Roger E; Brown, Kerry K; Carriero, Nicholas J; Cheung, Yee Him; Deanfield, John; DePalma, Steve; Fakhro, Khalid A; Glessner, Joseph; Hakonarson, Hakon; Italia, Michael J; Kaltman, Jonathan R; Kaski, Juan; Kim, Richard; Kline, Jennie K; Lee, Teresa; Leipzig, Jeremy; Lopez, Alexander; Mane, Shrikant M; Mitchell, Laura E; Newburger, Jane W; Parfenov, Michael; Pe'er, Itsik; Porter, George; Roberts, Amy E; Sachidanandam, Ravi; Sanders, Stephan J; Seiden, Howard S; State, Mathew W; Subramanian, Sailakshmi; Tikhonova, Irina R; Wang, Wei; Warburton, Dorothy; White, Peter S; Williams, Ismee A; Zhao, Hongyu; Seidman, Jonathan G; Brueckner, Martina; Chung, Wendy K; Gelb, Bruce D; Goldmuntz, Elizabeth; Seidman, Christine E; Lifton, Richard P

2013-05-12

388

Identification of candidate genes for lung cancer somatic mutation test kits  

PubMed Central

Over the past three decades, mortality from lung cancer has sharply and continuously increased in China, ascending to the first cause of death among all types of cancer. The ability to identify the actual sequence of gene mutations may help doctors determine which mutations lead to precancerous lesions and which produce invasive carcinomas, especially using next-generation sequencing (NGS) technology. In this study, we analyzed the latest lung cancer data in the COSMIC database, in order to find genomic “hotspots” that are frequently mutated in human lung cancer genomes. The results revealed that the most frequently mutated lung cancer genes are EGFR, KRAS and TP53. In recent years, EGFR and KRAS lung cancer test kits have been utilized for detecting lung cancer patients, but they presented many disadvantages, as they proved to be of low sensitivity, labor-intensive and time-consuming. In this study, we constructed a more complete catalogue of lung cancer mutation events including 145 mutated genes. With the genes of this list it may be feasible to develop a NGS kit for lung cancer mutation detection.

Chen, Yong; Shi, Jian-Xin; Pan, Xu-Feng; Feng, Jian; Zhao, Heng

2013-01-01

389

Screening for germ-line mutations in the NF2 gene.  

PubMed

Neurofibromatosis type 2 (NF2) is a monogenic dominantly inherited disease that predisposes to the development of tumors of the nervous system, particularly meningiomas and schwannomas. The gene which, when altered, causes NF2, is localized on chromosome 22 and has recently been identified. The NF2 gene is also the site of somatic mutation in tumors, suggesting that it might have a tumor suppressor activity. We here report a screening method for the detection of point mutations in NF2 which takes advantage of denaturing gradient gel electrophoresis (DGGE). This method efficiently screens 95% of the coding sequence and 90% of intron/exon junctions. When applied to 91 unrelated NF2 patients, it enabled the identification of 32 germ-line mutations. Since mutations are found in only one third of the patients, it is expected that mutations or deletions affecting the promoter and/or intronic regions of the NF2 gene occur frequently. The characterized mutations are preferentially located within the 5' half of the gene. Most of them are predicted to lead to the synthesis of a truncated protein. A search for genotype/phenotype correlations showed that, at least in this series of patients, mild manifestations of the disease were associated with mutations which preserve the C-terminal end of the protein. PMID:7535084

Mérel, P; Hoang-Xuan, K; Sanson, M; Bijlsma, E; Rouleau, G; Laurent-Puig, P; Pulst, S; Baser, M; Lenoir, G; Sterkers, J M

1995-02-01

390

Mutational analyses of the BRAF, KRAS, and PIK3CA genes in oral squamous cell carcinoma  

