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1

Gene Mutations  

Cancer.gov

One particularly well known monoclonal antibody, trastuzumab (Herceptin), developed in the 1990s, can exert its anti-cancer effects by several mechanisms, including targeting a cell-surface protein called HER2.

2

Capillary electrophoresis of gene mutation.  

PubMed

This chapter illustrates the usefulness of capillary electrophoresis (CE) for the detection of gene mutation, i.e., point mutation, methylation, and microsatellite analysis. In order to provide a general description of the main results and challenges in the field, some relevant applications and reviews on CE of gene mutation are tabulated. Furthermore, some detailed experimental procedures are shown. Several CE methods of gene mutation detection were developed including the following: (1) single-strand conformation polymorphism with capillary electrophoresis; (2) SNaPshot analysis; (3) constant denaturant capillary electrophoresis; (4) microsatellite analysis; and (5) methylation analysis. PMID:18392579

Xu, Guowang; Shi, Xianzhe; Zhao, Chunxia; Yuan, Kailong; Weng, Qianfeng; Gao, Peng; Tian, Jing

2008-01-01

3

Dysregulation of the TGFBI gene is involved in the oncogenic activity of the nonsense mutation of hepatitis B virus surface gene sW182*.  

PubMed

The nonsense mutations of the hepatitis B virus (HBV) surface (S) gene have been reported to have oncogenic potential. We have previously identified several transforming nonsense mutations of the HBV S gene from hepatocarcinoma (HCC) patients. Among them, the sW182* mutant (the stop codon for tryptophan 182) showed the most potent oncogenicity in a mouse xenograft model using stably transfected mouse fibroblast cells. This study is aimed at understanding the molecular mechanisms leading to the oncogenic activity of the sW182* mutant. A gene expression microarray in combination with gene set enrichment analysis (GSEA) revealed differentially expressed gene sets in the sW182* cells, including those related to cell-cycle regulation, deoxyribonucleic acid repair, and genome instability. Of the differentially expressed genes, the transforming growth factor-?-induced (TGFBI) gene was further validated to be dysregulated in the sW182* cells. This dysregulation was accompanied by hypermethylation of the TGFBI promoter. The level of cyclin D1, a negatively regulated TGFBI target, was highly elevated in the sW182* mutant cells, which is consistent with the potent oncogenicity. Furthermore, frequent abnormal mitosis and multinucleation were observed in the mutant cells. Exogenous expression of TGFBI alleviated the oncogenic activity of the sW182* cells. In human HBV-related HCC cancerous tissue, expression of TGFBI was downregulated in 25 of the 55 (45%) patients examined, suggesting that TGFBI dysregulation could occur in HBV-related HCC development in some cases. These results suggest that dysregulation of TGFBI is involved in the oncogenic activity of the sW182* mutant of the hepatitis B virus S gene. PMID:24662304

Jiang, Shih Sheng; Huang, Shiu-Feng; Huang, Min-Syuan; Chen, Yng-Tay; Jhong, Hsiang-Ju; Chang, Il-Chi; Chen, Ya-Ting; Chang, Jer-Wei; Chen, Wen-Ling; Lee, Wei-Chen; Chen, Miin-Fu; Yeh, Chau-Ting; Matsuura, Isao

2014-07-01

4

Human Immunoglobulin (Ig)M+IgD+ 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  

PubMed Central

Immunoglobulin (Ig)M+IgD+ B cells are generally assumed to represent antigen-inexperienced, naive B cells expressing variable (V) region genes without somatic mutations. We report here that human IgM+IgD+ peripheral blood (PB) B cells expressing the CD27 cell surface antigen carry mutated V genes, in contrast to CD27-negative IgM+IgD+ B cells. IgM+IgD+CD27+ B cells resemble class-switched and IgM-only memory cells in terms of cell phenotype, and comprise ?15% of PB B lymphocytes in healthy adults. Moreover, a very small population (<1% of PB B cells) of highly mutated IgD-only B cells was detected, which likely represent the PB counterpart of IgD-only tonsillar germinal center and plasma cells. Overall, the B cell pool in the PB of adults consists of ?40% mutated memory B cells and 60% unmutated, naive IgD+CD27? B cells (including CD5+ B cells). In the somatically mutated B cells, VH region genes carry a two- to threefold higher load of somatic mutation than rearranged V? genes. This might be due to an intrinsically lower mutation rate in ? light chain genes compared with heavy chain genes and/or result from ? light chain gene rearrangements in GC B cells. A common feature of the somatically mutated B cell subsets is the expression of the CD27 cell surface antigen which therefore may represent a general marker for memory B cells in humans. PMID:9802980

Klein, Ulf; Rajewsky, Klaus; Kuppers, Ralf

1998-01-01

5

Mutations in cardiovascular connexin genes.  

PubMed

Connexins (Cxs) form a family of transmembrane proteins comprising 21 members in humans. Cxs differ in their expression patterns, biophysical properties and ability to combine into homomeric or heteromeric gap junction channels between neighbouring cells. The permeation of ions and small metabolites through gap junction channels or hemichannels confers a crucial role to these proteins in intercellular communication and in maintaining tissue homeostasis. Among others, Cx37, Cx40, Cx43, Cx45 and Cx47 are found in heart, blood and lymphatic vessels. Mutations or polymorphisms in the genes coding for these Cxs have not only been implicated in cardiovascular pathologies but also in a variety of other disorders. While mutations in Cx43 are mostly linked to oculodentodigital dysplasia, Cx47 mutations are associated with Pelizaeus-Merzbacher-like disease and lymphoedema. Cx40 mutations are principally linked to atrial fibrillation. Mutations in Cx37 have not yet been described, but polymorphisms in the Cx37 gene have been implicated in the development of arterial disease. This review addresses current knowledge on gene mutations in cardiovascular Cxs systematically and links them to alterations in channel properties and disease. PMID:24966059

Molica, Filippo; Meens, Merlijn J P; Morel, Sandrine; Kwak, Brenda R

2014-09-01

6

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. PMID:23326453

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

2013-01-01

7

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. PMID:8139044

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

1994-01-01

8

Molecular basis of Mycoplasma surface antigenic variation: a novel set of divergent genes undergo spontaneous mutation of periodic coding regions and 5' regulatory sequences.  

PubMed Central

Antigenic diversity is generated in the wall-less pathogen Mycoplasma hyorhinis by combinatorial expression and phase variation of multiple, size-variant membrane surface lipoproteins (Vlps). The unusual structural basis for Vlp variation was revealed in a cluster of related but divergent vlp genes, vlpA, vlpB and vlpC, which occur as single chromosomal copies. These encode conserved N-terminal domains for membrane insertion and lipoprotein processing, but divergent external domains undergoing size variation by loss or gain of repetitive intragenic coding sequences while retaining a motif with distinctive charge distribution. Genetic analysis of phenotypically switched isogenic lineages representing ON or OFF expression states of Vlp products ruled out chromosomal rearrangement or frameshift mutations as mechanisms for Vlp phase variation. However, highly conserved vlp promoter regions contain a tract of contiguous A residues immediately upstream of the -10 box which is subject to frequent mutations altering its length in exact correspondence with the ON and OFF phase states of specific genes. This suggests a mechanism of transcriptional control regulating high frequency phase variation and random combinatorial expression of Vlps. The multiple levels of diversity embodied in the vlp gene cluster represents a novel adaptive capability particularly suited for this class of wall-less microbe. Images PMID:1721868

Yogev, D; Rosengarten, R; Watson-McKown, R; Wise, K S

1991-01-01

9

The Human Gene Mutation Database: 2008 update  

Microsoft Academic Search

The Human Gene Mutation Database (HGMDŽ) 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

Genes and mutations causing retinitis pigmentosa  

PubMed Central

Retinitis pigmentosa (RP) is a heterogeneous set of inherited retinopathies with many disease-causing genes, many known mutations, and highly varied clinical consequences. Progress in finding treatments is dependent on determining the genes and mutations causing these diseases, which includes both gene discovery and mutation screening in affected individuals and families. Despite the complexity, substantial progress has been made in finding RP genes and mutations. Depending on the type of RP, and the technology used, it is possible to detect mutations in 30–80% of cases. One of the most powerful approaches to genetic testing is high-throughput ‘deep sequencing’, that is, next-generation sequencing (NGS). NGS has identified several novel RP genes but a substantial fraction of previously unsolved cases have mutations in genes that are known causes of retinal disease but not necessarily RP. Apparent discrepancy between the molecular defect and clinical findings may warrant reevaluation of patients and families. In this review, we summarize the current approaches to gene discovery and mutation detection for RP, and indicate pitfalls and unsolved problems. Similar considerations apply to other forms of inherited retinal disease. PMID:23701314

Daiger, SP; Sullivan, LS; Bowne, SJ

2013-01-01

11

Researchers Find Gene Mutation That May Protect Against Heart Disease  

MedlinePLUS

... Researchers Find Gene Mutation That May Protect Against Heart Disease Rare genetic variation appears to cut the risk ... 2014 Related MedlinePlus Pages Genes and Gene Therapy Heart Diseases WEDNESDAY, Nov. 12, 2014 (HealthDay News) -- Mutations that ...

12

Mutation pattern of human immunodeficiency virus genes  

Microsoft Academic Search

Summary Human immunodeficiency viruses (HIVs) show extensive genetic variation. This feature is the fundamental cause of pathogenicity of HIVs and thwarts efforts to develop effective vaccines. To understand the mutation mechanism of these viruses, we analyzed nucleotide sequences ofenv andgag genes of the viruses by use of molecular evolutionary methods and estimated the direction and frequency of nucleotide substitutions. Results

Etsuko N. Moriyama; Yasuo Ina; Kazuho Ikeo; Nobuaki Shimizu; Takashi Gojobori

1991-01-01

13

Mutational robustness of ribosomal protein genes.  

PubMed

The distribution of fitness effects (DFE) of mutations is of fundamental importance for understanding evolutionary dynamics and complex diseases and for conserving threatened species. DFEs estimated from DNA sequences have rarely been subject to direct experimental tests. We used a bacterial system in which the fitness effects of a large number of defined single mutations in two ribosomal proteins were measured with high sensitivity. The obtained DFE appears to be unimodal, where most mutations (120 out of 126) are weakly deleterious and the remaining ones are potentially neutral. The DFEs for synonymous and nonsynonymous substitutions are similar, suggesting that in some genes, strong fitness constraints are present at the level of the messenger RNA. PMID:21051637

Lind, Peter A; Berg, Otto G; Andersson, Dan I

2010-11-01

14

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. PMID:22536974

2012-01-01

15

A Recurring FBN1 Gene Mutation in Neonatal Marfan Syndrome  

Microsoft Academic Search

Background: Marfan syndrome is an autosomal domi- nant disorder of connective tissue caused by mutations in the fibrillin 1 gene (FBN1). FBN1 mutations have been associated with a broad spectrum of phenotypes. Neo- natal Marfan syndrome has unique clinical manifesta- tions and mutations. Objective: To determine if there is a discernible geno- typic-phenotypic correlation associated with the unique mutation in

Amanda M. Jacobs; Ivanka Toudjarska; Andrew Racine; Petros Tsipouras; Michael W. Kilpatrick; Alan Shanske

2002-01-01

16

Childhood Peanut Allergy May Be Linked to Skin Gene Mutation  

MedlinePLUS

... on this page, please enable JavaScript. Childhood Peanut Allergy May Be Linked to Skin Gene Mutation Study ... Friday, October 24, 2014 Related MedlinePlus Pages Food Allergy Genes and Gene Therapy Skin Conditions FRIDAY, Oct. ...

17

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

18

Overview of skin diseases linked to connexin gene mutations.  

PubMed

Mutations in skin-expressed connexin genes, such as connexins 26, 30, 30.3, 31, and 43, have been linked to several human hereditary diseases with multiple organ involvement. Mutations in connexin 26 are linked to diseases including Vohwinkel syndrome, keratitis-ichthyosis deafness, and hystrix-like ichthyosis deafness syndromes, palmoplantar keratoderma with deafness, deafness with Clouston-like phenotype, and Bart-Pumphrey syndrome. Mutations in connexin 30 are correlated with Clouston syndrome. Connexin 30.3 and 31 mutations lead to erythrokeratoderma variabilis, and mutations in connexin 43 are correlated with oculodentodigital dysplasia. Provided is a review of these mutations and related skin disorders. PMID:23675785

Avshalumova, Lyubov; Fabrikant, Jordan; Koriakos, Angie

2014-02-01

19

Comparison of somatic mutation frequency among immunoglobulin genes  

PubMed Central

We analyzed the frequency of somatic mutation in immunoglobulin genes from hybridomas that secrete anti-(4-hydroxy-3-nitrophenyl)acetyl (NP) monoclonal antibodies. A high frequency of mutation (3.3-4.4%) was observed in both the rearranged VH186.2 and V lambda 1 genes, indicating that somatic mutation occurs with similar frequency in these genes in spite of the absence of an intron enhancer in lambda 1 chain genes. In contrast to the high frequency in J-C introns, only two nucleotide substitutions occurred at positions -462 and -555 in the 5' noncoding region in one of the lambda 1-chain genes and in none of the other three so far studied. Since a similar low frequency of somatic mutation was observed in the 5' noncoding region of inactive lambda 2- chain genes rendered inactive because of incorrect rearrangement, this region may not be a target or alternatively, may be protected from the mutator system. We observed a low frequency of nucleotide substitution in unrearranged V lambda 1 genes (approximately 1/15 that of rearranged genes). Together with previous results (Azuma T., N. Motoyama, L. Fields, and D. Loh, 1993. Int. Immunol. 5:121), these findings suggest that the 5' noncoding region, which contains the promoter element, provides a signal for the somatic mutator system and that rearrangement, which brings the promoter into close proximity to the enhancer element, should increase mutation efficiency. PMID:8294856

1994-01-01

20

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

21

Mutations of the BRAF gene in human cancer  

Microsoft Academic Search

Cancers arise owing to the accumulation of mutations in critical genes that alter normal programmes of cell proliferation, differentiation and death. As the first stage of a systematic genome-wide screen for these genes, we have prioritized for analysis signalling pathways in which at least one gene is mutated in human cancer. The RAS-RAF-MEK-ERK-MAP kinase pathway mediates cellular responses to growth

Helen Davies; Graham R. Bignell; Charles Cox; Philip Stephens; Sarah Edkins; Sheila Clegg; Jon Teague; Hayley Woffendin; Mathew J. Garnett; William Bottomley; Neil Davis; Ed Dicks; Rebecca Ewing; Yvonne Floyd; Kristian Gray; Sarah Hall; Rachel Hawes; Jaime Hughes; Vivian Kosmidou; Andrew Menzies; Catherine Mould; Adrian Parker; Claire Stevens; Stephen Watt; Steven Hooper; Rebecca Wilson; Hiran Jayatilake; Barry A. Gusterson; Colin Cooper; Janet Shipley; Darren Hargrave; Katherine Pritchard-Jones; Norman Maitland; Georgia Chenevix-Trench; Gregory J. Riggins; Darell D. Bigner; Giuseppe Palmieri; Antonio Cossu; Adrienne Flanagan; Andrew Nicholson; Judy W. C. Ho; Suet Y. Leung; Siu T. Yuen; Barbara L. Weber; Hilliard F. Seigler; Timothy L. Darrow; Hugh Paterson; Richard Marais; Christopher J. Marshall; Richard Wooster; Michael R. Stratton; P. Andrew Futreal

2002-01-01

22

Modeling Autism by SHANK Gene Mutations in Mice  

PubMed Central

Summary Shank family proteins (Shank1, Shank2, and Shank3) are synaptic scaffolding proteins that organize an extensive protein complex at the postsynaptic density (PSD) of excitatory glutamatergic synapses. Recent human genetic studies indicate that SHANK family genes (SHANK1, SHANK2, and SHANK3) are causative genes for idiopathic autism spectrum disorders (ASD). Neurobiological studies of Shank mutations in mice support a general hypothesis of synaptic dysfunction in the pathophysiology of ASD. However, the molecular diversity of SHANK family gene products, as well as the heterogeneity in human and mouse phenotypes, pose challenges to modeling human SHANK mutations. Here, we review the molecular genetics of SHANK mutations in human ASD and discuss recent findings where such mutations have been modeled in mice. Conserved features of synaptic dysfunction and corresponding behaviors in Shank mouse mutants may help dissect the pathophysiology of ASD, but also highlight divergent phenotypes that arise from different mutations in the same gene. PMID:23583105

Jiang, Yong-hui; Ehlers, Michael D.

2013-01-01

23

Novel KRAS Gene Mutations in Sporadic Colorectal Cancer  

PubMed Central

Introduction In this article, we report 7 novel KRAS gene mutations discovered while retrospectively studying the prevalence and pattern of KRAS mutations in cancerous tissue obtained from 56 Saudi sporadic colorectal cancer patients from the Eastern Province. Methods Genomic DNA was extracted from formalin-fixed, paraffin-embedded cancerous and noncancerous colorectal tissues. Successful and specific PCR products were then bi-directionally sequenced to detect exon 4 mutations while Mutector II Detection Kits were used for identifying mutations in codons 12, 13 and 61. The functional impact of the novel mutations was assessed using bioinformatics tools and molecular modeling. Results KRAS gene mutations were detected in the cancer tissue of 24 cases (42.85%). Of these, 11 had exon 4 mutations (19.64%). They harbored 8 different mutations all of which except two altered the KRAS protein amino acid sequence and all except one were novel as revealed by COSMIC database. The detected novel mutations were found to be somatic. One mutation is predicted to be benign. The remaining mutations are predicted to cause substantial changes in the protein structure. Of these, the Q150X nonsense mutation is the second truncating mutation to be reported in colorectal cancer in the literature. Conclusions Our discovery of novel exon 4 KRAS mutations that are, so far, unique to Saudi colorectal cancer patients may be attributed to environmental factors and/or racial/ethnic variations due to genetic differences. Alternatively, it may be related to paucity of clinical studies on mutations other than those in codons 12, 13, 61 and 146. Further KRAS testing on a large number of patients of various ethnicities, particularly beyond the most common hotspot alleles in exons 2 and 3 is needed to assess the prevalence and explore the exact prognostic and predictive significance of the discovered novel mutations as well as their possible role in colorectal carcinogenesis. PMID:25412182

Naser, Walid M.; Shawarby, Mohamed A.; Al-Tamimi, Dalal M.; Seth, Arun; Al-Quorain, Abdulaziz; Nemer, Areej M. Al; Albagha, Omar M. E.

2014-01-01

24

Germline mutations of TP53 gene in breast cancer.  