PubMed Central

OBJECTIVES The development of oral squamous cell carcinoma (OSCC) is a complex, multistep process. To date, numerous oncogenes and tumor-suppressor genes have been implicated in oral carcinogenesis. Of particular interest in this regard are genes involved in cell cycling and apoptosis, such BRAF, KRAS, and PIK3CA genes. STUDY DESIGN Mutations of BRAF, KRAS, and PIK3CA were evaluated by direct genomic sequencing of exons 1 of KRAS, 11 and 15 of BRAF, and 9 and 20 of PIK3CA in OSCC specimens. RESULTS Both BRAF and KRAS mutations were detected with a mutation frequency of 2% (1/42). PIK3CA mutations were detected at 3% (1/35). CONCLUSIONS This is the first report implicating BRAF mutation in OSCC. Our study supports that mutations in the BRAF, KRAS, and PIK3CA genes make at least a minor contribution to OSCC tumorigenesis, and pathway-specific therapies targeting these two pathways should be considered for OSCC in a subset of patients with these mutations.

Bruckman, Karl C.; Schonleben, Frank; Qiu, Wanglong; Woo, Victoria L.; Su, Gloria H.

2010-01-01

391

Iron overload and HFE gene mutations in Czech patients with chronic liver diseases.  

PubMed

The aim of the study was to identify the prevalence of HFE gene mutations in Czech patients with chronic liver diseases and the influence of the mutations on iron status. The presence of HFE gene mutations (C282Y, H63D, and S65C) analyzed by the PCR-RFLP method, presence of cirrhosis, and serum iron indices were compared among 454 patients with different chronic liver diseases (51 with chronic hepatitis B, 122 with chronic hepatitis C, 218 with alcoholic liver disease, and 63 patients with hemochromatosis). Chronic liver diseases patients other than hemochromatics did not have an increased frequency of HFE gene mutations compared to controls. Although 33.3% of patients with hepatitis B, 43% of patients with hepatitis C, and 73.2% of patients with alcoholic liver disease had elevated transferrin saturation or serum ferritin levels, the presence of HFE gene mutations was not significantly associated with iron overload in these patients. Additionally, patients with cirrhosis did not have frequencies of HFE mutations different from those without cirrhosis. This study emphasizes the importance, not only of C282Y, but also of the H63D homozygous genetic constellation in Czech hemochromatosis patients. Our findings show that increased iron indices are common in chronic liver diseases but {\\it HFE} mutations do not play an important role in the pathogenesis of chronic hepatitis B, chronic hepatitis C, and alcoholic liver disease. PMID:22297603

Dostalikova-Cimburova, Marketa; Kratka, Karolina; Stransky, Jaroslav; Putova, Ivana; Cieslarova, Blanka; Horak, Jiri

2012-01-01

392

Analysis of PTEN gene mutations in a Turkish patient with Cowden syndrome.  

PubMed

Cowden syndrome (CS), an autosomal dominant disorder, is associated with germline mutations of the PTEN (phosphatase, tensin homolog, deleted on chromosome TEN) gene. PTEN mutations were linked to several human neoplasms. Clinical diagnosis has been based on Consortium criteria, but detection of mutations in the PTEN gene has importance in accurate diagnosis. This article presents a female patient with classic features of the syndrome and gives the result of first PTEN mutation analysis result in a Turkish CS patient. The patient, who suffered from trichilemmomas, papillomatous lesions, lipomas, thyroid lesions, gastrointestinal hamartomas, and fibrocystic disease of the breast, is consistent with the diagnostic criteria of CS. The exons and intron/exon boundaries of the PTEN gene were analyzed by polymerase chain reaction and direct sequencing. We analyzed the clinical features and DNA in a Turkish patient with CS. We found a single-nucleotide substitution in the splicing acceptor site of intron 5 of the PTEN gene (IVS5-2A > C). It is not clear whether which types of PTEN mutations are responsible for particular phenotypes. This germline PTEN mutation, IVS5-2A --> C, has been reported once before, but the clinical features differ from our patient. Also, this is the first reported PTEN mutation from Turkey. PMID:19604110

Soysal, Yasemin; Tate, Genshu; Polat, Co?kun; Polat, Nevriye; Aktepe, Fatma; Sivaci, Ya?ar; Imirzalioglu, Necat

2009-08-01

393

Three novel mutations in the PHEX gene in Chinese subjects with hypophosphatemic rickets extends genotypic variability.  

PubMed

Mutations in the phosphate-regulating endopeptidase homolog, X-linked, gene (PHEX), which encodes a zinc-dependent endopeptidase that is involved in bone mineralization and renal phosphate reabsorption, cause the most common form of hypophosphatemic rickets, X-linked hypophosphatemic rickets (XLH). The distribution of PHEX mutations is extensive, but few mutations have been identified in Chinese with XLH. We extracted genomic DNA and total RNA from leukocytes obtained from nine unrelated Chinese subjects (three males and six females, age range 11-36 years) who were living in Taiwan. The PHEX gene was amplified from DNA by PCR, and the amplicons were directly sequenced. Expression studies were performed by reverse-transcription PCR of leukocyte RNA. Serum levels of FGF23 were significantly greater in the patients than in normal subjects (mean 69.4 ± 18.8 vs. 27.2 ± 8.4 pg/mL, P < 0.005), and eight of the nine patients had elevated levels of FGF23. Germline mutations in the PHEX gene were identified in five of 9 patients, including novel c.1843 delA, donor splice site mutations c.663+2delT and c.1899+2T>A, and two previously reported missense mutations, p.C733Y and p.G579R. These data extend the spectrum of mutations in the PHEX gene in Han Chinese and confirm variability for XLH in Taiwan. PMID:21293852

Jap, Tjin-Shing; Chiu, Chih-Yang; Niu, Dau-Ming; Levine, Michael A

2011-02-04

394

Systematic mutation analysis of seven dystonia genes in complex regional pain syndrome with fixed dystonia.  

PubMed

Complex regional pain syndrome type 1 (CRPS-1) is a chronic pain disorder that in some patients is associated with fixed dystonia. The pathogenesis of CRPS and its relation to dystonia remain poorly understood. Several genes (so-called DYT genes) identified in other causes of dystonia play a role in mechanisms that have been implicated in CRPS. Because different mutations in the same gene can result in diverse phenotypes, we sequenced all coding exons of the DYT1, DYT5a, DYT5b, DYT6, DYT11, DYT12, and DYT16 genes in 44 CRPS patients with fixed dystonia to investigate whether high-penetrant causal mutations play a role in CRPS. No such mutations were identified, indicating that these genes do not seem to play a major role in CRPS. PMID:20066431

Gosso, M Florencia; de Rooij, Annetje M; Alsina-Sanchis, Elisenda; Kamphorst, Jessica T; Marinus, Johan; van Hilten, Jacobus J; van den Maagdenberg, Arn M J M

2010-01-12

395

Pesticide-induced gene mutations and Parkinson disease risk: a meta-analysis.  

PubMed

Aims: Increasing scientific evidence suggests that pesticide-induced gene mutations may contribute to increasing susceptibility to Parkinson disease (PD), but many existing studies have yielded inconclusive results. This meta-analysis aims at assessing the exact roles of pesticide-induced gene mutations in the development of PD. Methods: An extensive literature search for relevant studies was conducted on PubMed, Embase, Web of Science, Cochrane Library, and CBM databases from their inception through May 1st, 2013. This meta-analysis was performed using the STATA 12.0 software. The crude odds ratio with 95% confidence interval was calculated. Results: Ten case-control studies were included with a total of 1248 PD patients and 1831 healthy controls. Our meta-analysis revealed that PD patients with pesticide exposure had higher gene mutation rates than those of healthy controls. Subgroup analysis by gene type indicated that the mutation rates in the GSTP1, SLC6A3, and MDR1 genes of PD patients with pesticide exposure were higher than those of healthy controls. No publication bias was detected in this meta-analysis. Conclusion: The current meta-analysis indicates that pesticide-induced gene mutations may contribute to increasing susceptibility to PD, especially in the GSTP1, SLC6A3, and MDR1 genes. PMID:23987116

Liu, Xiaowei; Ma, Tao; Qu, Bo; Ji, Yan; Liu, Zhi

2013-08-29

396

Highly efficient generation of heritable zebrafish gene mutations using homo- and heterodimeric TALENs.  