PubMed

Germline alterations of the TP53 gene encoding the p53 protein have been observed in the majority of families with the Li-Fraumeni syndrome, a rare dominantly inherited disorder with breast cancer. Genomic DNA samples of 182 breast cancer cases and 186 controls were sequenced for TP53 mutations in the exon 5-9 and intervening introns 5, 7-9. Direct sequencing was done using Applied Biosystem 3730 DNA analyzer. In the present study, we observed nine mutations in the sequenced region, of which five were novel. Hardy-Weinberg equilibrium (HWE) was done for all the mutations; C14181T, T14201G, and G13203A have shown deviation from HWE. High linkage disequilibrium (LD) was observed between C14181T (rs129547788) and T14201G (rs12951053) (r (2)?=?0.98.3; D'?=?1.00), whereas other observed mutations do not show strong LD with any of the other mutations. None of the intronic mutations has shown significant association with the breast cancer, two exonic mutations G13203A (rs28934578) and A14572G are significantly (P?=?0.04, P?=?0.007) associated with breast cancer. Germline mutations observed in DNA-binding domain of the gene showed significant association with breast cancer. This study reports five novel germline mutations in the TP53 gene out of which one mutation may confer significant risk to the breast cancer. Mutations in DNA-binding domain of TP53 gene may play role in the early onset and prognosis of breast cancer. The population-based studies of germline mutations in DNA-binding domain of TP53 gene helps in identification of individuals and families who are at risk of developing cancers. PMID:24929325

Damineni, Surekha; Rao, Vadlamudi Raghavendra; Kumar, Satish; Ravuri, Rajasekar Reddy; Kagitha, Sailaja; Dunna, Nageswara Rao; Digumarthi, Raghunadharao; Satti, Vishnupriya

2014-09-01

25

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

26

Hereditary gene mutations in Korean patients with isolated erythrocytosis.  

PubMed

Most cases of erythrocytosis occur secondary to chronic tissue hypoxia or as a clonal disease such as polycythemia vera with somatic mutations in the Janus kinase 2 (JAK2) gene. Rarely, erythrocytosis is caused by hereditary gene mutations. This study investigated hereditary gene mutations in 38 unrelated Korean patients with isolated erythrocytosis without (1) JAK2 mutation and (2) secondary causes of erythrocytosis other than smoking history. Direct sequencing analyses were performed on six genes associated with hereditary erythrocytosis [HBB, exon 2 and exon 3 of HBA2, VHL, EGLN1 (previously PHD2), exon 12 of EPAS1 (previously HIF2A), and exons 5-8 of EPOR]. As a result, mutations were detected in five patients (three never smokers and two current smokers) out of 38 patients (13.2 %). The mutations detected in those five patients were EPOR:p.W439*, EPOR:p.G212C, HBB:p.H98Q (or conventionally H97Q, Hb Malmö [? 97(FG4) His > Gln]), HBB:p.V138M (V137M), and EGLN1:p.L279Tfs43*, all in heterozygous state. No patient had mutations in HBA2, VHL, or in EPAS1. This study indicates that workup for hereditary gene mutations is needed for isolated erythrocytosis with or without smoking history. PMID:24482100

Jang, Ja-Hyun; Seo, Ja Young; Jang, Junho; Jung, Chul Won; Lee, Ki-O; Kim, Sun-Hee; Kim, Hee-Jin

2014-06-01

27

Amelogenesis Imperfecta and Screening of Mutation in Amelogenin Gene  

PubMed Central

The aim of this study was to report the clinical findings and the screening of mutations of amelogenin gene of a 7-year-old boy with amelogenesis imperfecta (AI). The genomic DNA was extracted from saliva of patient and his family, followed by PCR and direct DNA sequencing. The c.261C>T mutation was found in samples of mother, father, and brother, but the mutation was not found in the sequence of the patient. This mutation is a silent mutation and a single-nucleotide polymorphism (rs2106416). Thus, it is suggested that the mutation found was not related to the clinical presence of AI. Further research is necessary to examine larger number of patients and genes related to AI. PMID:25045544

Oliveira, Fernanda Veronese; Gurgel, Carla Vecchione; Kobayashi, Tatiana Yuriko; Dionisio, Thiago Jose; Neves, Lucimara Teixeira; Santos, Carlos Ferreira; Machado, Maria Aparecida Andrade Moreira

2014-01-01

28

Three novel aniridia mutations in the human PAX6 gene.  

PubMed

Aniridia (iris hypoplasia) is an autosomal dominant congenital disorder of the eye. Mutations in the human aniridia (PAX6) gene have now been identified in many patients from various ethnic groups. In the study reported here we describe PAX6 mutations in one sporadic and five familial cases with aniridia. Of the four different mutations identified, one was identical to a previously reported mutation (C-->T transition at codon 240), and three were novel: two in the glycine-rich region and one in the proline/serine/threonine-rich (PST) region. One PAX6 mutation found in the PST region was associated with cataracts in an aniridia family. Another splice mutation in the PST domain occurred in an aniridia patient with anosmia (inability to smell). The six new aniridia cases reported here have mutations predicted to generate incomplete PAX6 proteins. These results support the theory that human aniridia is caused by haploinsufficiency of PAX6. PMID:7550230

Martha, A; Strong, L C; Ferrell, R E; Saunders, G F

1995-01-01

29

Recessive truncating titin gene, TTN, mutations presenting as centronuclear myopathy  

PubMed Central

Objective: To identify causative genes for centronuclear myopathies (CNM), a heterogeneous group of rare inherited muscle disorders that often present in infancy or early life with weakness and hypotonia, using next-generation sequencing of whole exomes and genomes. Methods: Whole-exome or -genome sequencing was performed in a cohort of 29 unrelated patients with clinicopathologic diagnoses of CNM or related myopathy depleted for cases with mutations of MTM1, DNM2, and BIN1. Immunofluorescence analyses on muscle biopsies, splicing assays, and gel electrophoresis of patient muscle proteins were performed to determine the molecular consequences of mutations of interest. Results: Autosomal recessive compound heterozygous truncating mutations of the titin gene, TTN, were identified in 5 individuals. Biochemical analyses demonstrated increased titin degradation and truncated titin proteins in patient muscles, establishing the impact of the mutations. Conclusions: Our study identifies truncating TTN mutations as a cause of congenital myopathy that is reported as CNM. Unlike the classic CNM genes that are all involved in excitation-contraction coupling at the triad, TTN encodes the giant sarcomeric protein titin, which forms a myofibrillar backbone for the components of the contractile machinery. This study expands the phenotypic spectrum associated with TTN mutations and indicates that TTN mutation analysis should be considered in cases of possible CNM without mutations in the classic CNM genes. PMID:23975875

Ceyhan-Birsoy, Ozge; Agrawal, Pankaj B.; Hidalgo, Carlos; Schmitz-Abe, Klaus; DeChene, Elizabeth T.; Swanson, Lindsay C.; Soemedi, Rachel; Vasli, Nasim; Iannaccone, Susan T.; Shieh, Perry B.; Shur, Natasha; Dennison, Jane M.; Lawlor, Michael W.; Laporte, Jocelyn; Markianos, Kyriacos; Fairbrother, William G.; Granzier, Henk

2013-01-01

30

Fukutin Gene Mutations Cause Dilated Cardiomyopathy with Minimal  

E-print Network

Fukutin Gene Mutations Cause Dilated Cardiomyopathy with Minimal Muscle Weakness Terumi Murakami cardiomyopathy with no or minimal limb girdle muscle involvement and normal intelligence, associated with a compound heterozygous FKTN mutation. One patient died by rapid progressive dilated cardiomyopathy at 12

Campbell, Kevin P.

31

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

32

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, ...

33

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

34

Independent mutational events are rare in the ATM gene: haplotype prescreening enhances mutation detection rate.  

PubMed

Mutations in the ATM gene are responsible for the autosomal recessive disorder ataxia-telangiectasia (A-T). Many different mutations have been identified using various techniques, with detection efficiencies ranging from 57 to 85%. In this study, we employed short tandem repeat (STR) haplotypes to enhance mutation identification in 55 unrelated A-T families of Iberian origin (20 Spanish, 17 Brazilian, and 18 Hispanic-American); we were able to identify 95% of the expected mutations. Allelic sizes were standardized based on a reference sample (CEPH 1347-2). Subsequent mutation screening was performed by PTT, SSCP, and DHPLC, and abnormal regions were sequenced. Many STR haplotypes were found within each population and six haplotypes were observed across several of these populations. Single nucleotide polymorphism (SNP) haplotypes further suggested that most of these common mutations are ancestrally related, and not hot spots. However, two mutations (8977C>T and 8264_8268delATAAG) may indeed be recurring mutational events. Common haplotypes were present in 13 of 20 Spanish A-T families (65%), in 11 of 17 Brazilian A-T families (65%), and, in contrast, in only eight of 18 Hispanic-American families (44%). Three mutations were identified that would be missed by conventional screening strategies. In all, 62 different mutations (28 not previously reported) were identified and their associated haplotypes defined, thereby establishing a new database for Iberian A-T families, and extending the spectrum of worldwide ATM mutations. PMID:12815592

Mitui, Midori; Campbell, Catarina; Coutinho, Gabriela; Sun, Xia; Lai, Chih-Hung; Thorstenson, Yvonne; Castellvi-Bel, Sergi; Fernandez, Luis; Monros, Eugenia; Carvalho, Beatriz Tavares Costa; Porras, Oscar; Fontan, Gumersindo; Gatti, Richard A

2003-07-01

35

DNA Methylation and Mutator Genes in Escherichia coli K-12  

PubMed Central

Mutator strains of Escherichia coli have been used to define mechanisms that account for the high fidelity of chromosome duplication and chromosome stability. Mutant strains defective in post-replicative mismatch repair display a strong mutator phenotype consistent with a role for correction of mismatches arising from replication errors. Inactivation of the gene (dam) encoding DNA adenine methyltransferase results in a mutator phenotype consistent with a role for DNA methylation in strand discrimination during mismatch repair. This review gives a personal perspective on the discovery of dam mutants in E. coli and their relationship to mismatch repair and mutator phenotypes. PMID:20471491

Marinus, Martin G.

2010-01-01

36

DNA methylation and mutator genes in Escherichia coli K-12.  

PubMed

Mutator strains of Escherichia coli have been used to define mechanisms that account for the high fidelity of chromosome duplication and chromosome stability. Mutant strains defective in post-replicative mismatch repair display a strong mutator phenotype consistent with a role for correction of mismatches arising from replication errors. Inactivation of the gene (dam) encoding DNA adenine methyltransferase results in a mutator phenotype consistent with a role for DNA methylation in strand discrimination during mismatch repair. This review gives a personal perspective on the discovery of dam mutants in E. coli and their relationship to mismatch repair and mutator phenotypes. PMID:20471491

Marinus, Martin G

2010-10-01

37

Spectrum of Perforin Gene Mutations in Familial Hemophagocytic Lymphohistiocytosis  

PubMed Central

Familial hemophagocytic lymphohistiocytosis (FHL) is an autosomal recessive disease of early childhood characterized by nonmalignant accumulation and multivisceral infiltration of activated T lymphocytes and histiocytes (macrophages). Cytotoxic T and natural killer (NK) cell activity is markedly reduced or absent in these patients, and mutations in a lytic granule constituent, perforin, were recently identified in a number of FHL individuals. Here, we report a comprehensive survey of 34 additional patients with FHL for mutations in the coding region of the perforin gene and the relative frequency of perforin mutations in FHL. Perforin mutations were identified in 7 of the 34 families investigated. Six children were homozygous for the mutations, and one patient was a compound heterozygote. Four novel mutations were detected: one nonsense, two missense, and one deletion of one amino acid. In four families, a previously reported mutation at codon 374, causing a premature stop codon, was identified, and, therefore, this is the most common perforin mutation identified so far in FHL patients. We found perforin mutations in 20% of all FHL patients investigated (7/34), with a somewhat higher prevalence, ?30% (6/20), in children whose parents originated from Turkey. No other correlation between the type of mutation and the phenotype of the patients was evident from the present study. Our combined results from mutational analysis of 34 families and linkage analysis of a subset of consanguineous families indicate that perforin mutations account for 20%–40% of the FHL cases and the FHL 1 locus on chromosome 9 for ?10%, whereas the major part of the FHL cases are caused by mutations in not-yet-identified genes. PMID:11179007

Göransdotter Ericson, Kim; Fadeel, Bengt; Nilsson-Ardnor, Sofie; Söderhäll, Cilla; Samuelsson, AnnaCarin; Janka, Gritta; Schneider, Marion; Gürgey, Aytemiz; Yalman, Nevin; Révész, Tom; Egeler, R. Maarten; Jahnukainen, Kirsi; Storm-Mathiesen, Ingebjörg; Haraldsson, Ásgeir; Poole, Janet; de Saint Basile, Genevičve; Nordenskjöld, Magnus; Henter, Jan-Inge

2001-01-01

38

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

39

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. PMID:21873494

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

40

Mutational and phylogenetic analyses of the mycobacterial mbt gene cluster.  

PubMed

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. PMID:21873494

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

2011-11-01

41

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

42

Pyridoxine responsiveness in novel mutations of the PNPO gene  

PubMed Central

Objective: To determine whether patients with pyridoxine-responsive seizures but normal biomarkers for antiquitin deficiency and normal sequencing of the ALDH7A1 gene may have PNPO mutations. Methods: We sequenced the PNPO gene in 31 patients who fulfilled the above-mentioned criteria. Results: We were able to identify 11 patients carrying 3 novel mutations of the PNPO gene. In 6 families, a homozygous missense mutation p.Arg225His in exon 7 was identified, while 1 family was compound heterozygous for a novel missense mutation p.Arg141Cys in exon 5 and a deletion c.279_290del in exon 3. Pathogenicity of the respective mutations was proven by absence in 100 control alleles and expression studies in CHO-K1 cell lines. The response to pyridoxine was prompt in 4, delayed in 2, on EEG only in 2, and initially absent in another 2 patients. Two unrelated patients homozygous for the p.Arg225His mutation experienced status epilepticus when switched to pyridoxal 5?-phosphate (PLP). Conclusions: This study challenges the paradigm of exclusive PLP responsiveness in patients with pyridoxal 5?-phosphate oxidase deficiency and underlines the importance of consecutive testing of pyridoxine and PLP in neonates with antiepileptic drug–resistant seizures. Patients with pyridoxine response but normal biomarkers for antiquitin deficiency should undergo PNPO mutation analysis. PMID:24658933

Paul, Karl; Mills, Philippa; Clayton, Peter; Paschke, Eduard; Maier, Oliver; Hasselmann, Oswald; Schmiedel, Gudrun; Kanz, Simone; Connolly, Mary; Wolf, Nicole; Struys, Eduard; Stockler, Sylvia; Abela, Lucia; Hofer, Doris

2014-01-01

43

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

2011-12-01

44

Mutations in the filaggrin gene and food allergy  

PubMed Central

The results of long-term epidemiological studies show that the number of people suffering from allergic diseases, especially from food allergies and atopic dermatitis (AD), is still increasing. Although the research thus far has been conducted mainly in Europe, North America, and Asia, there are also data appearing from the first studies in that field among the African population. This may indicate the importance of the problem of allergic diseases. The discovery that loss-of-function mutations in the gene coding filaggrin (FLG) are the cause of ichthyosis vulgaris marked a significant breakthrough in understanding the pathogenesis of allergic diseases. The presence of mutations in the filaggrin gene is also an important factor that predisposes to such allergic diseases as: allergic rhinitis, atopic dermatitis, atopic asthma, and food allergy. So far, over 40 loss-of-function mutations and numerous silent mutations in filaggrin have been discovered. PMID:25276250

Markiewicz, Lidia; Wroblewska, Barbara

2014-01-01

45

Translational readthrough at nonsense mutations in the HSF1 gene of Saccharomyces cerevisme  

Microsoft Academic Search

The HSF1 gene of Saccharomyces cerevisiae directs the synthesis of the heat shock transcription factor, HSF. The gene is essential; disruption mutations are lethal. Using a plasmid shuffle screen, we isolated mutations in the HSF1 gene after in vitro mutagenesis of plasmid DNA with hydroxylamine. From a collection of both conditional (temperature-sensitive) and unconditional lethal mutations, we recovered mutations that

Jennifer B. Kopczynski; Amanda C. Raff; J. José Bonner

1992-01-01

46

Frequent mutations in chromatin-remodeling genes in pulmonary carcinoids  

PubMed Central

Pulmonary carcinoids are rare neuroendocrine tumors of the lung. The molecular alterations underlying the pathogenesis of these tumors have not been systematically studied so far. Here we perform gene copy number analysis (n=54), genome/exome (n=44) and transcriptome (n=69) sequencing of pulmonary carcinoids and observe frequent mutations in chromatin-remodeling genes. Covalent histone modifiers and subunits of the SWI/SNF complex are mutated in 40% and 22.2% of the cases respectively, with MEN1, PSIP1 and ARID1A being recurrently affected. In contrast to small-cell lung cancer and large-cell neuroendocrine tumors, TP53 and RB1 mutations are rare events, suggesting that pulmonary carcinoids are not early progenitor lesions of the highly aggressive lung neuroendocrine tumors but arise through independent cellular mechanisms. These data also suggest that inactivation of chromatin remodeling genes is sufficient to drive transformation in pulmonary carcinoids. PMID:24670920

Lu, Xin; Sun, Ruping; Ozretic, Luka; Seidal, Danila; Zander, Thomas; Leenders, Frauke; George, Julie; Muller, Christian; Dahmen, Ilona; Pinther, Berit; Bosco, Graziella; Konrad, Kathryn; Altmuller, Janine; Nurnberg, Peter; Achter, Viktor; Lang, Ulrich; Schneider, Peter M; Bogus, Magdalena; Soltermann, Alex; Brustugun, Odd Terje; Helland, Aslaug; Solberg, Steinar; Lund-Iversen, Marius; Ansen, Sascha; Stoelben, Erich; Wright, Gavin M.; Russell, Prudence; Wainer, Zoe; Solomon, Benjamin; Field, John K; Hyde, Russell; Davies, Michael PA.; Heukamp, Lukas C; Petersen, Iver; Perner, Sven; Lovly, Christine; Cappuzzo, Federico; Travis, William D; Wolf, Jurgen; Vingron, Martin; Brambilla, Elisabeth; Haas, Stefan A.; Buettner, Reinhard; Thomas, Roman K

2014-01-01

47

Gene-Specific Function Prediction for Non-Synonymous Mutations in Monogenic Diabetes Genes  