PubMed

Transcription activator-like effector nucleases (TALENs) are powerful new research tools that enable targeted gene disruption in a wide variety of model organisms. Recent work has shown that TALENs can induce mutations in endogenous zebrafish genes, but to date only four genes have been altered, and larger-scale tests of the success rate, mutation efficiencies and germline transmission rates have not been described. Here, we constructed homodimeric TALENs to 10 different targets in various endogenous zebrafish genes and found that 7 nuclease pairs induced targeted indel mutations with high efficiencies ranging from 2 to 76%. We also tested obligate heterodimeric TALENs and found that these nucleases induce mutations with comparable or higher frequencies and have better toxicity profiles than their homodimeric counterparts. Importantly, mutations induced by both homodimeric and heterodimeric TALENs are passed efficiently through the germline, in some cases reaching 100% transmission. For one target gene sequence, we observed substantially reduced mutagenesis efficiency for a variant site bearing two mismatched nucleotides, raising the possibility that TALENs might be used to perform allele-specific gene disruption. Our results suggest that construction of one to two heterodimeric TALEN pairs for any given gene will, in most cases, enable researchers to rapidly generate knockout zebrafish. PMID:22684503

Cade, Lindsay; Reyon, Deepak; Hwang, Woong Y; Tsai, Shengdar Q; Patel, Samir; Khayter, Cyd; Joung, J Keith; Sander, Jeffry D; Peterson, Randall T; Yeh, Jing-Ruey Joanna

2012-06-07

397

The implications of genetic mutations in the sodium channel gene (SCN5A).  

PubMed

Mutations in sodium channel alpha-subunit gene (SCN5A) result in multiple arrhythmic syndromes, including long QT3 (LQT3), Brugada syndrome (BS), an inherited cardiac conduction defect, sudden unexpected nocturnal death syndrome (SUNDS) and sudden infant death syndrome (SIDS), constituting a spectrum of disease entities termed Na+ channelopathies. These diseases are allelic disorders, if not the same disease with variable penetrance and variable modifiers worldwide. Interestingly, death occurs during sleep in all of these disorders, suggesting a common mechanism. To date, mutational analyses have revealed about 103 distinct mutations in SCN5A, of which at least more than 30 mutations are associated with LQT3, whereas the rest of the mutations are affiliated with the remaining sodium channel disorders. The majority of these mutations are missense. However, other types such as deletions, insertions, frameshifts, nonsense and splice-donor errors have also been reported. PMID:14753626

Moric, E; Herbert, E; Trusz-Gluza, M; Filipecki, A; Mazurek, U; Wilczok, T

2003-10-01

398

Seven novel point mutations in the F11 gene in Iranian FXI-deficient patients.  

PubMed

Factor XI (FXI) deficiency disorder is caused by defects in the F11 gene. The affected patients may suffer unexpected and major bleeding after trauma. Hence, the aim of this study was to identify the mutations underlying FXI deficiency in Iranian patients. The genetic basis of FXI deficiency was investigated in nine Iranian patients from unrelated families using conformation-sensitive gel electrophoresis (CSGE) and direct sequencing. Nine different mutations were detected among which seven changes were not previously reported. Among the novel mutations, one was a point mutation that interfered with normal splicing of the mRNA; the other six changes were missense mutations that resulted in amino acid substitutions. Five mutations out of nine were heterozygous and were found in moderately affected patients, whereas the other four changes were homozygous among severely affected patients. PMID:18005151

Fard-Esfahani, P; Lari, G R; Ravanbod, S; Mirkhani, F; Allahyari, M; Rassoulzadegan, M; Ala, F

2007-11-13

399

Heteroduplex analysis of the dystrophin gene: Application to point mutation and carrier detection  

SciTech Connect

Approximately one-third of Duchenne muscular dystrophy patients have undefined mutations in the dystrophin gene. For carrier and prenatal studies in families without detectable mutations, the indirect restriction fragment length polymorphism linkage approach is used. Using a multiplex amplification and heteroduplex analysis of dystrophin exons, the authors identified nonsense mutations in two DMD patients. Although the nonsense mutations are predicted to severely truncate the dystrophin protein, both patients presented with mild clinical courses of the disease. As a result of identifying the mutation in the affected boys, direct carrier studies by heteroduplex analysis were extended to other relatives. The authors conclude that the technique is not only ideal for mutation detection but is also useful for diagnostic testing. 29 refs., 4 figs.

Prior, T.W.; Papp, A.C.; Snyder, P.J.; Sedra, M.S.; Western, L.M.; Bartolo, C.; Mendell, J.R. [Ohio State Univ., Columbus, OH (United States); Moxley, R.T. [Univ. of Rochester Medical Center, NY (United States)

1994-03-01

400

A bacterial model for expression of mutations in the human ornithine transcarbamylase (OTC) gene  

SciTech Connect

OTC is a mitochondrial enzyme catalyzing the formation of citrulline from carbamyl phosphate and ornithine. X-linked deficiency of OTC is the most prevalent genetic defect of ureagenesis. Mutations and polymorphisms in the OTC gene identified in deficient patients have indicated the occurrence of many family-specific, unique alleles. Due to the low frequency of recurrent mutations, distinguishing between deleterious mutations and polymorphisms is difficult. Using a human OTC gene containing plasmid driven by a tac promoter, we have devised a simple and efficient method for expressing mutations in the mature human OTC enzyme. To demonstrate this method, PCR engineered site-directed mutagenesis was employed to generated cDNA fragments which contained either the R151Q or R277W known mutations found in patients with neonatal and late-onset OTC deficiency, respectively. The normal allele for each mutation was also generated by an identical PCR procedure. Digestion with Bgl II- and Sty I-generated mutant and normal replacement cassettes containing the respective mutant and wild type sequences. Upon transformation of JM109 E.coli cells, OTC enzymatic activity was measured at log and stationary phases of growth using a radiochromatographic method. The R141Q mutation abolished enzymatic activity (<0.02% of normal), whereas the R277W mutation expressed partial activity (2.3% of normal). In addition, a PCR-generated mutation, A280V, resulted in 73% loss of catalytic activity. This OTC expression system is clinically applicable for distinguishing between mutations and polymorphisms, and it can be used to investigate the effects of mutations on various domains of the OTC gene.

Tuchman, M.; McCann, M.T.; Qureshi, A.A. [Univ. of Minnesota, Mineapolis (United States)

1994-09-01

401

Likelihood models of somatic mutation and codon substitution in cancer genes.  

PubMed Central

The role of somatic mutation in cancer is well established and several genes have been identified that are frequent targets. This has enabled large-scale screening studies of the spectrum of somatic mutations in cancers of particular organs. Cancer gene mutation databases compile the results of many studies and can provide insight into the importance of specific amino acid sequences and functional domains in cancer, as well as elucidate aspects of the mutation process. Past studies of the spectrum of cancer mutations (in particular genes) have examined overall frequencies of mutation (at specific nucleotides) and of missense, nonsense, and silent substitution (at specific codons) both in the sequence as a whole and in a specific functional domain. Existing methods ignore features of the genetic code that allow some codons to mutate to missense, or stop, codons more readily than others (i.e., by one nucleotide change, vs. two or three). A new codon-based method to estimate the relative rate of substitution (fixation of a somatic mutation in a cancer cell lineage) of nonsense vs. missense mutations in different functional domains and in different tumor tissues is presented. Models that account for several potential influences on rates of somatic mutation and substitution in cancer progenitor cells and allow biases of mutation rates for particular dinucleotide sequences (CGs and dipyrimidines), transition vs. transversion bias, and variable rates of silent substitution across functional domains (useful in detecting investigator sampling bias) are considered. Likelihood-ratio tests are used to choose among models, using cancer gene mutation data. The method is applied to analyze published data on the spectrum of p53 mutations in cancers. A novel finding is that the ratio of the probability of nonsense to missense substitution is much lower in the DNA-binding and transactivation domains (ratios near 1) than in structural domains such as the linker, tetramerization (oligomerization), and proline-rich domains (ratios exceeding 100 in some tissues), implying that the specific amino acid sequence may be less critical in structural domains (e.g., amino acid changes less often lead to cancer). The transition vs. transversion bias and effect of CpG dinucleotides on mutation rates in p53 varied greatly across cancers of different organs, likely reflecting effects of different endogenous and exogenous factors influencing mutation in specific organs.

Yang, Ziheng; Ro, Simon; Rannala, Bruce

2003-01-01

402

Mutations in the consensus helicase domains of the Werner syndrome gene. Werner's Syndrome Collaborative Group.  