PubMed Central

The rapid progress of genomic technologies has been providing new opportunities to address the need of maturity-onset diabetes of the young (MODY) molecular diagnosis. However, whether a new mutation causes MODY can be questionable. A number of in silico methods have been developed to predict functional effects of rare human mutations. The purpose of this study is to compare the performance of different bioinformatics methods in the functional prediction of nonsynonymous mutations in each MODY gene, and provides reference matrices to assist the molecular diagnosis of MODY. Our study showed that the prediction scores by different methods of the diabetes mutations were highly correlated, but were more complimentary than replacement to each other. The available in silico methods for the prediction of diabetes mutations had varied performances across different genes. Applying gene-specific thresholds defined by this study may be able to increase the performance of in silico prediction of disease-causing mutations. PMID:25136813

Li, Quan; Liu, Xiaoming; Gibbs, Richard A.; Boerwinkle, Eric; Polychronakos, Constantin; Qu, Hui-Qi

2014-01-01

48

Mutations in many genes affect aggressive behavior in Drosophila melanogaster  

PubMed Central

Background Aggressive behavior in animals is important for survival and reproduction. Identifying the underlying genes and environmental contexts that affect aggressive behavior is important for understanding the evolutionary forces that maintain variation for aggressive behavior in natural populations, and to develop therapeutic interventions to modulate extreme levels of aggressive behavior in humans. While the role of neurotransmitters and a few other molecules in mediating and modulating levels of aggression is well established, it is likely that many additional genetic pathways remain undiscovered. Drosophila melanogaster has recently been established as an excellent model organism for studying the genetic basis of aggressive behavior. Here, we present the results of a screen of 170 Drosophila P-element insertional mutations for quantitative differences in aggressive behavior from their co-isogenic control line. Results We identified 59 mutations in 57 genes that affect aggressive behavior, none of which had been previously implicated to affect aggression. Thirty-two of these mutants exhibited increased aggression, while 27 lines were less aggressive than the control. Many of the genes affect the development and function of the nervous system, and are thus plausibly relevant to the execution of complex behaviors. Others affect basic cellular and metabolic processes, or are mutations in computationally predicted genes for which aggressive behavior is the first biological annotation. Most of the mutations had pleiotropic effects on other complex traits. We characterized nine of these mutations in greater detail by assessing transcript levels throughout development, morphological changes in the mushroom bodies, and restoration of control levels of aggression in revertant alleles. All of the P-element insertions affected the tagged genes, and had pleiotropic effects on brain morphology. Conclusion This study reveals that many more genes than previously suspected affect aggressive behavior, and that these genes have widespread pleiotropic effects. Given the conservation of aggressive behavior among different animal species, these are novel candidate genes for future study in other animals, including humans. PMID:19519879

Edwards, Alexis C; Zwarts, Liesbeth; Yamamoto, Akihiko; Callaerts, Patrick; Mackay, Trudy FC

2009-01-01

49

Novel Somatic and Germline Mutations in Cancer Candidate Genes in Glioblastoma, Melanoma, and Pancreatic Carcinoma  

Microsoft Academic Search

A recent systematic sequence analysis of well-annotated human protein coding genes or consensus coding sequences led to the identification of 189 genes displaying somatic mutations in breast and colorectal cancers. Based on their mutation prevalence, a subset of these genes was identified as cancer candidate (CAN)genes as they could be potentially involved in cancer. We evaluated the mutational profiles of

Asha Balakrishnan; Fonnet E. Bleeker; Simona Lamba; Monica Rodolfo; Maria Daniotti; Aldo Scarpa; Sieger Leenstra; Carlo Zanon; Alberto Bardelli

2007-01-01

50

Mutator gene and hereditary non-polyposis colorectal cancer  

DOEpatents

The human MSH2 gene, responsible for hereditary non-polyposis colorectal cancer, was identified by virtue of its homology to the MutS class of genes, which are involved in DNA mismatch repair. The sequence of cDNA clones of the human gene are provided, and the sequence of the gene can be used to demonstrate the existence of germ line mutations in hereditary non-polyposis colorectal cancer (HNPCC) kindreds, as well as in replication error.sup.+ (RER.sup.+) tumor cells.

de la Chapelle, Albert (Helsingfors, FI); Vogelstein, Bert (Baltimore, MD); Kinzler, Kenneth W. (Baltimore, MD)

2008-02-05

51

DCEG Scientists Identify New Gene Mutation Related to Familial Melanoma  

Cancer.gov

Scientists have identified a rare inherited mutation in a gene that can increase the risk of familial melanoma, according to a study that appeared online in Nature Genetics on March 30, 2014. Although the finding does not offer immediate benefit to patients, variation in the Protection of Telomeres-1 (POT1) gene provides additional clues as to the origins of melanoma and may open new avenues in prevention and treatment research. Read the full NCI Benchmarks blog post about this study.

52

Dominant negative mutator mutations in the mutS gene of Escherichia coli.  

PubMed Central

The MutS protein of Escherichia coli is part of the dam-directed MutHLS mismatch repair pathway which rectifies replication errors and which prevents recombination between related sequences. In order to more fully understand the role of MutS in these processes, dominant negative mutS mutations on a multicopy plasmid were isolated by screening transformed wild-type cells for a mutator phenotype, using a Lac+ papillation assay. Thirty-eight hydroxylamine- and 22 N-methyl-N'-nitro-N-nitrosoguanidine-induced dominant mutations were isolated. Nine of these mutations altered the P-loop motif of the ATP-binding site, resulting in four amino acid substitutions. With one exception, the remaining sequenced mutations all caused substitution of amino acids conserved during evolution. The dominant mutations in the P-loop consensus caused severely reduced repair of heteroduplex DNA in vivo in a mutS mutant host strain. In a wild-type strain, the level of repair was decreased by the dominant mutations to between 12 to 90% of the control value, which is consistent with interference of wild-type MutS function by the mutant proteins. Increasing the wild-type mutS gene dosage resulted in a reversal of the mutator phenotype in about 60% of the mutant strains, indicating that the mutant and wild-type proteins compete. In addition, 20 mutant isolates showed phenotypic reversal by increasing the gene copies of either mutL or mutH. There was a direct correlation between the levels of recombination and mutagenesis in the mutant strains, suggesting that these phenotypes are due to the same function of MutS. PMID:8071216

Wu, T H; Marinus, M G

1994-01-01

53

Mutations in the p53 Tumor Suppressor Gene  

PubMed Central

Inactivation of the p53 tumor suppressor is a frequent event in tumorigenesis. In most cases, the p53 gene is mutated, giving rise to a stable mutant protein whose accumulation is regarded as a hallmark of cancer cells. Mutant p53 proteins not only lose their tumor suppressive activities but often gain additional oncogenic functions that endow cells with growth and survival advantages. Interestingly, mutations in the p53 gene were shown to occur at different phases of the multistep process of malignant transformation, thus contributing differentially to tumor initiation, promotion, aggressiveness, and metastasis. Here, the authors review the different studies on the involvement of p53 inactivation at various stages of tumorigenesis and highlight the specific contribution of p53 mutations at each phase of cancer progression. PMID:21779514

Rivlin, Noa; Brosh, Ran; Oren, Moshe; Rotter, Varda

2011-01-01

54

MODY2 caused by a novel mutation of GCK gene.  

PubMed

Maturity-onset diabetes of the young type 2 (MODY2) is an autosomal dominant inherited disease caused by heterozygous inactivating mutations in the glucokinase (GCK) gene and is characterized by mild noninsulin-dependent fasting hyperglycemia. It is treated with diet only, and complications are extremely rare. We present a report of a family with MODY2 caused by a novel NM_000162.3:c.878T>C mutation in exon 8 of the GCK gene. Testing for MODY2 and reporting all novel mutations are important to avoid difficulties in the interpretation of genetic test results and to provide fast and definitive diagnosis for all patients with this disease. PMID:23155715

Pulst, Kerti; Arbo, Triin; Kahre, Tiina; Peet, Aleksandr; Tillmann, Vallo

2012-01-01

55

International team identifies critical genes mutated in stomach cancer  

Cancer.gov

An international team of scientists, led by researchers from the Duke-NUS Graduate Medical School in Singapore and National Cancer Centre of Singapore, has identified hundreds of novel genes that are mutated in stomach cancer, the second-most lethal cancer worldwide.

56

Growth and Skeletal Development in Families with NOGGIN Gene Mutations  

Microsoft Academic Search

Introduction: There is a scarcity of data on height as well as bone densitometry in humans with NOGGIN mutations. Methods: In 2 families with symphalangism, anthropometry, bone densitometry and genetic analysis of the NOGGIN gene were performed. Results: In family A, the height standard deviation scores of the affected father and son were –0.4 and 3.5, respectively. In family B,

C. D. Oxley; R. Rashid; D. R. Goudie; G. Stranks; D. U. Baty; W. Lam; C. J. Kelnar; S. F. Ahmed

2008-01-01

57

Genome truncation vs mutational opportunity: can new genes arise via gene duplication?—Part 1  

Microsoft Academic Search

Gene duplication and lateral gene transfer are observed biological phenomena. Their purpose is still a matter of deliberation among creationist and Intelligent Design researchers, but both may serve functions in a process leading to rapid acquisition of adaptive phenotypes in novel environments. Evolutionists claim that copies of duplicate genes are free to mutate and that natural selection subsequently favours useful

Royal Truman; Peter Borger

58

Detecting negative selection on recurrent mutations using gene genealogy  

PubMed Central

Background Whether or not a mutant allele in a population is under selection is an important issue in population genetics, and various neutrality tests have been invented so far to detect selection. However, detection of negative selection has been notoriously difficult, partly because negatively selected alleles are usually rare in the population and have little impact on either population dynamics or the shape of the gene genealogy. Recently, through studies of genetic disorders and genome-wide analyses, many structural variations were shown to occur recurrently in the population. Such “recurrent mutations” might be revealed as deleterious by exploiting the signal of negative selection in the gene genealogy enhanced by their recurrence. Results Motivated by the above idea, we devised two new test statistics. One is the total number of mutants at a recurrently mutating locus among sampled sequences, which is tested conditionally on the number of forward mutations mapped on the sequence genealogy. The other is the size of the most common class of identical-by-descent mutants in the sample, again tested conditionally on the number of forward mutations mapped on the sequence genealogy. To examine the performance of these two tests, we simulated recurrently mutated loci each flanked by sites with neutral single nucleotide polymorphisms (SNPs), with no recombination. Using neutral recurrent mutations as null models, we attempted to detect deleterious recurrent mutations. Our analyses demonstrated high powers of our new tests under constant population size, as well as their moderate power to detect selection in expanding populations. We also devised a new maximum parsimony algorithm that, given the states of the sampled sequences at a recurrently mutating locus and an incompletely resolved genealogy, enumerates mutation histories with a minimum number of mutations while partially resolving genealogical relationships when necessary. Conclusions With their considerably high powers to detect negative selection, our new neutrality tests may open new venues for dealing with the population genetics of recurrent mutations as well as help identifying some types of genetic disorders that may have escaped identification by currently existing methods. PMID:23651527

2013-01-01

59

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

Code of Federal Regulations, 2010 CFR

...true Detection of gene mutations in somatic cells in culture. 798.5300 Section 798.5300...5300 Detection of gene mutations in somatic cells in culture. (a) Purpose. Mammalian cell culture systems may be used to detect...

2010-07-01

60

Localization of temperature-sensitive transformation mutations and back mutations in the Rous sarcoma virus src gene.  

PubMed Central

Cloning and sequencing of two temperature-sensitive transforming mutations of Rous sarcoma virus reveal that their lesions are due to distinct but close single amino acid changes near the carboxy terminus of the v-src gene product. Back mutations to wild type result from second mutations at either nearby or distant sites. Images PMID:3009882

Fincham, V J; Wyke, J A

1986-01-01

61

Gene Mutations Gene a finite segment of DNA specified  

E-print Network

for humans ranges from 50 to 250 rads (0.5 -2.5 Gy). ¡ Drosophila fruit flies have a doubling dose 15 times of needed amino acids or by addition of drugs. ¡ Looked for growth of mutated cells. ¡ Rate for a specific established. #12;Damage to Nucleic Acids #12;Examples for human repair ¡ Xeroderma pigmantosum ­ inability

Massey, Thomas N.

62

AID-initiated purposeful mutations in immunoglobulin genes.  

PubMed

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 within the variable (V) and switch regions (SR) of the immunoglobulin (Ig) genes that are responsible for binding to and neutralizing foreign antigens throughout the body. These mutations are truly purposeful. This chapter is centered on activation-induced cytidine deaminase (AID). AID is required for initiating somatic hypermutation (SHM) in the V regions and class switch recombination (CSR) in the SR portions of Ig genes. By converting C --> U, while transcription takes place, AID instigates a cascade of mutational events involving error-prone DNA polymerases, base excision and mismatch repair enzymes, and recombination pathways. Together, these processes culminate in highly mutated antibody genes and the B cells expressing antibodies that have achieved optimal antigenic binding undergo positive selection in germinal centers. We will discuss the biological role of AID in this complex process, primarily in terms of its biochemical properties in relation to SHM in vivo. The chapter also discusses recent advances in experimental methods to characterize antibody dynamics as a function of SHM to help elucidate the role that the AID-induced mutations play in tailoring molecular recognition. The emerging experimental techniques help to address long-standing conundrums concerning evolution-imposed constraints on antibody structure and function. PMID:17560274

Goodman, Myron F; Scharff, Matthew D; Romesberg, Floyd E

2007-01-01

63

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

64

PDCD10 Gene Mutations in Multiple Cerebral Cavernous Malformations  

PubMed Central

Cerebral cavernous malformations (CCMs) are vascular abnormalities that may cause seizures, intracerebral haemorrhages, and focal neurological deficits. Familial form shows an autosomal dominant pattern of inheritance with incomplete penetrance and variable clinical expression. Three genes have been identified causing familial CCM: KRIT1/CCM1, MGC4607/CCM2, and PDCD10/CCM3. Aim of this study is to report additional PDCD10/CCM3 families poorly described so far which account for 10-15% of hereditary cerebral cavernous malformations. Our group investigated 87 consecutive Italian affected individuals (i.e. positive Magnetic Resonance Imaging) with multiple/familial CCM through direct sequencing and Multiplex Ligation-Dependent Probe Amplification (MLPA) analysis. We identified mutations in over 97.7% of cases, and PDCD10/CCM3 accounts for 13.1%. PDCD10/CCM3 molecular screening revealed four already known mutations and four novel ones. The mutated patients show an earlier onset of clinical manifestations as compared to CCM1/CCM2 mutated patients. The study of further families carrying mutations in PDCD10/CCM3 may help define a possible correlation between genotype and phenotype; an accurate clinical follow up of the subjects would help define more precisely whether mutations in PDCD10/CCM3 lead to a characteristic phenotype. PMID:25354366

Cigoli, Maria Sole; Avemaria, Francesca; De Benedetti, Stefano; Gesu, Giovanni P.; Accorsi, Lucio Giordano; Parmigiani, Stefano; Corona, Maria Franca; Capra, Valeria; Mosca, Andrea; Giovannini, Simona; Notturno, Francesca; Ciccocioppo, Fausta; Volpi, Lilia; Estienne, Margherita; De Michele, Giuseppe; Antenora, Antonella; Bilo, Leda; Tavoni, Antonietta; Zamponi, Nelia; Alfei, Enrico; Baranello, Giovanni; Riva, Daria; Penco, Silvana

2014-01-01

65

Mutation analysis of the HFE gene in Brazilian populations.  

PubMed

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 the African-derived population, 1.1% in the racially mixed normal controls and 0% in the Parakană Indians. In the African-derived population, the C282Y mutation was present on chromosomes bearing the haplotype 6/1h according to Beutler and West (1997). Allelic frequency of the mutation C. 187C(G (H63D) was 16.3% in the Caucasian population, 7.5% in the African-derived population, 9.8% in the racially mixed controls and 0% in the Amerindians. The presence of these mutations in the African-derived population reflects the fact that these subjects may have undergone a non-identified racial admixture in their past history. The absence of both defects in the Amerindians suggests that these mutations have emerged after the migration of Polynesians to America, or that they may not have reached the Polynesian population until after the migration to America had occurred. PMID:10660479

Agostinho, M F; Arruda, V R; Basseres, D S; Bordin, S; Soares, M C; Menezes, R C; Costa, F F; Saad, S T

1999-01-01

66

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. PMID:22876129

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

2012-01-01

67

Novel truncating thyroglobulin gene mutations associated with congenital hypothyroidism.  

PubMed

Mutations in the thyroglobulin (TG) gene have been reported to cause congenital hypothyroidism (CH) and we have been investigating the genetic architecture of CH in a large cohort of consanguineous/multi-case families. Our aim in this study was to determine the genetic basis of CH in four affected individuals coming from two separate consanguineous families. Since CH is usually inherited in autosomal recessive manner in consanguineous/multi-case families, we adopted a two-stage strategy of genetic linkage studies and targeted sequencing of the TG gene. First we investigated the potential genetic linkage of families to any known CH locus using microsatellite markers and then determined the pathogenic mutations in linked-genes by Sanger sequencing. Both families showed potential linkage to TG locus and we detected two previously unreported nonsense TG mutations (p.Q630X and p.W637X) that segregated with the disease status in both families. This study highlights the importance of molecular genetic studies in the definitive diagnosis and classification of CH, and also adds up to the limited number of nonsense TG mutations in the literature. It also suggests a new clinical testing strategy using next-generation sequencing in all primary CH cases. PMID:23949896

Cangul, Hakan; Boelaert, Kristien; Dogan, Murat; Saglam, Yaman; Kendall, Michaela; Barrett, Timothy G; Maher, Eamonn R

2014-03-01

68

Rapid detection of common mutations in the arylsulfatase A gene  

SciTech Connect

Metachromatic leukodystrophy (MLD), an autosomal recessive lysosomal storage disease results from a deficiency of arylsulfatase A activity. This disease is usually fatal within a few years of onset in the pediatric age group. A pseuodeficiency occurs in up to 15% of alleles in the general population which significantly decreases enzyme activity. Although there is no clinical phenotype associated with the pseudodeficiency, the decreased enzyme activity can complicate interpretation of biochemical assay results particularly in the case of potential heterozygous carriers of MLD. Two mutations have been found to be simultaneously associated with the pseudodeficiency: one at a glycosylatin site in exon 6 and one in the polyA addition signal. Another mutation, the `I` allele has been reported in up to 50% of alleles in the severe infantile onset form of MLD. The deleterious mutation in this case is in the +1 position of intron 2. In order to screen for these commonly occurring mutations in the arylsulfatase A gene, a simple combination of PCR amplification from genomic DNA and restriction enzyme digestions was developed for each situation. In the case of the pseuodeficiency mutations, oligonucleotide primers were designed which incorporated a single base mismatch 3 bases upstream from the 3{prime} end of the primer so that the presence of the mutation created new MaeIII restriction site in the case of the glycosylation site or an RsaI site in the case of the polyA site. The `I` allele mutation creates a new MvaI site without the use of mismatches. These tests have successfully detected the mutations in individuals suspected of having the pseudodeficiency on the basis of biochemical assay. The `I` allele was detected in 1 of 16 MLD alleles analyzed.

Coulter-Mackie, M.B. [Univ. of Western Ontario (Canada)]|[CPRI, London, Ontario (Canada)

1994-09-01

69

40 CFR 799.9530 - TSCA in vitro mammalian cell gene mutation test.  

Code of Federal Regulations, 2010 CFR

...2010-07-01 true TSCA in vitro mammalian cell gene mutation test. 799.9530 Section... § 799.9530 TSCA in vitro mammalian cell gene mutation test. (a) Scope. ...section 4 of TSCA. The in vitro mammalian cell gene mutation test can be used to...

2010-07-01

70

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

71

Effects of destrin pathway mutations on the gene expression profile.  

PubMed

This study aimed to explore the interaction and crosstalk between pathways in response to destrin mutations. All the pathways from the MINT database were downloaded, a protein-protein interaction network was then constructed, and the crosstalk between pathways was investigated, in particular, the overlap of 2 significant pathway analysis results. As expected, the results showed that regulation of the actin cytoskeleton was the significant pathway of destrin mutations in mice. Further analysis indicated that 28 significant pathways cross-talked with the pathway regulating the actin cytoskeleton. Importantly, 3 pathways, including regulation of actin cytoskeleton pathway, pathways in cancer, and the B cell receptor signaling pathway were linked by inositol phosphate metabolism based on crosstalk analysis of Gene Ontology relationships among pathways. All of these pathways have been demonstrated to participate in cytoskeleton dynamics. These findings might provide valuable insights into cytoskeleton dynamic abnormalities in destrin mutations of corneal diseases. PMID:24782051

Xu, J N; Liu, X; Wang, H; Hu, C M; Luo, Q H; Zhou, Q Q

2014-01-01

72

De Novo Mutations in Ataxin-2 Gene and ALS Risk  

PubMed Central

Pathogenic CAG repeat expansion in the ataxin-2 gene (ATXN2) is the genetic cause of spinocerebellar ataxia type 2 (SCA2). Recently, it has been associated with Parkinsonism and increased genetic risk for amyotrophic lateral sclerosis (ALS). Here we report the association of de novo mutations in ATXN2 with autosomal dominant ALS. These findings support our previous conjectures based on population studies on the role of large normal ATXN2 alleles as the source for new mutations being involved in neurodegenerative pathologies associated with CAG expansions. The de novo mutations expanded from ALS/SCA2 non-risk alleles as proven by meta-analysis method. The ALS risk was associated with SCA2 alleles as well as with intermediate CAG lengths in the ATXN2. Higher risk for ALS was associated with pathogenic CAG repeat as revealed by meta-analysis. PMID:23936447

Laffita-Mesa, Jose Miguel; Rodriguez Pupo, Jorge Michel; Moreno Sera, Raciel; Vazquez Mojena, Yaimee; Kouri, Vivian; Laguna-Salvia, Leonides; Martinez-Godales, Michael; Valdevila Figueira, Jose A.; Bauer, Peter O.; Rodriguez-Labrada, Roberto; Zaldivar, Yanetza Gonzalez; Paucar, Martin; Svenningsson, Per; Perez, Luis Velazquez

2013-01-01

73

Endemic polycythemia in Russia: mutation in the VHL gene.  

PubMed

Chuvash polycythemia (CP) is an autosomal recessive condition that is endemic in the Russian mid-Volga River region of Chuvashia. We previously found that CP patients may have increased serum erythropoietin (EPO) levels, ruled out linkage to both the EPO and EPO receptor (EPOR) gene loci, and hypothesized that the defect may lie in the oxygen homeostasis pathway. We now report a study of five multiplex Chuvash families which confirms that CP is associated with significant elevations of serum EPO levels and rules out a location for the CP gene on chromosome 11 as had been reported by other investigators or a mutation of the HIF-1 alpha gene. Using a genome-wide screen, we localized a region on chromosome 3 with a LOD score >2. After sequencing three candidate genes, we identified a C to T transition at nucleotide 598 (an R200W mutation) in the von Hippel-Lindau (VHL) gene. The VHL protein (pVHL) downregulates the alpha subunit of hypoxia-inducible factor 1 (HIF-1 alpha), the main regulator of hypoxia adaptation, by targeting the protein for degradation. In the simplest scenario, disruption of pVHL function causes a failure to degrade HIF-1 alpha resulting in accumulation of HIF-1 alpha, upregulation of downstream target genes such as EPO, and the clinical manifestation of polycythemia. These findings strongly suggest that CP is a congenital disorder of oxygen homeostasis. PMID:11987242

Ang, Sonny O; Chen, Hua; Gordeuk, Victor R; Sergueeva, Adelina I; Polyakova, Lydia A; Miasnikova, Galina Y; Kralovics, Robert; Stockton, David W; Prchal, Josef T

2002-01-01

74

Mutational Analysis of Angiogenin Gene in Parkinson's Disease  

PubMed Central

Mutations in the angiogenic factor, angiogenin (ANG), have been identified in patients with both familial and sporadic amyotrophic lateral sclerosis (ALS) and are thought to have a neuroprotective function. Parkinsonism has been noted in kindreds with ANG mutations and variants in the ANG gene have been found to associate with PD in two Caucasian populations. We therefore hypothesized that mutations in ANG may also contribute to idiopathic Parkinson's disease (PD). We sequenced ANG gene in a total of 1498 participants comprising 750 PD patients and 748 age/gender matched controls from Taiwan. We identified one novel synonymous substitution, c.C100T (p.L10L), in a single heterozygous state in one PD patient, which was not observed in controls. The clinical phenotypes and [99mTc]-TORDAT-SPECT images of the p.L10L carrier were similar to that seen in idiopathic PD. In addition, we also identified one common variant, c.T330G (p.G110G, rs11701), which was previously reported to associate with PD risk in Caucasians. However, the frequency of TG/GG genotype was comparable between PD cases and controls (odds ratio: 0.85, 95% confidence interval: 0.29–2.55, P?=?0.78). Our results did not support that ANG rs11701 variant is a genetic risk factor for PD in our population. We conclude that mutations in ANG are not a common cause for idiopathic PD. PMID:25386690

Chen, Meng-Ling; Wu, Ruey-Meei; Tai, Chun-Hwei; Lin, Chin-Hsien

2014-01-01

75

Mutation profile of BBS genes in Iranian patients with Bardet-Biedl syndrome: genetic characterization and report of nine novel mutations in five BBS genes.  

PubMed

Bardet-Biedl syndrome (BBS) is a rare ciliopathy disorder that is clinically and genetically heterogeneous with 18 known genes. This study was performed to characterize responsible genes and mutation spectrum in a cohort of 14 Iranian families with BBS. Sanger sequencing of the most commonly mutated genes (BBS1, BBS2 and BBS10) accounting for ?50% of BBS patients determined mutations only in BBS2, including three novel mutations. Next, three of the remaining patients were subjected to whole exome sequencing with 96% at 20 × depth of coverage that revealed novel BBS4 mutation. Observation of no mutation in the other patients represents the possible presence of novel genes. Screening of the remaining patients for six other genes (BBS3, BBS4, BBS6, BBS7, BBS9 and BBS12) revealed five novel mutations. This result represents another indication for the genetic heterogeneity of BBS and extends the mutational spectrum of the disease by introducing nine novel mutations in five BBS genes. In conclusion, although BBS1 and BBS10 are among the most commonly mutated genes in other populations like Caucasian, these two seem not to have an important role in Iranian patients. This suggests that a different strategy in molecular genetics diagnostic approaches in Middle Eastern countries such as Iran should be considered. PMID:24849935

Fattahi, Zohreh; Rostami, Parvin; Najmabadi, Amin; Mohseni, Marzieh; Kahrizi, Kimia; Akbari, Mohammad Reza; Kariminejad, Ariana; Najmabadi, Hossein

2014-07-01

76

Autosomal Recessive Retinitis Pigmentosa and E150K Mutation in the Opsin Gene*S  

E-print Network

Autosomal Recessive Retinitis Pigmentosa and E150K Mutation in the Opsin Gene*S Received with an autosomal dominant (adRP), autosomal recessive (arRP), or X-linked pattern of inheritance. Although to be associated with autosomal recessive retinitis pigmentosa (arRP). The first reported case of arRP associated

Palczewski, Krzysztof

77

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

78

Optimization of gene sequences under constant mutational pressure and selection  

NASA Astrophysics Data System (ADS)

We have analyzed the influence of constant mutational pressure and selection on the nucleotide composition of DNA sequences of various size, which were represented by the genes of the Borrelia burgdorferi genome. With the help of MC simulations we have found that longer DNA sequences accumulate much less base substitutions per sequence length than short sequences. This leads us to the conclusion that the accuracy of replication may determine the size of genome.

Kowalczuk, M.; Gierlik, A.; Mackiewicz, P.; Cebrat, S.; Dudek, M. R.

1999-12-01

79

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

80

Mutations in Known Genes Account for 58% of Autosomal Dominant Retinitis Pigmentosa (adRP)  

Microsoft Academic Search

Inherited retinal diseases such as autosomal dominant retinitis pigmentosa (adRP) are strikingly complex, with mutations in\\u000a many different genes causing the same disease, with many different mutations in each gene, and with different clinical consequences\\u000a resulting from the same mutation, even within the same family. for example, mutations in sixteen genes are known to cause\\u000a adRP and an additional two

Stephen P. Daiger; Lori S. Sullivan; Anisa I. Gire; David G. Birch; John R. Heckenlively; Sara J. Bowne

81

The FBN2 gene: new mutations, locus-specific database (Universal Mutation Database FBN2), and genotype-phenotype correlations.  

PubMed

Congenital contractural arachnodactyly (CCA) is an extremely rare disease, due to mutations in the FBN2 gene encoding fibrillin-2. Another member of the fibrillin family, the FBN1 gene, is involved in a broad phenotypic continuum of connective-tissue disorders including Marfan syndrome. Identifying not only what is in common but also what differentiates these two proteins should enable us to better comprehend their respective functions and better understand the multitude of diseases in which these two genes are involved. In 1995 we created a locus-specific database (LSDB) for FBN1 mutations with the Universal Mutation Database (UMD) tool. To facilitate comparison of identified mutations in these two genes and search for specific functional areas, we created an LSDB for the FBN2 gene: the UMD-FBN2 database. This database lists 26 published and six newly identified mutations that mainly comprise missense and splice-site mutations. Although the number of described FBN2 mutations was low, the frequency of joint dislocation was significantly higher with missense mutations when compared to splice site mutations. PMID:18767143

Frédéric, Melissa Yana; Monino, Christine; Marschall, Christoph; Hamroun, Dalil; Faivre, Laurence; Jondeau, Guillaume; Klein, Hanns-Georg; Neumann, Luitgard; Gautier, Elodie; Binquet, Christine; Maslen, Cheryl; Godfrey, Maurice; Gupta, Prateek; Milewicz, Dianna; Boileau, Catherine; Claustres, Mireille; Béroud, Christophe; Collod-Béroud, Gwenaëlle

2009-02-01

82

Analysis of gene mutations among South Indian patients with maple syrup urine disease: identification of four novel mutations.  

PubMed

Maple syrup urine disease (MSUD) is predominantly caused by mutations in the BCKDHA, BCKDHB and DBT genes, which encode for the E1alpha, E1beta and E2 subunits of the branched-chain alpha-keto acid dehydrogenase complex, respectively. Because disease causing mutations play a major role in the development of the disease, prenatal diagnosis at gestational level may have significance in making decisions by parents. Thus, this study was aimed to screen South Indian MSUD patients for mutations and assess the genotype-phenotype correlation. Thirteen patients diagnosed with MSUD by conventional biochemical screening such as urine analysis by DNPH test, thin layer chromatography for amino acids and blood amino acid quantification by HPLC were selected for mutation analysis. The entire coding regions of the BCKDHA, BCKDHB and DBT genes were analyzed for mutations by PCR-based direct DNA sequencing. BCKDHA and BCKDHB mutations were seen in 43% of the total ten patients, while disease-causing DBT gene mutation was observed only in 14%. Three patients displayed no mutations. Novel mutations were c.130C>T in BCKDHA gene, c. 599C>T and c.121_122delAC in BCKDHB gene and c.190G>A in DBT gene. Notably, patients harbouring these mutations were non-responsive to thiamine supplementation and other treatment regimens and might have a worse prognosis as compared to the patients not having such mutations. Thus, identification of these mutations may have a crucial role in the treatment as well as understanding the molecular mechanisms in MSUD. PMID:24772966

Narayanan, M P; Menon, Krishnakumar N; Vasudevan, D M

2013-10-01

83

Visual DNA microarray for detection of epidermal growth factor receptor (EGFR) gene mutations.  

PubMed

Abstract Objective. To develop a gold nanoparticle-based visual DNA microarray for simple and rapid screening of EGFR gene mutations. Methods. The DNA fragments contain epidermal growth factor receptor (EGFR) exons 18, 19, 20 and 21 were amplified by polymerase chain reaction (PCR) using biotin-modified primers. The amino-modified oligonucleotides were immobilized on glass surface, which were used as the capturing probes to bind the complement biotinylated target DNA. After the PCR product has been hybridized to the immobilized capture probe DNA on the glass slides, the Streptavidin-conjugated gold nanoparticles were introduced to the microarray via specific binding to 5'-end biotin of the PCR products. The hybridization signal on array spots was enhanced and visualized by silver amplification. The EGFR mutation in 286 clinical samples from cancer patients were tested using the gold nanoparticle-based microarray and verified with Sanger DNA sequencing method. Results. A novel visual DNA microarray has been developed to detect EGFR mutations in tumor tissue specimens rapidly; its limit of detection (LOD) is up to 10(-9) mol/L and distinguishes power to detect 5% gene mutation in the mixture samples. Conclusion. For its high specificity and sensitivity, simplicity, lower price and higher speed, the present visual mutation detecting technique has potential application in clinical fields. PMID:25223598

Xue, Li; Fei, Jing-Jing; Song, Yi; Xu, Rong-Hua; Bai, Yu-Jie

2014-11-01

84

[Analysis of mutations in the phenylalanine hydroxylase gene in Ukrainian families at high risk for phenylketonuria].  

PubMed

The data on analysis of phenylalanine hydroxilase (PAH) gene mutations in 39 phenylketonuria (PKU) families from Ukraine are presented. Obtained results indicate that the most common mutation observed in the Ukrainian population is R408W mutation (66.6%). Besides two minor mutations R158Q (2.6%) and Y414C (1.25%) were revealed. PMID:11391893

Nechiporenko, M V; Lalivshits, L A

2000-01-01

85

Atrichia Caused by Mutations in the Vitamin D Receptor Gene is a Phenocopy of Generalized Atrichia Caused by Mutations in the Hairless Gene  

Microsoft Academic Search

Generalized atrichia with papules is a rare disorder characterized by loss of hair shortly after birth and development of cutaneous cysts. Mutations in the hairless gene (HR) cause this phenotype in both mouse and human. Here we present a case of atrichia with papules in a patient with a normal HAIRLESS gene but with mutations in both alleles of the

Jeffrey Miller; Karima Djabali; Tai Chen; Yaping Liu; Michael Ioffreda; Stephen Lyle; Angela M. Christiano; Michael Holick; George Cotsarelis

2001-01-01

86

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

87

Mutations and a polymorphism in the tuberin gene  

SciTech Connect

Two deletions and a polymorphism have been identified in the recently described tuberin gene. The tuberin gene (designated TSC2) when mutated causes tuberous sclerosis complex (TSC). Fifty-three affected individuals (30 from families with multiple affected and 23 isolated cases) were screened with the tuberin cDNA for gross deletions or rearrangements. Both deletions were found in families with multiple affected members (family designations: HOU-5 and HOU-22). The approximate size of the deletion in HOU-5 is ten kilobases and eliminates a BamHI restriction site. The deletion includes a portion of the 5{prime} half of the tuberin cDNA. The deletion in HOU-22 occurs in the 3{prime} half of the gene. The deletions are being further characterized. A HindIII restriction site polymorphism was detected by a 0.5 kilobase probe from the 5{prime} coding region of the tuberin gene in an individual from a family linked to chromosome 9 (posterior probability of linkage 93%). The polymorphism did not segregate with TSC in the family. The family had previously been shown to give negative results with multiple markers on chromosome 16. The polymorphism was also seen in one individual among a panel of 20 randomly selected unaffected individuals. Thirty-five additional affected probands (five from families and 30 isolated cases) are being tested with the tuberin cDNA. Testing for subtle mutations is our panel of 80 affected probands is underway utilizing SSCP. Additional mutations or polymorphisms detected will be reported. The tuberin cDNA was a kind gift of The European Chromosome 16 Tuberous Sclerosis Consortium.

Northup, H.; Rodriguez, J.A.; Au, K.S.; Rodriguez, E. [Univ. of Texas Medical School, Houston, TX (United States)

1994-09-01

88

Cohesin gene mutations in tumorigenesis: from discovery to clinical significance.  

PubMed

Cohesin is a multi-protein complex composed of four core subunits (SMC1A, SMC3, RAD21, and either STAG1 or STAG2) that is responsible for the cohesion of sister chromatids following DNA replication until its cleavage during mitosis thereby enabling faithful segregation of sister chromatids into two daughter cells. Recent cancer genomics analyses have discovered a high frequency of somatic mutations in the genes encoding the core cohesin subunits as well as cohesin regulatory factors (e.g. NIPBL, PDS5B, ESPL1) in a select subset of human tumors including glioblastoma, Ewing sarcoma, urothelial carcinoma, acute myeloid leukemia, and acute megakaryoblastic leukemia. Herein we review these studies including discussion of the functional significance of cohesin inactivation in tumorigenesis and potential therapeutic mechanisms to selectively target cancers harboring cohesin mutations. PMID:24856830

Solomon, David A; Kim, Jung-Sik; Waldman, Todd

2014-06-01

89

Cohesin gene mutations in tumorigenesis: from discovery to clinical significance  

PubMed Central

Cohesin is a multi-protein complex composed of four core subunits (SMC1A, SMC3, RAD21, and either STAG1 or STAG2) that is responsible for the cohesion of sister chromatids following DNA replication until its cleavage during mitosis thereby enabling faithful segregation of sister chromatids into two daughter cells. Recent cancer genomics analyses have discovered a high frequency of somatic mutations in the genes encoding the core cohesin subunits as well as cohesin regulatory factors (e.g. NIPBL, PDS5B, ESPL1) in a select subset of human tumors including glioblastoma, Ewing sarcoma, urothelial carcinoma, acute myeloid leukemia, and acute megakaryoblastic leukemia. Herein we review these studies including discussion of the functional significance of cohesin inactivation in tumorigenesis and potential therapeutic mechanisms to selectively target cancers harboring cohesin mutations. [BMB Reports 2014; 47(6): 299-310] PMID:24856830

Solomon, David A.; Kim, Jung-Sik; Waldman, Todd

2014-01-01

90

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

Code of Federal Regulations, 2011 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,” Mutation Research,...