PubMed Central

Werner syndrome (WS) is an autosomal recessive disease with a complex phenotype that is suggestive of accelerated aging. WS is caused by mutations in a gene, WRN, that encodes a predicted 1,432-amino-acid protein with homology to DNA and RNA helicases. Previous work identified four WS mutations in the 3' end of the gene, which resulted in predicted truncated protein products of 1,060-1,247 amino acids but did not disrupt the helicase domain region (amino acids 569-859). Here, additional WS subjects were screened for mutations, and the intron-exon structure of the gene was determined. A total of 35 exons were defined, with the coding sequences beginning in the second exon. Five new WS mutations were identified: two nonsense mutations at codons 369 and 889; a mutation at a splice-junction site, resulting in a predicted truncated protein of 760 amino acids; a 1-bp deletion causing a frameshift; and a predicted truncated protein of 391 amino acids. Another deletion is >15 kb of genomic DNA, including exons 19-23; the predicted protein is 1,186 amino acids long. Four of these new mutations either partially disrupt the helicase domain region or result in predicted protein products completely missing the helicase region. These results confirm that mutations in the WRN gene are responsible for WS. Also, the location of the mutations indicates that the presence or absence of the helicase domain does not influence the WS phenotype and suggests that WS is the result of complete loss of function of the WRN gene product.

Yu, C E; Oshima, J; Wijsman, E M; Nakura, J; Miki, T; Piussan, C; Matthews, S; Fu, Y H; Mulligan, J; Martin, G M; Schellenberg, G D

1997-01-01

403

Mutations in the consensus helicase domains of the Werner syndrome gene  

SciTech Connect

Werner syndrome (WS) is an autosomal recessive disease with a complex phenotype that is suggestive of accelerated aging. WS is caused by mutations in a gene, WRN, that encodes a predicted 1,432-amino-acid protein with homology to DNA and RNA helicases. Previous work identified four WS mutations in the 3{prime} end of the gene, which resulted in predicted truncated protein products of 1,060-1,247 amino acids but did not disrupt the helicase domain region (amino acids 569-859). Here, additional WS subjects were screened for mutations, and the intron-exon structure of the gene was determined. A total of 35 exons were defined, with the coding sequences beginning in the second exon. Five new WS mutations were identified: two nonsense mutations at codons 369 and 889; a mutation at a splice-junction site, resulting in a predicted truncated protein of 760 amino acids; a 1-bp deletion causing a frameshift; and a predicted truncated protein of 391 amino acids. Another deletion is >15 kb of genomic DNA, including exons 19-23; the predicted protein is 1,186 amino acids long. Four of these new mutations either partially disrupt the helicase domain region or result in predicted protein products completely missing the helicase region. These results confirm that mutations in the WRN gene are responsible for WS. Also, the location of the mutations indicates that the presence or absence of the helicase domain does not influence the WS phenotype and suggests that WS is the result of complete loss of function of the WRN gene product. 63 refs., 1 fig., 5 tabs.

Yu, Chang-En; Oshima, Junko; Wijsman, E.M. [Univ. of Washington, Seattle, WA (United States)] [and others

1997-02-01

404

Array CGH improves detection of mutations in the GALC gene associated with Krabbe disease  

PubMed Central

Background Krabbe disease is an autosomal recessive lysosomal storage disorder caused by mutations in the GALC gene. The most common mutation in the Caucasian population is a 30-kb deletion of exons 11 through 17. There are few other reports of intragenic GALC deletions or duplications, due in part to difficulties detecting them. Methods and results We used gene-targeted array comparative genomic hybridization (CGH) to analyze the GALC gene in individuals with Krabbe disease in whom sequence analysis with 30-kb deletion analysis identified only one mutation. In our sample of 33 cases, traditional approaches failed to identify two pathogenic mutations in five (15.2%) individuals with confirmed Krabbe disease. The addition of array CGH deletion/duplication analysis to the genetic testing strategy led to the identification of a second pathogenic mutation in three (9.1%) of these five individuals. In all three cases, the deletion or duplication identified through array CGH was a novel GALC mutation, including the only reported duplication in the GALC gene, which would have been missed by traditional testing methodologies. We report these three cases in detail. The second mutation remains unknown in the remaining two individuals (6.1%), despite our full battery of testing. Conclusions Analysis of the GALC gene using array CGH deletion/duplication testing increased the two-mutation detection rate from 84.8% to 93.9% in affected individuals. Better mutation detection rates are important for improving molecular diagnosis of Krabbe disease, as well as for providing prenatal and carrier testing in family members.