2011-07-01

91

U Penn researchers classify gene mutations in a children's cancer that may point to improved treatments  

Cancer.gov

Oncology researchers studying gene mutations in the childhood cancer neuroblastoma are refining their diagnostic tools to predict which patients are more likely to respond to drugs called ALK inhibitors that target such mutations.

92

BCS1L gene mutation causing GRACILE syndrome: case report.  

PubMed

GRACILE syndrome is a rare autosomal recessive disease characterized by fetal growth retardation, Fanconi type aminoaciduria, cholestasis, iron overload, profound lactic acidosis, and early death. It is caused by homozygosity for a missense mutation in the BCS1L gene. The BCS1L gene encodes a chaperone responsible for assembly of respiratory chain complex III. Here we report that a homozygous mutation c.296C > T (p.P99L), in the first exon of BCS1L gene found in an affected 2-month-old boy of asymptomatic consanguineous parents results in GRACILE syndrome. This genotype is associated with a severe clinical presentation. So far no available treatments have changed the fatal course of the disease, and the metabolic disturbance responsible is still not clearly identified. Therefore, providing prenatal diagnosis in families with previous affected infants is of major importance. Mitochondrial disorders are an extremely heterogeneous group of diseases sharing, in common, the fact that they all ultimately impair the function of the mitochondrial respiratory chain. A clinical picture with fetal growth restriction, postnatal lactacidosis, aminoaciduria, hypoglycemia, coagulopathy, elevated liver enzymes, and cholestasis should direct investigations on mitochondrial disorder. PMID:24655110

Kasapkara, Çi?dem Seher; Tümer, Leyla; Ezgü, Fatih Suheyl; Küçükçongar, Aynur; Hasano?lu, Alev

2014-07-01

93

Differential Recognition of Surface Proteins in Streptococcus pyogenes by Two Sortase Gene Homologs  

Microsoft Academic Search

The interaction of Streptococcus pyogenes (group A streptococcus (GAS)) with its human host requires several surface proteins. In this study, we isolated mutations in a gene required for the surface localization of protein F by transposon mutagenesis of the M6 strain JRS4. This gene (srtA) encodes a protein homologous to Staphylococcus aureus sortase, which covalently links proteins containing an LPXTG

Timothy C. Barnett; June R. Scott

2002-01-01

94

High prevalence of founder mutations of the succinate dehydrogenase genes in the Netherlands.  

PubMed

Mutations in four genes encoding subunits or cofactors of succinate dehydrogenase (SDH) cause hereditary paraganglioma and pheochromocytoma syndromes. Mutations in SDHB and SDHD are generally the most common, whereas mutations in SDHC and SDHAF2 are far less frequently observed. A total of 1045 DNA samples from Dutch paraganglioma and pheochromocytoma patients and their relatives were analyzed for mutations of SDHB, SDHC, SDHD or SDHAF2. Mutations in these genes were identified in 690 cases, 239 of which were index cases. The vast majority of mutation carriers had a mutation in SDHD (87.1%). The second most commonly affected gene was SDHAF2 (6.7%). Mutations in SDHB were found in only 5.9% of samples, whereas SDHC mutations were found in 0.3% of samples. Remarkably, 69.1% of all carriers of a mutation in an SDH gene in the Netherlands can be attributed to a single founder mutation in SDHD, c.274G>T and p.Asp92Tyr. Moreover, 88.8% of all SDH mutation carriers carry one of just six Dutch founder mutations in SDHB, SDHD and SDHAF2. The dominance of SDHD mutations is unique to the Netherlands, contrasting with the higher prevalence of SDHB mutations found elsewhere. In addition, we found that most SDH mutation-related paragangliomas-pheochromocytomas in the Netherlands can be explained by only six founder mutations in SDHAF2, SDHB and SDHD. The findings underline the regional differences in the SDH mutation spectrum, differences that should be taken into account in the development of effective screening protocols. The results show the crucial role that demographic factors play in the frequency of gene mutations. PMID:21348866

Hensen, E F; van Duinen, N; Jansen, J C; Corssmit, E P M; Tops, C M J; Romijn, J A; Vriends, A H J T; van der Mey, A G L; Cornelisse, C J; Devilee, P; Bayley, J P

2012-03-01

95

Corin mutations K317E and S472G from preeclamptic patients alert zymogen activation and cell surface targeting.  

PubMed

Corin is a membrane-bound serine protease that acts as the atrial natriuretic peptide (ANP) convertase in the heart. Recent studies show that corin also activates ANP in the pregnant uterus to promote spiral artery remodeling and prevent pregnancy-induced hypertension. Two CORIN gene mutations, K317E and S472G, were identified in preeclamptic patients and shown to have reduced activity in vitro. In this study, we carried out molecular modeling and biochemical experiments to understand how these mutations impair corin function. By molecular modeling, the mutation K317E was predicted to alter corin LDL receptor-2 module conformation. Western blot analysis of K317E mutant in HEK293 cells showed that the mutation did not block corin expression on the cell surface but inhibited corin zymogen activation. In contrast, the mutation S472G was predicted to abolish a ?-sheet critical for corin frizzled-2 module structure. In Western blot analysis and flow cytometry, S472G mutant was not detected on the cell surface in transfected HEK293 cells. By immunostaining, the S472G mutant was found in the ER, indicating that the mutation S472G disrupted the ?-sheet, causing corin misfolding and ER retention. Thus, these results show that mutations in the CORIN gene may impair corin function by entirely different mechanisms. Together, our data provide important insights into the molecular basis underlying corin mutations that may contribute to preeclampsia in patients. PMID:24828501

Dong, Ningzheng; Zhou, Tiantian; Zhang, Yue; Liu, Meng; Li, Hui; Huang, Xiaoyi; Liu, Zhenzhen; Wu, Yi; Fukuda, Koichi; Qin, Jun; Wu, Qingyu

2014-06-20

96

Mutation in a reporter gene depends on proximity to and transcription of immunoglobulin variable transgenes.  

PubMed Central

Somatic mutation in immunoglobulin genes is localized to a 2-kilobase region of DNA surrounding and including rearranged variable (V), diversity, and joining (J) gene segments encoding heavy and light chains. To examine the structural basis for targeted mutation, we developed an assay to score mutation on plasmid substrates by using a reporter gene: a bacterial gene encoding an amber-suppressor tRNA molecule was placed 3' of a rearranged kappa VJ gene within the boundaries of mutation. The reporter gene is exquisitely suited for mutational analysis because it is only 200 base pairs (bp), which should not greatly disrupt structure of the immunoglobulin locus, and gene function depends on secondary structure, which means mutation can be scored in many different nucleotide positions. The plasmid was used to make transgenic mice, which were then immunized. The shuttle vector was retrieved by plasmid rescue into an indicator strain of Escherichia coli that contained an amber mutation in its beta-galactosidase gene. Integrity of the tRNA molecule was monitored by colony color, which permitted many transformants to be screened visually. Mutations were not seen in DNA from a transfected B-cell line grown in vitro or in DNA from nonlymphoid tissue of transgenic mice, indicating that the reporter gene was stable during cell division and DNA manipulations. However, when the transgenic mice were immunized, DNA from splenic B cells contained point mutations in the reporter gene at a frequency of 10(-3) per transformant. Sequence analysis of 17 mutated transgenes revealed that the mutations were 1- and 2-bp deletions in the tRNA gene, and one plasmid had an additional 2-bp deletion in the V gene. In contrast, previous studies have shown that mutations in endogenous VJ genes are predominantly nucleotide substitutions and have only 6% deletions. Two other plasmid constructs were analyzed in transgenic lines: no mutations were found when the tRNA gene was placed distal to the VJ gene, and no mutations were seen when the immunoglobulin promoter was deleted. Although we lack direct evidence that the deletions in the tRNA gene are caused by the same mechanism that acts on VJ genes, we have shown that mutations in this assay occur in a manner consistent with immunoglobulin-specific mutation in that they are found in splenic B cells and not in tail tissue, depend on position next to the VJ gene, and require transcription of the VJ gene. Images PMID:1905016

Umar, A; Schweitzer, P A; Levy, N S; Gearhart, J D; Gearhart, P J

1991-01-01

97

Using protein complexes to predict phenotypic effects of gene mutation  

Microsoft Academic Search

Background  Predicting the phenotypic effects of mutations is a central goal of genetics research; it has important applications in elucidating\\u000a how genotype determines phenotype and in identifying human disease genes.\\u000a \\u000a \\u000a \\u000a \\u000a Results  Using a wide range of functional genomic data from the yeast Saccharomyces cerevisiae, we show that the best predictor of a protein's knockout phenotype is the knockout phenotype of other proteins

Hunter B Fraser; Joshua B Plotkin

2007-01-01

98

No Gene-Specific Optimization of Mutation Rate in Escherichia coli  

E-print Network

selection, E. coli. Because mutation is the ultimate source of genetic variation and evolution, accurately to approximately 0.3 among E. coli genes (Martincorena and Luscombe 2013). Assuming that Áf between genes of multiple genes with similar fractions of deleterious mutations. Analyzing published genome sequences of E

Zhang, Jianzhi

99

Identifying photoreceptors in blind eyes caused by RPE65 mutations: Prerequisite for human gene therapy success  

Microsoft Academic Search

Mutations in RPE65, a gene essential to normal operation of the visual (retinoid) cycle, cause the childhood blindness known as Leber congenital amaurosis (LCA). Retinal gene therapy restores vision to blind canine and murine models of LCA. Gene therapy in blind humans with LCA from RPE65 mutations may also have potential for success but only if the retinal photoreceptor layer

Samuel G. Jacobson; Tomas S. Aleman; Artur V. Cideciyan; Alexander Sumaroka; Sharon B. Schwartz; Elizabeth A. M. Windsor; Elias I. Traboulsi; Elise Heon; Steven J. Pittler; Ann H. Milam; Albert M. Maguire; Krzysztof Palczewski; Edwin M. Stone; Jean Bennett

2005-01-01

100

NPHS1 gene mutations in children with Nephrotic Syndrome in northwest Iran.  

PubMed

Idiopathic Nephrotic Syndrome (NS) is the prevalent glomerular disease in childhood. It is treated with steroid and according to its response is defined as steroid sensitive NS (SSNS) and steroid resistance NS (SRNS). Mutation in NPHS 1 gene is reported in children with SRNS and few cases of SSNS. The aim of current study is to evaluate NPHS1 gene mutations in idiopathic NS (SSNS and SSRS) in Northwest Iran. In this cross-sectional analytic study 20 children from Azeri population in Iran with idiopathic NS including 10 cases with SRNS (5 male and 5 female) and 10 cases with SSNS (7 male and 3 female) were evaluated for NPHS1 gene mutations. DNA was extracted from peripheral blood and NPHSI gene analysis was performed by PCR and direct sequencing method with the use of standard primers. Mutations in NPHS1 gene occurred in 6 cases of SSNS including 3 heterozygous and 3 homozygous mutations and in 8 cases of SRNS including 5 homozygous, one compound heterozygous and 2 heterozygous mutations. Overall 6 different mutations were detected in NPHS1 gene: one deletion, one insertion, 3 missense and one nonsense mutations. Mutations in exon 4 and 27 were only seen in SRNS patients. Mutations in NPHS1 gene could occur in both SRNS and SSNS patients; however, considering higher incidence of heterozygous mutations in SSNS, the existence of milder phenotype in these cases would be the reason for steroid response. PMID:24498843

Behbahan, A G; Poorshiri, B; Mortazavi, F; Khaniani, M S; Derakhshan, S M

2013-09-01

101

Novel and convenient methods for Candida tropicalis gene disruption using a mutated hygromycin B resistance gene  

Microsoft Academic Search

We established a novel and convenient method to construct a ura3 strain (ura3\\/ura3) of the asporogenous and diploid yeast, Candida tropicalis, that produces dicarboxylic acid. One copy of the URA3 gene was disrupted using a mutated hygromycin B resistance gene (HYG#). The obtained hygromycin-resistant strain was further transformed with a URA3 disruption cassette and selected on a plate containing 5-fluoroorotic

Akihiro Hara; Mami Arie; Tamotsu Kanai; Toru Matsui; Hitoshi Matsuda; Keizo Furuhashi; Mitsuyoshi Ueda; Atsuo Tanaka

2001-01-01

102

[Acquisition of the drug resistance and Helicobacter pylori gene mutation].  

PubMed

The currently recommended regimen in Japan is a proton pump inhibitor-based triple therapy with two of the antibiotics between clarithromycin, amoxicillin and metronidazole. However, recent years have witnessed a decrease in the rate of eradication due to antimicrobial resistance. Resistance mechanisms of H. pylori are explained by the occurrence of mutations in genomic genes, which may correspond to the 23S rRNA gene in clarithromycin, the pbp1A in amoxicillin, and the rdxA in metronidazole, gyrA in levofloxacin. The resistance of H. pylori strains to clarithromycin is currently estimated at about 30% in Japan, while the resistant rates to metoronidazole and amoxicillin are quite low. The resistant rates of each antibiotics may increase in future, so we need to observe those changes. PMID:19999127

Okimoto, Tadayoshi; Murakami, Kazunari

2009-12-01

103

Mutations of the p53 Gene in Nasal NK\\/T-Cell Lymphoma  

Microsoft Academic Search

Mutations of the p53 tumor suppressor gene are reported in various kinds of malignancies including lymphomas. However, p53 gene mutations in nasal NK\\/T-cell lymphoma have not been reported because most parts of tumors are necrotic and a small amount of living tumor tissues is available for the molecular study. Expression and mutations of the p53 gene were examined in the

Ting Li; Tadashi Hongyo; Mukh Syaifudin; Taisei Nomura; Zhiming Dong; Norihisa Shingu; Shizuo Kojya; Shin-ichi Nakatsuka; Katsuyuki Aozasa

2000-01-01

104

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

105

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. PMID:21664996

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

2011-01-01

106

Kras gene codon 12 mutation detection enabled by gold nanoparticles conducted in a nanobioarray chip.  

PubMed

This study employs a nanobioarray (NBA) chip for multiple biodetection of single base pair mutations at the Kras gene codon 12. To distinguish between the mutant and wild-type target DNAs, current bioarray methods use high-temperature hybridization of the targets to the allele-specific probes. However, these techniques need prior temperature optimization and become harder to implement in the case of the detection of multiple mutations. We aimed to detect these mutations at a single temperature (room temperature), enabled by the use of gold nanoparticles (AuNPs) on the bioarray created within nanofluidic channels. In this method, a low amount of target oligonucleotides (5fmol) and polymerase chain reaction (PCR) products (300pg) were first loaded on the AuNP surface, and then these AuNP-bound targets were introduced into the channels of a polydimethylsiloxane (PDMS) glass chip. The targets hybridized to their complementary probes at the intersection of the target channels to the pre-printed oligonucleotide probe lines on the glass surface, creating a bioarray. Using this technique, fast and high-throughput multiple discrimination of the Kras gene codon 12 were achieved at room temperature using the NBA chip, and the specificity of the method was proved to be as high as that with the temperature stringency method. PMID:24291640

Sedighi, Abootaleb; Li, Paul C H

2014-03-01

107

Recurrent mutation, gene conversion, or recombination at the human phenylalanine hydroxylase locus: evidence in French-Canadians and a catalog of mutations.  

PubMed

The codon 408 mutation (CGG----TGG, Arg----Trp) in exon 12 of the phenylalanine hydroxylase (PAH) gene occurs on haplotype 1 in French-Canadians; elsewhere this mutation (R408W) occurs on haplotype 2. A CpG dinucleotide is involved. The finding is compatible with a recurrent mutation, gene conversion, or a single recombination between haplotypes 2 and 1. A tabulation of 20 known mutations at the PAH locus reveals three instances of putative recurrent mutation. PMID:1971147

John, S W; Rozen, R; Scriver, C R; Laframboise, R; Laberge, C

1990-05-01

108

Recurrent mutation, gene conversion, or recombination at the human phenylalanine hydroxylase locus: evidence in French-Canadians and a catalog of mutations.  

PubMed Central

The codon 408 mutation (CGG----TGG, Arg----Trp) in exon 12 of the phenylalanine hydroxylase (PAH) gene occurs on haplotype 1 in French-Canadians; elsewhere this mutation (R408W) occurs on haplotype 2. A CpG dinucleotide is involved. The finding is compatible with a recurrent mutation, gene conversion, or a single recombination between haplotypes 2 and 1. A tabulation of 20 known mutations at the PAH locus reveals three instances of putative recurrent mutation. PMID:1971147

John, S W; Rozen, R; Scriver, C R; Laframboise, R; Laberge, C

1990-01-01

109

Identification of a novel missense mutation of PEX7 gene in an Iranian patient with rhizomelic chondrodysplasia punctata type 1.  

PubMed

Deficiency in the PTS2 protein import pathway due to mutations in PEX7 gene results in the rhizomelic chondrodysplasia punctata (RCDP) type 1. In the present study, we have reported a novel missense mutation, W75R, in the PEX7 gene in an Iranian patient with the RCDP type 1. The inability of PEX7 protein to transport PTS2 containing proteins including peroxisomal 3-ketoacyl-CoA thiolase and PTS2-EGFP protein to the surface of the peroxisomes showed that the W75R mutation in PEX7 gene severely impaired the function of PEX7 protein and was responsible for RCDP type 1 in this patient. PMID:23357221

Mohamadynejad, Parisa; Ghaedi, Kamran; Shafeghati, Yousef; Salamian, Ahmad; Tanhaie, Somayeh; Karamali, Fereshteh; Rabiee, Farzaneh; Parivar, Kazem; Baharvand, Hossein; Nasr-Esfahani, Mohammad Hossein

2013-04-15

110

The Berkeley Drosophila Genome Project Gene Disruption Project: Single P-Element Insertions Mutating 25% of Vital Drosophila Genes  

Microsoft Academic Search

A fundamental goal of genetics and functional genomics is to identify and mutate every gene in model organisms such as Drosophila melanogaster. The Berkeley Drosophila Genome Project (BDGP) gene disruption project generates single P-element insertion strains that each mutate unique genomic open reading frames. Such strains strongly facilitate further genetic and molecular studies of the disrupted loci, but it has

Allan C. Spradling; Dianne Stern; Amy Beaton; E. Jay Rhem; Todd Laverty; Nicole Mozden; Sima Misra; Gerald M. Rubin

111

Spinal Muscular Atrophy with Pontocerebellar Hypoplasia Is Caused by a Mutation in the VRK1 Gene  

E-print Network

REPORT Spinal Muscular Atrophy with Pontocerebellar Hypoplasia Is Caused by a Mutation in the VRK1 and identified a nonsense mutation in the vaccinia-related kinase 1 gene (VRK1) as a cause of SMA-PCH. VRK1, one]) accounts for 80%­90% of all SMA cases and is primarily caused by recessive mutations in SMN1 (MIM 600354

Friedman, Nir

112

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

113

Rifampicin resistance and mutation of the rpoB gene in Mycobacterium tuberculosis  

Microsoft Academic Search

Using 39 clinical isolates of Mycobacterium tuberculosis strains with a broad range of susceptibility to rifampicin, we examined the relationship between the degree of resistance to rifampicin and mutational sites of the rpoB gene. All rifampicin-resistant strains had missense mutations. Twenty strains (95%) had a mutation in the cluster I region, which has also been reported in Escherichia coli [Jin

Hatsumi Taniguchi; Hironori Aramaki; Yoshihiko Nikaido; yasuo Mizuguchi; Masahiro Nakamura; Toshihiko Koga; Shin-ichi Yoshida

1996-01-01

114

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

115

A report of a national mutation testing service for the MEN1 gene: clinical presentations and implications for mutation testing  

PubMed Central

Introduction: Mutation testing for the MEN1 gene is a useful method to diagnose and predict individuals who either have or will develop multiple endocrine neoplasia type 1 (MEN 1). Clinical selection criteria to identify patients who should be tested are needed, as mutation analysis is costly and time consuming. This study is a report of an Australian national mutation testing service for the MEN1 gene from referred patients with classical MEN 1 and various MEN 1-like conditions. Results: All 55 MEN1 mutation positive patients had a family history of hyperparathyroidism, had hyperparathyroidism with one other MEN1 related tumour, or had hyperparathyroidism with multiglandular hyperplasia at a young age. We found 42 separate mutations and six recurring mutations from unrelated families, and evidence for a founder effect in five families with the same mutation. Discussion: Our results indicate that mutations in genes other than MEN1 may cause familial isolated hyperparathyroidism and familial isolated pituitary tumours. Conclusions: We therefore suggest that routine germline MEN1 mutation testing of all cases of "classical" MEN1, familial hyperparathyroidism, and sporadic hyperparathyroidism with one other MEN1 related condition is justified by national testing services. We do not recommend routine sequencing of the promoter region between nucleotides 1234 and 1758 (Genbank accession no. U93237) as we could not detect any sequence variations within this region in any familial or sporadic cases of MEN1 related conditions lacking a MEN1 mutation. We also suggest that testing be considered for patients <30 years old with sporadic hyperparathyroidism and multigland hyperplasia. PMID:15635078

Cardinal, J; Bergman, L; Hayward, N; Sweet, A; Warner, J; Marks, L; Learoyd, D; Dwight, T; Robinson, B; Epstein, M; Smith, M; Teh, B; Cameron, D; Prins, J

2005-01-01

116

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

2013-04-01

117

Free-Radical-Induced Mutation vs Redox Regulation: Costs and Benefits of Genes in Organelles  

E-print Network

Focus Free-Radical-Induced Mutation vs Redox Regulation: Costs and Benefits of Genes in Organelles -- Cytoplasmic genomes -- Gene transfer -- Redox regulation -- Free radical mutagenesis -- Nitrogen fixation, and the precursor polypep- tides are

Allen, John F.

118

Fabry disease: six gene rearrangements and an exonic point mutation in the alpha-galactosidase gene.  

PubMed Central

Fabry disease, an X-linked recessive disorder of glycosphingolipid catabolism, results from the deficient activity of the lysosomal hydrolase, alpha-galactosidase. Southern hybridization analysis of the alpha-galactosidase gene in affected hemizygous males from 130 unrelated families with Fabry disease revealed six with different gene rearrangements and one with an exonic point mutation resulting in the obliteration of an Msp I restriction site. Five partial gene deletions were detected ranging in size from 0.4 to greater than 5.5 kb. Four of these deletions had breakpoints in intron 2, a region in the gene containing multiple Alu repeat sequences. A sixth genomic rearrangement was identified in which a region of about 8 kb, containing exons 2 through 6, was duplicated by a homologous, but unequal crossover event. The Msp I site obliteration, which mapped to exon 7, was detected in an affected hemizygote who had residual enzyme activity. Genomic amplification by the polymerase chain reaction and sequencing revealed that the obliteration resulted from a C to T transition at nucleotide 1066 in the coding sequence. This point mutation, the first identified in Fabry disease, resulted in an arginine356 to tryptophan356 substitution which altered the enzyme's kinetic and stability properties. The detection of these abnormalities provided for the precise identification of Fabry heterozygotes, thereby permitting molecular pedigree analysis in these families which revealed paternity exclusions and the first documented new mutations in this disease. Images PMID:2539398

Bernstein, H S; Bishop, D F; Astrin, K H; Kornreich, R; Eng, C M; Sakuraba, H; Desnick, R J

1989-01-01

119

A polymorphism but no mutations in the GADD45 gene in breast cancers  

Microsoft Academic Search

The p53 gene product is part of a pathway regulating growth arrest at the G1 checkpoint of the cell cycle. Mutation of other components of this pathway, including the products of the ataxia telangiectasia (AT), GADD45, mdm2, and p21WAF1\\/CIP1 genes may have effects comparable to mutations in the p53 gene. The GADD45 gene is induced by ionizing radiation and several

H. Blaszyk; A. Hartmann; S. S. Sommer; J. S. Kovach

1996-01-01

120

Mutation update for GNE gene variants associated with GNE myopathy.  

PubMed

The GNE gene encodes the rate-limiting, bifunctional enzyme of sialic acid biosynthesis, uridine diphosphate-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE). Biallelic GNE mutations underlie GNE myopathy, an adult-onset progressive myopathy. GNE myopathy-associated GNE mutations are predominantly missense, resulting in reduced, but not absent, GNE enzyme activities. The exact pathomechanism of GNE myopathy remains unknown, but likely involves aberrant (muscle) sialylation. Here, we summarize 154 reported and novel GNE variants associated with GNE myopathy, including 122 missense, 11 nonsense, 14 insertion/deletions, and seven intronic variants. All variants were deposited in the online GNE variation database (http://www.dmd.nl/nmdb2/home.php?select_db=GNE). We report the predicted effects on protein function of all variants well as the predicted effects on epimerase and/or kinase enzymatic activities of selected variants. By analyzing exome sequence databases, we identified three frequently occurring, unreported GNE missense variants/polymorphisms, important for future sequence interpretations. Based on allele frequencies, we estimate the world-wide prevalence of GNE myopathy to be ?4-21/1,000,000. This previously unrecognized high prevalence confirms suspicions that many patients may escape diagnosis. Awareness among physicians for GNE myopathy is essential for the identification of new patients, which is required for better understanding of the disorder's pathomechanism and for the success of ongoing treatment trials. PMID:24796702

Celeste, Frank V; Vilboux, Thierry; Ciccone, Carla; de Dios, John Karl; Malicdan, May Christine V; Leoyklang, Petcharat; McKew, John C; Gahl, William A; Carrillo-Carrasco, Nuria; Huizing, Marjan

2014-08-01

121

Five novel mutations in the L1CAM gene in families with X linked hydrocephalus  

Microsoft Academic Search

Five novel mutations have been identified in the gene encoding L1CAM, a neural cell adhesion protein, in families with X linked hydrocephalus (XHC). Interestingly, all five mutations are in the evolutionarily highly conserved Ig-like domains of the protein. The two frameshift mutations (52insC and 955delG) and the nonsense mutation (Trp276Ter) most probably result in functional null alleles and complete absence

S M Gu; U Orth; A Veske; H Enders; K Klunder; M Schlosser; W Engel; E Schwinger; A Gal

1996-01-01

122

Identification of p53 Gene Mutations in Bladder Cancers and Urine Samples  

Microsoft Academic Search

Although bladder cancers are very common, little is known about their molecular pathogenesis. In this study, invasive bladder cancers were evaluated for the presence of gene mutations in the p53 suppressor gene. Of 18 tumors evaluated, 11 (61 percent) were found to have genetic alterations of p53. The alterations included ten point mutations resulting in single amino acid substitutions, and

David Sidransky; Andrew von Eschenbach; Yvonne C. Tsai; Peter Jones; Ian Summerhayes; Fray Marshall; Meera Paul; Pearl Green; Philip Frost; Bert Vogelstein

1991-01-01

123

[The MDR3 gene mutation: a rare cause of progressive familial intrahepatic cholestasis (PFIC)].  

PubMed

A 47-year old man complained about persistant pain and cholestasis 12-years after a cholescystectomy. In his family, all his brothers and sisters had cholecystectomy. Genetic explorations revealed a MDR3 gene mutation. All symptoms disappeared with a treatment by ursodesoxycholic acid. MDR3 gene mutation is to be researched in all cases of familial cholestasis. PMID:16199000

Maisonnette, F; Abita, T; Barriere, E; Pichon, N; Vincensini, J F; Descottes, B

2005-10-01

124

Functional characterization of novel mutations in the human cytochrome b gene  

Microsoft Academic Search

The great variability of the human mitochondrial DNA (mtDNA) sequence induces many difficulties in the search for its deleterious mutations. We illustrate these pitfalls by the analysis of the cytochrome b gene of 21 patients affected with a mitochondrial disease. Eighteen different sequence variations were found, five of which were new mutations. Extensive analysis of the cytochrome b gene of

Frédéric Legros; Evi Chatzoglou; Paule Frachon; Hélčne Ogier de Baulny; Pascal Laforęt; Claude Jardel; Catherine Godinot; Anne Lombčs

2001-01-01

125

Frequent Somatic Mutations of the APC Gene in Human Pancreatic Cancer 1  

Microsoft Academic Search

The APC (adenomatous polyposis coli) gene is responsible for famil- ial adenomatous polyposis and is also associated with the development of sporadic tumors of the colon and stomach. To investigate whether or not mutations of APC play any role in tumors arising in other organs, we examined somatic mutations of this gene in sporadic (nonfamilial) renal cell carcinomas, hepatocellular carcinomas,

Akira Horii; Shuichi Nakatsuru; Yasuo Miyoshi; Hiroki Nagase; Hiroshi Ando; Akio Yanagisawa; Eiju Tsuchiya; Yo Kato; Yusuke Nakamura

126

Mutation analysis of the NSD1 gene in patients with autism spectrum disorders and macrocephaly  

E-print Network

Mutation analysis of the NSD1 gene in patients with autism spectrum disorders and macrocephaly is an overgrowth syndrome characterized by macrocephaly, advanced bone age, characteristic facial features, and learning disabilities, caused by mutations or deletions of the NSD1 gene, located at 5q35. Sotos syndrome

127

A Fixed Point Analysis of a Gene Pool GA with Mutation Alden H. Wright  

E-print Network

A Fixed Point Analysis of a Gene Pool GA with Mutation Alden H. Wright Computer Science University This paper analyzes a recombina- tion/mutation/selection genetic algorithm that uses gene pool recombination grant GR/R47394. repeated applications of crossover is a population in link- age equilibrium (also known

Wright, Alden H.

128

A Fixed Point Analysis of a Gene Pool GA with Mutation Alden H. Wright #  

E-print Network

A Fixed Point Analysis of a Gene Pool GA with Mutation Alden H. Wright # Computer Science This paper analyzes a recombina­ tion/mutation/selection genetic algorithm that uses gene pool recombination by EPSRC grant GR/R47394. repeated applications of crossover is a population in link­ age equilibrium (also

Wright, Alden H.

129

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

130

Leber congenital amaurosis due to RPE65 mutations and its treatment with gene therapy  

Microsoft Academic Search

Leber congenital amaurosis (LCA) is a rare hereditary retinal degeneration caused by mutations in more than a dozen genes. RPE65, one of these mutated genes, is highly expressed in the retinal pigment epithelium where it encodes the retinoid isomerase enzyme essential for the production of chromophore which forms the visual pigment in rod and cone photoreceptors of the retina. Congenital

Artur V. Cideciyan

2010-01-01

131

Novel mutations in TLR genes cause hyporesponsiveness to Mycobacterium avium subsp. paratuberculosis infection  

Microsoft Academic Search

BACKGROUND: Toll like receptors (TLR) play the central role in the recognition of pathogen associated molecular patterns (PAMPs). Mutations in the TLR1, TLR2 and TLR4 genes may change the ability to recognize PAMPs and cause altered responsiveness to the bacterial pathogens. RESULTS: The study presents association between TLR gene mutations and increased susceptibility to Mycobacterium avium subsp. paratuberculosis (MAP) infection.

Mangesh R Bhide; Rastislav Mucha; Ivan Mikula Jr; Lucia Kisova; Rostislav Skrabana; Michal Novak

2009-01-01

132

Identification of mutation sites on Delta12 desaturase genes from Mortierella alpina 1S-4 mutants.  

PubMed

The mutation sites on the Delta12 desaturase gene in Mortierella alpina Delta12 desaturase-defective mutants SR88, TM912, and Mut48 accumulating Mead acid were identified. Each mutation resulted in an amino acid replacement (H116Y and P166L) in the Delta12 desaturase gene from SR88 and Mut48, respectively. PMID:19217543

Sakuradani, Eiji; Abe, Takahiro; Matsumura, Kenji; Tomi, Akiko; Shimizu, Sakayu

2009-02-01

133

Identification of mutation sites on ?12 desaturase genes from Mortierella alpina 1S-4 mutants  

Microsoft Academic Search

The mutation sites on the ?12 desaturase gene in Mortierella alpina ?12 desaturase-defective mutants SR88, TM912, and Mut48 accumulating Mead acid were identified. Each mutation resulted in an amino acid replacement (H116Y and P166L) in the ?12 desaturase gene from SR88 and Mut48, respectively.

Eiji Sakuradani; Takahiro Abe; Kenji Matsumura; Akiko Tomi; Sakayu Shimizu

2009-01-01

134

Germline Mutations in Genes Within the MAPK Pathway Cause Cardio-facio-cutaneous Syndrome  

Microsoft Academic Search

Cardio-facio-cutaneous (CFC) syndrome is a sporadic developmental disorder involving characteristic craniofacial features, cardiac defects, ectodermal abnormalities, and developmental delay. We demonstrate that heterogeneous de novo missense mutations in three genes within the mitogen-activated protein kinase (MAPK) pathway cause CFC syndrome. The majority of cases (18 out of 23) are caused by mutations in BRAF, a gene frequently mutated in cancer.

Pablo Rodriguez-Viciana; Osamu Tetsu; William E. Tidyman; Anne L. Estep; Brenda A. Conger; Molly Santa Cruz; Frank McCormick; Katherine A. Rauen

2006-01-01

135

Unusual deep intronic mutations in the COL4A5 gene cause X linked Alport syndrome  

Microsoft Academic Search

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

Kathy King; Frances A. Flinter; Vandana Nihalani; Peter M. Green

2002-01-01

136

Identification of mutation sites on delta5 desaturase genes from Mortierella alpina 1S-4 mutants.  

PubMed

The mutation sites on delta5 desaturase genes in delta5 desaturase-defective mutants derived from arachidonic acid-producing Mortierella alpina 1S-4 were identified. The mutations resulted in an amino acid replacement (G189E or W301Stop) and uncorrected transcription caused by recognition of an AG-terminal newly created on C207A gene mutation, resulting in low or no delta5 desaturase activity in these mutants. PMID:16233793

Abe, Takahiro; Sakuradani, Eiji; Ueda, Takuji; Shimizu, Sakayu

2005-03-01

137

Recurrent and founder mutations in the PMS2 gene  

PubMed Central

Germline mutations in PMS2 are associated with Lynch syndrome (LS), the most common known cause of hereditary colorectal cancer. Mutation detection in PMS2 has been difficult due to the presence of several pseudogenes, but a custom-designed long-range PCR strategy now allows adequate mutation detection. Many mutations are unique. However some mutations are observed repeatedly, across individuals not known to be related, due to the mutation being either recurrent, arising multiple times de novo at hot spots for mutations, or of founder origin, having occurred once in an ancestor. Previously, we observed 36 distinct mutations in a sample of 61 independently ascertained Caucasian probands of mixed European background with PMS2 mutations. Eleven of these mutations were detected in more than one individual not known to be related and of these, six were detected more than twice. These six mutations accounted for 31 (51%) ostensibly unrelated probands. Here we performed genotyping and haplotype analysis in four mutations observed in multiple probands and found two (c.137G>T and exon 10 deletion) to be founder mutations, one (c.903G>T) a probable founder, and one (c.1A>G) where founder mutation status could not be evaluated. We discuss possible explanations for the frequent occurrence of founder mutations in PMS2. PMID:22577899

Tomsic, Jerneja; Senter, Leigha; Liyanarachchi, Sandya; Clendenning, Mark; Vaughn, Cecily P.; Jenkins, Mark A.; Hopper, John L.; Young, Joanne; Samowitz, Wade; de la Chapelle, Albert

2012-01-01

138

Recurrent and founder mutations in the PMS2 gene.  

PubMed

Germline mutations in PMS2 are associated with Lynch syndrome (LS), the most common known cause of hereditary colorectal cancer. Mutation detection in PMS2 has been difficult due to the presence of several pseudogenes, but a custom-designed long-range PCR strategy now allows adequate mutation detection. Many mutations are unique. However, some mutations are observed repeatedly across individuals not known to be related due to the mutation being either recurrent, arising multiple times de novo at hot spots for mutations, or of founder origin, having occurred once in an ancestor. Previously, we observed 36 distinct mutations in a sample of 61 independently ascertained Caucasian probands of mixed European background with PMS2 mutations. Eleven of these mutations were detected in more than one individual not known to be related and of these, six were detected more than twice. These six mutations accounted for 31 (51%) ostensibly unrelated probands. Here, we performed genotyping and haplotype analysis in four mutations observed in multiple probands and found two (c.137G>T and exon 10 deletion) to be founder mutations and one (c.903G>T) a probable founder. One (c.1A>G) could not be evaluated for founder mutation status. We discuss possible explanations for the frequent occurrence of founder mutations in PMS2. PMID:22577899

Tomsic, J; Senter, L; Liyanarachchi, S; Clendenning, M; Vaughn, C P; Jenkins, M A; Hopper, J L; Young, J; Samowitz, W; de la Chapelle, A

2013-03-01

139

Gene mutation patterns in patients with minimally differentiated acute myeloid leukemia.  