2012-01-01

405

p16 tumor suppressor gene mutations in Chinese esophageal carcinomas in Hong Kong.  

PubMed

The frequency and nature of genetic alterations in the p16 tumor suppressor gene in 25 esophageal squamous cell carcinoma specimens from Chinese patients were investigated by PCR-SSCP and DNA sequencing techniques. No gross deletions occurred in either exon 1 and 2 of the gene by PCR amplification. However, genetic changes were observed in three cases. These included a point mutation in codon 12 of exon 1 with a resulting Ala --> Thr amino acid substitution, a point mutation at base 91 in the non-coding region of exon 1, and a 1 base pair insertion in codon 116 of exon 2. The low mutation frequency of 12% is consistent with that of three previous studies involving Japanese and Caucasian patients (8, 16 and 21% frequency: Esteve et al., 1996, Igaki et al., 1995 and Zhou et al., 1994). p16 gene mutations do not appear to play a major role in esophageal carcinogenesis. PMID:9149125

Chan, W C; Tang, C M; Lau, K W; Lung, M L

1997-05-19

406

Comparison of p53 gene mutation and protein overexpression in colorectal carcinomas.  

PubMed Central

Immunocytochemistry (ICC) has been used routinely to stain for p53 overexpression in a range of human tumours. The underlying assumption has been that positive staining indicates a mutation in the p53 coding sequence. Recently, however, discordancy has been observed and the accuracy of ICC as a marker of p53 gene mutation has been questioned. In this study of 109 colorectal adenocarcinomas, we compared ICC staining with p53 gene mutations detected by single-strand conformation polymorphism (SSCP) analysis. Concordancy between the two techniques was found in 69% of tumours. ICC-positive/SSCP-negative cases accounted for 20% of tumours and ICC-negative/SSCP-positive cases for the remaining 11%. These results caution against the assumption that p53 protein overexpression is always associated with a gene mutation. Epigenetic phenomena may account for a significant proportion of ICC-positive tumours. Images Figure 1 Figure 2 Figure 3

Dix, B.; Robbins, P.; Carrello, S.; House, A.; Iacopetta, B.

1994-01-01

407

Infantile systemic hyalinosis associated with a putative splice-site mutation in the ANTXR2 gene.  

PubMed

Infantile systemic hyalinosis (ISH) is a rare autosomal recessive genetic disorder characterized by dermal and subcutaneous fibromatosis, joint contractures and bone deformities. The condition usually presents at birth, resulting in death in infancy. ISH is caused by mutations in the anthrax toxin receptor 2 gene, ANTXR2, also known as CMG2. We report an Indian child with ISH in whom we identified a homozygous acceptor splice site mutation, IVS2-4G>A. In silico analysis of this sequence showed that it changed predicted cryptic splicing, leading to out-of-frame transcripts and little, if any, functional protein. Mutations in the ANTXR2 gene can also cause juvenile hyaline fibromatosis (JHF). Although there are currently no effective treatments for ISH or JHF, identification of pathogenetic mutations in the ANTXR2 gene makes DNA-based prenatal diagnosis feasible for subsequent pregnancies. PMID:22300424

Fong, K; Rama Devi, A R; Lai-Cheong, J E; Chirla, D; Panda, S K; Liu, L; Tosi, I; McGrath, J A

2012-02-02

408

Loss-of-Function Mutations in the Keratin 5 Gene Lead to Dowling-Degos Disease  

PubMed Central

Dowling-Degos disease (DDD) is an autosomal dominant genodermatosis characterized by progressive and disfiguring reticulate hyperpigmentation of the flexures. We performed a genomewide linkage analysis of two German families and mapped DDD to chromosome 12q, with a total LOD score of