PubMed

Minimally differentiated acute myeloid leukemia (AML-M0) is a rare subtype of AML with poor prognosis. Although genetic alterations are increasingly reported in AML, the gene mutations have not been comprehensively studied in AML-M0. We aimed to examine a wide spectrum of gene mutations in patients with AML-M0 to determine their clinical relevance. Twenty gene mutations including class I, class II, class III of epigenetic regulators (IDH1, IDH2, TET2, DNMT3A, MLL-PTD, ASXL1, and EZH2), and class IV (tumor suppressor genes) were analyzed in 67 patients with AML-M0. Mutational analysis was performed with polymerase chain reaction-based assays followed by direct sequencing. The most frequent gene mutations from our data were FLT3-ITD/FLT3-TKD (28.4%), followed by mutations in IDH1/IDH2 (28.8%), RUNX1 (23.9%), N-RAS/K-RAS (12.3%), TET2 (8.2%), DNMT3A (8.1%), MLL-PTD (7.8%), and ASXL1 (6.3%). Seventy-nine percent (53/67) of patients had at least one gene mutation. Class I genes (49.3%) were the most common mutated genes, which were mutually exclusive. Class III genes of epigenetic regulators were also frequent (43.9%). In multivariate analysis, old age [hazard ratio (HR) 1.029, 95% confidence interval (CI) 1.013-1.044, P=.001) was the independent adverse factor for overall survival, and RUNX1 mutation (HR 2.326, 95% CI 0.978-5.533, P=.056) had a trend toward inferior survival. In conclusion, our study showed a high frequency of FLT3, RUNX1, and IDH mutations in AML-M0, suggesting that these mutations played a role in the pathogenesis and served as potential therapeutic targets in this rare and unfavorable subtype of AML. PMID:25022553

Kao, Hsiao-Wen; Liang, Der-Cherng; Wu, Jin-Hou; Kuo, Ming-Chung; Wang, Po-Nan; Yang, Chao-Ping; Shih, Yu-Shu; Lin, Tung-Huei; Huang, Yu-Hui; Shih, Lee-Yung

2014-06-01

140

Gene Mutation Patterns in Patients with Minimally Differentiated Acute Myeloid Leukemia?  

PubMed Central

Minimally differentiated acute myeloid leukemia (AML-M0) is a rare subtype of AML with poor prognosis. Although genetic alterations are increasingly reported in AML, the gene mutations have not been comprehensively studied in AML-M0. We aimed to examine a wide spectrum of gene mutations in patients with AML-M0 to determine their clinical relevance. Twenty gene mutations including class I, class II, class III of epigenetic regulators (IDH1, IDH2, TET2, DNMT3A, MLL-PTD, ASXL1, and EZH2), and class IV (tumor suppressor genes) were analyzed in 67 patients with AML-M0. Mutational analysis was performed with polymerase chain reaction–based assays followed by direct sequencing. The most frequent gene mutations from our data were FLT3-ITD/FLT3-TKD (28.4%), followed by mutations in IDH1/IDH2 (28.8%), RUNX1 (23.9%), N-RAS/K-RAS (12.3%), TET2 (8.2%), DNMT3A (8.1%), MLL-PTD (7.8%), and ASXL1 (6.3%). Seventy-nine percent (53/67) of patients had at least one gene mutation. Class I genes (49.3%) were the most common mutated genes, which were mutually exclusive. Class III genes of epigenetic regulators were also frequent (43.9%). In multivariate analysis, old age [hazard ratio (HR) 1.029, 95% confidence interval (CI) 1.013-1.044, P = .001) was the independent adverse factor for overall survival, and RUNX1 mutation (HR 2.326, 95% CI 0.978-5.533, P = .056) had a trend toward inferior survival. In conclusion, our study showed a high frequency of FLT3, RUNX1, and IDH mutations in AML-M0, suggesting that these mutations played a role in the pathogenesis and served as potential therapeutic targets in this rare and unfavorable subtype of AML. PMID:25022553

Kao, Hsiao-Wen; Liang, Der-Cherng; Wu, Jin-Hou; Kuo, Ming-Chung; Wang, Po-Nan; Yang, Chao-Ping; Shih, Yu-Shu; Lin, Tung-Huei; Huang, Yu-Hui; Shih, Lee-Yung

2014-01-01

141

Novel germline APC gene mutation in a large familial adenomatous polyposis kindred displaying variable phenotypes.  

PubMed Central

The APC gene is mutated in the germline of people from families where there is a predisposition to develop polyposis coli. Many mutations have been described but the relation between their site and the phenotypic expression of the disease remains unclear. The most commonly seen mutation occurs at codon 1309. Many other mutations have been described towards the 5' end of exon 15 of the APC gene but comparatively few have been seen towards the 3' end. Recent reports have indicated the possibility of a functional boundary with respect to severity and age of onset of disease, which lies towards the 5' end of the gene. This report describes a large family whose affected members present with a very variable phenotype ranging from an early onset and severe form to a comparatively mild later onset one. The mutation that predisposes to disease in this family is at a previously undescribed site that lies towards the 3' end of exon 15 of the APC gene, which results in a stop codon. Interestingly, the stop codon is 63 codons downstream of the mutation and therefore may affect the expression of the disease. The addition of this mutation to the growing list of mutations described in the APC gene may provide some insight into the genotype/phenotype relation of the disease thus contributing to the understanding and significance of mutations at specific sites in the APC gene. Images Figure 2 PMID:7797123

Scott, R J; van der Luijt, R; Spycher, M; Mary, J L; Müller, A; Hoppeler, T; Haner, M; Müller, H; Martinoli, S; Brazzola, P L

1995-01-01

142

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. PMID:22004887

2011-01-01

143

A P-element insertion screen identified mutations in 455 novel essential genes in Drosophila.  

PubMed Central

With the completion of the nucleotide sequences of several complex eukaryotic genomes, tens of thousands of genes have been predicted. However, this information has to be correlated with the functions of those genes to enhance our understanding of biology and to improve human health care. The Drosophila transposon P-element-induced mutations are very useful for directly connecting gene products to their biological function. We designed an efficient transposon P-element-mediated gene disruption procedure and performed genetic screening for single P-element insertion mutations, enabling us to recover 2500 lethal mutations. Among these, 2355 are second chromosome mutations. Sequences flanking >2300 insertions that identify 850 different genes or ESTs (783 genes on the second chromosome and 67 genes on the third chromosome) have been determined. Among these, 455 correspond to genes for which no lethal mutation has yet been reported. The Drosophila genome is thought to contain approximately 3600 vital genes; 1400 are localized on the second chromosome. Our mutation collection represents approximately 56% of the second chromosome vital genes and approximately 24% of the total vital Drosophila genes. PMID:12586707

Oh, Su-Wan; Kingsley, Tracy; Shin, Hyun-hee; Zheng, Zhiyu; Chen, Hua-Wei; Chen, Xiu; Wang, Hong; Ruan, Peizheng; Moody, Michelle; Hou, Steven X

2003-01-01

144

Genes governing swarming in Bacillus subtilis and evidence for a phase variation mechanism controlling surface motility.  

PubMed

Undomesticated strains of Bacillus subtilis, but not laboratory strains, exhibit robust swarming motility on solid surfaces. The failure of laboratory strains to swarm is caused by a mutation in a gene (sfp) needed for surfactin synthesis and a mutation(s) in an additional unknown gene(s). Insertional mutagenesis of the undomesticated 3610 strain with the transposon mini-Tn10 was carried out to discover genes needed for swarming but not swimming motility. Four such newly identified swarming genes are reported, three of which (swrA, swrB, and efp) had not been previously characterized and one of which (swrC) was known to play a role in resistance to the antibacterial effect of surfactin. Laboratory strains were found to harbour a frameshift mutation in the swrA gene. When corrected for the swrA mutation, as well as the mutation in sfp, laboratory strains regained the capacity to swarm and did so as robustly as the wild strain. The swrA mutation was an insertion of an A:T base pair in a homopolymeric stretch of eight A:T base pairs, and readily reverted to the wild type. These findings suggest that the swrA insertion and its reversion take place by slipped-strand mispairing during DNA replication and that swarming motility is subject to phase variation. PMID:15066026

Kearns, Daniel B; Chu, Frances; Rudner, Rivka; Losick, Richard

2004-04-01

145

Molecular Analysis of Bardet-Biedl Syndrome Families: Report of 21 Novel Mutations in 10 Genes  

PubMed Central

Purpose. Bardet-Biedl syndrome (BBS) is genetically heterogeneous with 15 BBS genes currently identified, accounting for approximately 70% of cases. The aim of our study was to define further the spectrum of BBS mutations in a cohort of 44 European-derived American, 8 Tunisian, 1 Arabic, and 2 Pakistani families (55 families in total) with BBS. Methods. A total of 142 exons of the first 12 BBS-causing genes were screened by dideoxy sequencing. Cases in which no mutations were found were then screened for BBS13, BBS14, BBS15, RPGRIP1L, CC2D2A, NPHP3, TMEM67, and INPP5E. Results. Forty-three mutations, including 8 frameshift mutations, 10 nonsense mutations, 4 splice site mutations, 1 deletion, and 20 potentially or probably pathogenic missense variations, were identified in 46 of the 55 families studied (84%). Of these, 21 (2 frameshift mutations, 4 nonsense mutations, 4 splice site mutations, 1 deletion, and 10 missense variations) were novel. The molecular genetic findings raised the possibility of triallelic inheritance in 7 Caucasian families, 1 Arabian family, and 1 Tunisian patient. No mutations were detected for BBS4, BBS11, BBS13, BBS14, BBS15, RPGRIP1L, CC2D2A, NPHP3, TMEM67, or INPP5E. Conclusions. This mutational analysis extends the spectrum of known BBS mutations. Identification of 21 novel mutations highlights the genetic heterogeneity of this disorder. Differences in European and Tunisian patients, including the high frequency of the M390R mutation in Europeans, emphasize the population specificity of BBS mutations with potential diagnostic implications. The existence of some BBS cases without mutations in any currently identified BBS genes suggests further genetic heterogeneity. PMID:21642631

Chen, Jianjun; Smaoui, Nizar; Hammer, Monia Ben Hamed; Jiao, Xiaodong; Riazuddin, S. Amer; Harper, Shyana; Katsanis, Nicholas; Riazuddin, Sheikh; Chaabouni, Habiba; Berson, Eliot L.

2011-01-01

146

Relation of Gene Expression Phenotype to Immunoglobulin Mutation Genotype in B Cell Chronic Lymphocytic Leukemia  

PubMed Central

The most common human leukemia is B cell chronic lymphocytic leukemia (CLL), a malignancy of mature B cells with a characteristic clinical presentation but a variable clinical course. The rearranged immunoglobulin (Ig) genes of CLL cells may be either germ-line in sequence or somatically mutated. Lack of Ig mutations defined a distinctly worse prognostic group of CLL patients raising the possibility that CLL comprises two distinct diseases. Using genomic-scale gene expression profiling, we show that CLL is characterized by a common gene expression “signature,” irrespective of Ig mutational status, suggesting that CLL cases share a common mechanism of transformation and/or cell of origin. Nonetheless, the expression of hundreds of other genes correlated with the Ig mutational status, including many genes that are modulated in expression during mitogenic B cell receptor signaling. These genes were used to build a CLL subtype predictor that may help in the clinical classification of patients with this disease. PMID:11733578

Rosenwald, Andreas; Alizadeh, Ash A.; Widhopf, George; Simon, Richard; Davis, R. Eric; Yu, Xin; Yang, Liming; Pickeral, Oxana K.; Rassenti, Laura Z.; Powell, John; Botstein, David; Byrd, John C.; Grever, Michael R.; Cheson, Bruce D.; Chiorazzi, Nicholas; Wilson, Wyndham H.; Kipps, Thomas J.; Brown, Patrick O.; Staudt, Louis M.

2001-01-01

147

Terminal Osseous Dysplasia Is Caused by a Single Recurrent Mutation in the FLNA Gene  

PubMed Central

Terminal osseous dysplasia (TOD) is an X-linked dominant male-lethal disease characterized by skeletal dysplasia of the limbs, pigmentary defects of the skin, and recurrent digital fibroma with onset in female infancy. After performing X-exome capture and sequencing, we identified a mutation at the last nucleotide of exon 31 of the FLNA gene as the most likely cause of the disease. The variant c.5217G>A was found in six unrelated cases (three families and three sporadic cases) and was not found in 400 control X chromosomes, pilot data from the 1000 Genomes Project, or the FLNA gene variant database. In the families, the variant segregated with the disease, and it was transmitted four times from a mildly affected mother to a more seriously affected daughter. We show that, because of nonrandom X chromosome inactivation, the mutant allele was not expressed in patient fibroblasts. RNA expression of the mutant allele was detected only in cultured fibroma cells obtained from 15-year-old surgically removed material. The variant activates a cryptic splice site, removing the last 48 nucleotides from exon 31. At the protein level, this results in a loss of 16 amino acids (p.Val1724_Thr1739del), predicted to remove a sequence at the surface of filamin repeat 15. Our data show that TOD is caused by this single recurrent mutation in the FLNA gene. PMID:20598277

Sun, Yu; Almomani, Rowida; Aten, Emmelien; Celli, Jacopo; van der Heijden, Jaap; Venselaar, Hanka; Robertson, Stephen P.; Baroncini, Anna; Franco, Brunella; Basel-Vanagaite, Lina; Horii, Emiko; Drut, Ricardo; Ariyurek, Yavuz; den Dunnen, Johan T.; Breuning, Martijn H.

2010-01-01

148

An Ashkenazi founder mutation in the MSH6 gene leading to HNPCC.  

PubMed

Mutations in DNA mismatch repair genes underlie lynch syndrome (HNPCC). Lynch syndrome resulting from mutations in MSH6 is considered to be attenuated in comparison to that caused by mutations in MLH1 and MSH2, thus more likely to be under diagnosed. In this study we report of a common mutation in the MSH6 gene in Ashkenazi Jews. Genetic counseling and diagnostic work-up for HNPCC was conducted in families who attended the high risk clinic for inherited cancer. We identified the mutation c.3984_3987dup in the MSH6 gene in 19 members of four unrelated Ashkenazi families. This mutation results in truncation of the transcript and in loss of expression of the MSH6 protein in tumors. Tumor spectrum among carriers included colon, endometrial, gastric, ovarian, urinary, and breast cancer. All but one family qualified for the Bethesda guidelines and none fulfilled the Amsterdam Criteria. Members of one family also co-inherited the c.6174delT mutation in the BRCA2 gene. The c.3984_3987dup in the MSH6 gene is a mutation leading to HNPCC among Ashkenazi Jews. This is most probably a founder mutation. In contrast to the c.1906G>C founder mutation in the MSH2 gene, tumors tend to occur later in life, and none of the families qualified for the Amsterdam criteria. c.3984_3987dup is responsible for 1/6 of the mutations identified among Ashkenazi HNPCC families in our cohort. Both mutations: c.3984_3987dup and c.1906G>C account for 61% of HNPCC Ashkenazi families in this cohort. These findings are of great importance for counseling, diagnosis, management and surveillance for Ashkenazi families with Lynch syndrome. PMID:19851887

Goldberg, Yael; Porat, Rinnat M; Kedar, Inbal; Shochat, Chen; Galinsky, Daliah; Hamburger, Tamar; Hubert, Ayala; Strul, Hana; Kariiv, Revital; Ben-Avi, Liat; Savion, Moran; Pikarsky, Eli; Abeliovich, Dvorah; Bercovich, Dani; Lerer, Israela; Peretz, Tamar

2010-06-01

149

DHPLC-based mutation analysis of ENG and ALK-1 genes in HHT Italian population.  

PubMed

Hereditary haemorrhagic telangiectasia (HHT or Rendu-Osler-Weber syndrome) is an autosomal dominant disorder characterized by localized angiodysplasia due to mutations in endoglin, ALK-1 gene, and a still unidentified locus. The lack of highly recurrent mutations, locus heterogeneity, and the presence of mutations in almost all coding exons of the two genes makes the screening for mutations time-consuming and costly. In the present study, we developed a DHPLC-based protocol for mutation detection in ALK1 and ENG genes through retrospective analysis of known sequence variants, 20 causative mutations and 11 polymorphisms, and a prospective analysis on 47 probands with unknown mutation. Overall DHPLC analysis identified the causative mutation in 61 out 66 DNA samples (92.4%). We found 31 different mutations in the ALK1 gene, of which 15 are novel, and 20, of which 12 are novel, in the ENG gene, thus providing for the first time the mutational spectrum in a cohort of Italian HHT patients. In addition, we characterized the splicing pattern of ALK1 gene in lymphoblastoid cells, both in normal controls and in two individuals carrying a mutation in the non-invariant -3 position of the acceptor splice site upstream exon 6 (c.626-3C>G). Functional essay demonstrated the existence, also in normal individuals, of a small proportion of ALK1 alternative splicing, due to exon 5 skipping, and the presence of further aberrant splicing isoforms in the individuals carrying the c.626-3C>G mutation. PMID:16429404

Lenato, Gennaro M; Lastella, Patrizia; Di Giacomo, Marilena C; Resta, Nicoletta; Suppressa, Patrizia; Pasculli, Giovanna; Sabbŕ, Carlo; Guanti, Ginevra

2006-02-01

150

Mutations in the CACNA1F and NYX genes in British CSNBX families.  

PubMed

X-linked congenital stationary night blindness (CSNBX) is a genetically and phenotypically heterogeneous non-progressive disorder, characterised by impaired night vision but grossly normal retinal appearance. Other more variable features include reduction in visual acuity, myopia, nystagmus and strabismus. Genetic mapping studies by other groups, and our own studies of British patients, identified key recombination events indicating the presence of at least 2 disease genes on Xp11. Two causative genes (CACNA1F and NYX) for CSNBX have now been identified through positional cloning strategies. In this report, we present the results of comprehensive mutation screening in 14 CSNBX families, three with mutations in the CACNA1F gene and 10 with mutations in the NYX gene. In one family we failed to identify the mutation after testing RP2, RPGR, NYX and CACNA1F. NYX gene mutations are a more frequent cause of CSNBX, although there is evidence for founder mutations. Our report of patient population mutation screening for both CSNBX genes, and our exclusion of RP2 and RGPR, indicates that mutations in CACNA1F and NYX are likely to account for all CSNBX. PMID:12552565

Zito, Ilaria; Allen, Louise E; Patel, Reshma J; Meindl, Alfons; Bradshaw, Keith; Yates, John R; Bird, Alan C; Erskine, Lynda; Cheetham, Michael E; Webster, Andrew R; Poopalasundaram, Subathra; Moore, Anthony T; Trump, Dorothy; Hardcastle, Alison J

2003-02-01

151

Two Arabidopsis methylation-deficiency mutations confer only partial effects on a methylated endogenous gene family  

Microsoft Academic Search

In Arabidopsis a SWI2\\/SNF2 chromatin remodeling factor-related protein DDM1 and a cytosine methyl- transferase MET1 are required for maintenance of genomic cytosine methylation. Mutations in either gene cause global demethylation. In this work we have assessed the effects of these mutations on the PAI tryptophan biosynthetic gene family, which consists of four densely methylated genes arranged as a tail-to-tail inverted

Lisa Bartee; Judith Bender

2001-01-01

152

A novel ANT1 gene mutation with probable germline mosaicism in autosomal dominant progressive external ophthalmoplegia.  

PubMed

Only four different mutations in the adenine nucleotide translocator 1 (ANT1) gene have been found in families with progressive external ophthalmoplegia (PEO). We report a novel heterozygous C to A transversion at nucleotide 269 in the ANT1 gene in a German family with PEO, predicted to convert a highly conserved alanine at codon 90 to aspartic acid. The mutation was identified in three siblings with PEO, one of them additionally suffered from schizoaffective disorder. Microsatellite analysis showed that the mutation was dominant and inherited from the mother who did not carry the mutation in blood, indicating germ-line mosaicism. PMID:15792871

Deschauer, Marcus; Hudson, Gavin; Müller, Tobias; Taylor, Robert W; Chinnery, Patrick F; Zierz, Stephan

2005-04-01

153

Different mutations in the COL4A5 collagen gene in two patients with different features of Alport syndrome  

Microsoft Academic Search

Different mutations in the COL4A5 collagen gene in two patients with different features of Alport syndrome. Alport syndrome is a hereditary renal disease in which progressive renal failure is often accompanied by sensorineural deafness and ocular abnormalities. Recently, mutations were detected in the type IV collagen ?5 chain gene in Alport syndrome patients. We searched for mutations in this gene

Hubert JM Smeets; Jos J Melenhorst; Henny H Lemmink; Cock H Schröder; Marcel R Nelen; Jing Zhou; Sirkka L Hostikka; Karl Tryggvason; Hans-Hilger Ropers; Maaike CE Jansweijer; Leo AH Monnens; Han G Brunner; Bernard A van Oost

1992-01-01

154

[Analysis of mutations and VNTR-polymorphism in the phenylalanine hydroxylase gene].  

PubMed

The data on 5 PAH gene mutations analysis are presented. The most common mutation observed in Ukrainian population was determined to be R408W (66.6%). As well two minor mutations R158Q (2.5%) and Y414C (1.25%) were identified. The allelic variation of the VNTR-polymorphism in 470 healthy volunteers and 39 PKU-patients were analysed. 7 allelic variants and 15 haplotypes were found. The linkage disequilibrium was displayed between mutation R408W and VNTR-haplotypes 03. An advantages of molecular genetic analysis of mutations and VNTR-polymorphism for diagnosis of PKU in Ukraine are discussed. PMID:11642047

Hechyporenko, M V; Kravchenko, S A; Livshyts, L A

2001-01-01

155

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

PubMed

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. PMID:8659548

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

1996-07-01

156

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 PMID:8659548

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

157

Ocular Surface Development and Gene Expression  

PubMed Central

The ocular surface—a continuous epithelial surface with regional specializations including the surface and glandular epithelia of the cornea, conjunctiva, and lacrimal and meibomian glands connected by the overlying tear film—plays a central role in vision. Molecular and cellular events involved in embryonic development, postnatal maturation, and maintenance of the ocular surface are precisely regulated at the level of gene expression by a well-coordinated network of transcription factors. A thorough appreciation of the biological characteristics of the ocular surface in terms of its gene expression profiles and their regulation provides us with a valuable insight into the pathophysiology of various blinding disorders that disrupt the normal development, maturation, and/or maintenance of the ocular surface. This paper summarizes the current status of our knowledge related to the ocular surface development and gene expression and the contribution of different transcription factors to this process. PMID:23533700

Swamynathan, Shivalingappa K.

2013-01-01

158

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

159

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 PMID:8940272

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

1996-01-01

160

Rare mutations in the PIK3CA gene contribute to aggressive endometrial cancer.  

PubMed

The molecular basis of endometrial cancer (EC), a common gynecologic malignancy, often includes mutational activation of the PIK3CA and KRAS genes. We aimed to determine the distribution of mutations in the two genes depending on patient clinocopathological characteristics. We sequenced exon 1 of the KRAS gene and exons 9 and 20 of the PIK3CA gene in 108 consecutive EC tumor samples. PIK3CA mutations were present in 24 of the 108 (22.2%) cases and KRAS mutations in 18 of the 108 (16.7%) cases. PIK3CA mutations occurred more frequently in KRAS-mutated samples (7/18, 38.9%; p = 0.06) than in KRAS wild type (17/90, 18.9%) and showed a very high frequency in metastatic tumors (4/9, 44.4%; p = 0.1) and in samples displaying serous differentiation-serous and mixed endometrioid/serous tumors (6/12, 50.0%; p = 0.021)-where KRAS mutations were rare (11.1% and 16.7%, respectively) and did not exist independently of a PIK3CA mutation. Non-hotspot (i.e., non-E542K, -E545K, and -H1047R) mutations in the PIK3CA gene showed higher frequency in metastatic cases (3/9, 33.3%; p = 0.05). Tumors displaying serous differentiation showed a particular pattern-they harbored exclusively mutations in PIK3CA exon 20 (5/12, 41.7%; p = 0.005) and most of these were non-hotspot (4/12, 33.3%; p = 0.02). In all other comparisons exons 9 and 20 mutation distribution did not differ. These results suggest the need for further exploration of the significance of PIK3CA mutations in respect to aggressive EC. PMID:19839777

Konstantinova, Darina; Kaneva, Radka; Dimitrov, Roumen; Savov, Alexey; Ivanov, Stephan; Dyankova, Tzvetanka; Kremensky, Ivo; Mitev, Vanio

2010-02-01

161

Congenital nephrogenic diabetes insipidus with a novel mutation in the aquaporin 2 gene  

PubMed Central

Congenital nephrogenic diabetes insipidus (CNDI) is a rare disorder caused by mutations of the arginine vasopressin (AVP) V2 receptor or aquaporin 2 (AQP2) genes. The current study presented the case of CNDI in a 1-month-old male with a novel mutation in the AQP2 gene. The patient was referred due to the occurrence of hypernatremia and mild-intermittent fever since birth. An AVP stimulation test was compatible with CNDI as there was no significant response to desmopressin. Molecular genetic analysis demonstrated two mutations in exon 1 of the AQP2 gene: C to T transition, which resulted in a missense mutation of 108Thr (ACG) to Met (ATG); and a 127, 128 delCA, which resulted in a deletion mutation of glutamine in position 43 at codon CAG as the first affected amino acid, with the new reading frame endign in a termination codon at position 62. The molecular genetic analysis of the parents showed that the missense mutation was inherited maternally and the deletion mutation was inherited paternally. The parents showed no signs or symptoms of CNDI, indicating autosomal recessive inheritance. The 108Thr (ACG) to Met (ATG) mutation was confirmed as a novel mutation. Therefore, the molecular identification of the AQP2 gene has clinical significance, as early recognition of CNDI in infants that show only non-specific symptoms, can be facilitated. Thus, repeated episodes of dehydration, which may cause physical and mental retardation can be avoided. PMID:24944815

PARK, YOUN JONG; BAIK, HAING WOON; CHEONG, HAE IL; KANG, JU HYUNG

2014-01-01

162

Expression of Von Hippel – Lindau (VHL) gene mutation in diagnosed cases of renal cell carcinoma  

PubMed Central

Objective: To evaluate the expression of Von Hippel Lindau (VHL) gene in diagnosed cases of renal cell carcinoma. Methods: This cross sectional study was conducted in department of Pathology, Basic Medical Sciences Institute, JPMC, Karachi, from January 2007 to December 2012. Paraffin embedded blocks of 30 cases of radical nephrectomy specimens diagnosed as renal cell carcinoma including CCRCC 21 (70%) CCPRCC, 3 (10%), PRCC 2 (6.79%), hybrid tumor 4 (13.3%), chromophobe tumor (0%) processed for VHL gene expression on Polymerase Chain Reaction. Results: All the 30 cases previously diagnosed as renal cell carcinoma were processed on PCR, VHL gene mutations were seen in 20 (95.23%) of CCRCC while a single case was negative for VHL mutations. All CCPRCC were negative for VHL mutation. Among the hybrid tumor 03 cases with foci of clear cells show VHL mutation while a single case showing combination of clear cells and chromophobe cells was negative for mutation. Both the cases of PRCC were positive for mutation. Exon 3 mutation at base pair 194 seen in 8 (32%) cases and Exon 2 mutation at base pair 150-159 seen in 17 (68%) cases. None of the cases showed Exon 1 mutation. Conclusion: The present study shows that majority of CCRCC showed VHL mutation including the hybrid tumor with clear cell component in our population. PMID:25097537

Shahzad, Humera; Kehar, Shahnaz Imdad; Ali, Shahzad; Tariq, Naila

2014-01-01

163

TET2 gene mutation is unfavorable prognostic factor in cytogenetically normal acute myeloid leukemia patients with NPM1+ and FLT3-ITD - mutations.  

PubMed

Cytogenetically normal acute myeloid leukemia (cn-AML) is a group of heterogeneous diseases. Gene mutations are increasingly used to assess the prognosis of cn-AML patients and guide risk-adapted treatment. In the present study, we analyzed the molecular genetics characteristics of 373 adult cn-AML patients and explored the relationship between TET2 gene mutations or different genetic mutation patterns and prognosis. We found that 16.1 % of patients had TET2 mutations, 31.6 % had FLT3 internal tandem duplications (ITDs), 6.2 % had FLT3 tyrosine kinase domain mutations, 2.4 % had c-KIT mutations, 37.8 % had NPM1 mutations, 11.3 % had WT1 mutations, 5.9 % had RUNX1 mutations, 11.5 % had ASXL1 mutations, 3.8 % had MLL-PTDs, 7.8 % had IDH1 mutations, 7.8 % had NRAS mutations, 12.3 % had IDH2 mutations, 1.6 % had EZH2 mutations, and 14.7 % had DNMT3A mutations, while none had CBL mutations. Gene mutations were detected in 76.94 % (287/373) of all patients. In the NPM1m(+) patients, those with TET2 mutations were associated with a shorter median overall survival (OS) as compared to TET2 wild-type (wt) patients (9.9 vs. 27.0 months, respectively; P = 0.023); Interestingly, the TET2 mutation was identified as an unfavorable prognostic factor and was closely associated with a shorter median OS as compared to TET2-wt (9.5 vs. 32.2 months, respectively; P = 0.013) in the NPM1m(+)/FLT3-ITDm(-) patient group. Thus, identification of TET2 combined with classic NPM1 and FLT3-ITD mutations allowed us to stratify cn-AML into distinct subtypes. PMID:24859829

Tian, Xiaopeng; Xu, Yang; Yin, Jia; Tian, Hong; Chen, Suning; Wu, Depei; Sun, Aining

2014-07-01

164

Determining the frequency of de novo germline mutations in DNA mismatch repair genes  

PubMed Central

Background Carriers of a germline mutation in a DNA mismatch repair (MMR) gene—that is, persons with Lynch syndrome—have substantially high risks of colorectal (CRC), endometrial, and several other cancers. The proportion of carriers who have de novo mutations (not inherited from either parent) is not known. This study reports a case series of de novo mutations in MMR genes and estimates the frequency of de novo mutation in MMR genes using the Colon Cancer Family Registry. Methods Screening for germline MLH1, MSH2, MSH6, and PMS2 mutations was performed for all incident CRC cases recruited from cancer registries (population based probands) displaying microsatellite instability (MSI) or loss of expression of MMR genes by immunohistochemistry (IHC) and probands with CRC in multi-case families recruited from clinics (clinic based probands), regardless of MSI or IHC status. All relatives of probands with a pathogenic mutation who donated a blood sample underwent testing for the mutation identified in the proband. Results Of 261 probands (202 clinic based, 59 population based) with MMR gene mutations for whom it was possible to determine the origin of the mutation, six (2.3%, 95% CI 0.9% to 5.0%) were confirmed as de novo, and the remaining 255 (97.7%, 95% CI 95.0% to 99.1%) were inherited. Of the de novo mutation carriers, three were clinic based probands (1.5%, 95% CI 0.3% to 4.5%) and three were population based probands (5.1%, 95% CI 1.2% to 14.5%). Two were in MLH1, three in MSH2, and one in MSH6. Conclusion De novo MMR gene mutations are uncommon causes of Lynch syndrome. PMID:21636617

Win, Aung Ko; Jenkins, Mark A; Buchanan, Daniel D; Clendenning, Mark; Young, Joanne P; Giles, Graham G; Goldblatt, Jack; Leggett, Barbara A; Hopper, John L; Thibodeau, Stephen N; Lindor, Noralane M

2012-01-01

165

Mutation analysis of the cathepsin C gene in Indian families with Papillon-Lef?vre syndrome  

PubMed Central

Background PLS is a rare autosomal recessive disorder characterized by early onset periodontopathia and palmar plantar keratosis. PLS is caused by mutations in the cathepsin C (CTSC) gene. Dipeptidyl-peptidase I encoded by the CTSC gene removes dipeptides from the amino-terminus of protein substrates and mainly plays an immune and inflammatory role. Several mutations have been reported in this gene in patients from several ethnic groups. We report here mutation analysis of the CTSC gene in three Indian families with PLS. Methods Peripheral blood samples were obtained from individuals belonging to three Indian families with PLS for genomic DNA isolation. Exon-specific intronic primers were used to amplify DNA samples from individuals. PCR products were subsequently sequenced to detect mutations. PCR-SCCP and ASOH analyses were used to determine if mutations were present in normal control individuals. Results All patients from three families had a classic PLS phenotype, which included palmoplantar keratosis and early-onset severe periodontitis. Sequence analysis of the CTSC gene showed three novel nonsense mutations (viz., p.Q49X, p.Q69X and p.Y304X) in homozygous state in affected individuals from these Indian families. Conclusions This study reported three novel nonsense mutations in three Indian families. These novel nonsense mutations are predicted to produce truncated dipeptidyl-peptidase I causing PLS phenotype in these families. A review of the literature along with three novel mutations reported here showed that the total number of mutations in the CTSC gene described to date is 41 with 17 mutations being located in exon 7. PMID:12857359

Selvaraju, Veeriah; Markandaya, Manjunath; Prasad, Pullabatla Venkata Siva; Sathyan, Parthasarathy; Sethuraman, Gomathy; Srivastava, Satish Chandra; Thakker, Nalin; Kumar, Arun

2003-01-01

166

Effect of KCNJ5 Mutations on Gene Expression in Aldosterone-Producing Adenomas and Adrenocortical Cells  

PubMed Central

Context: Primary aldosteronism is a heterogeneous disease that includes both sporadic and familial forms. A point mutation in the KCNJ5 gene is responsible for familial hyperaldosteronism type III. Somatic mutations in KCNJ5 also occur in sporadic aldosterone producing adenomas (APA). Objective: The objective of the study was to define the effect of the KCNJ5 mutations on gene expression and aldosterone production using APA tissue and human adrenocortical cells. Methods: A microarray analysis was used to compare the transcriptome profiles of female-derived APA samples with and without KCNJ5 mutations and HAC15 adrenal cells overexpressing either mutated or wild-type KCNJ5. Real-time PCR validated a set of differentially expressed genes. Immunohistochemical staining localized the KCNJ5 expression in normal adrenals and APA. Results: We report a 38% (18 of 47) prevalence of KCNJ5 mutations in APA. KCNJ5 immunostaining was highest in the zona glomerulosa of NA and heterogeneous in APA tissue, and KCNJ5 mRNA was 4-fold higher in APA compared with normal adrenals (P < 0.05). APA with and without KCNJ5 mutations displayed slightly different gene expression patterns, notably the aldosterone synthase gene (CYP11B2) was more highly expressed in APA with KCNJ5 mutations. Overexpression of KCNJ5 mutations in HAC15 increased aldosterone production and altered expression of 36 genes by greater than 2.5-fold (P < 0.05). Real-time PCR confirmed increases in CYP11B2 and its transcriptional regulator, NR4A2. Conclusions: KCNJ5 mutations are prevalent in APA, and our data suggest that these mutations increase expression of CYP11B2 and NR4A2, thus increasing aldosterone production. PMID:22628608

Monticone, Silvia; Hattangady, Namita G.; Nishimoto, Koshiro; Mantero, Franco; Rubin, Beatrice; Cicala, Maria Verena; Pezzani, Raffaele; Auchus, Richard J.; Ghayee, Hans K.; Shibata, Hirotaka; Kurihara, Isao; Williams, Tracy A.; Giri, Judith G.; Bollag, Roni J.; Edwards, Michael A.; Isales, Carlos M.

2012-01-01

167

Profile of TP53 gene mutations in sinonasal cancer.  

PubMed

Genetic alterations underlying the development of the cancer of the nose and paranasal sinuses (sinonasal cancer, SNC), a rare cancer that can be included in the group of head and neck cancers, are still largely unknown. We recently reported that TP53 mutations are a common feature of SNC, with an overall frequency of 77%, and they show association to adenocarcinoma and wood-dust exposure [15]. In this study, we report in detail the sequence change for 159 TP53 mutations identified by direct sequencing. More than half of the mutations (60%, 95/159) were missense mutations; there were also 28 (18%) frameshift or nonsense mutations, and 36 (23%) intronic or silent mutations. In coding region, the most common base change detected was C-->T transition (43/125; 34% of base changes in the coding region). G-->T transversions occurred at a frequency of 10% (12/125), which is less than reported in mutation databases for head and neck squamous cell carcinoma (24%). Characteristically, in our SNC series, the mutations were scattered over a large number of codons, codon 248 being the most frequent target of base substitution. Codon 135 was the second most frequently mutated codon; this nucleotide position has not been reported before as frequently mutated in head and neck cancer or human cancer in general. About half of all tumours with TP53 mutations carried more than one mutation. Interestingly, 86% (19/22) of the silent mutations detected had occurred in tumours with multiple mutations. PMID:20025891

Holmila, Reetta; Bornholdt, Jette; Suitiala, Tuula; Cyr, Diane; Dictor, Michael; Steiniche, Torben; Wolff, Henrik; Wallin, Hĺkan; Luce, Daničle; Husgafvel-Pursiainen, Kirsti

2010-04-01

168

Exclusion of growth factor gene mutations as a common cause of Sotos syndrome.  

PubMed

Sotos syndrome is characterized by somatic overgrowth, i.e., macrocephaly and tall stature. Because the cause and pathogenesis of Sotos syndrome remain unknown, we selected nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and neurotrophin 3 (NT-3) as possible genes mutated in Sotos syndrome. In seven patients with the classic phenotype, we excluded mutations in these growth factor genes. It is possible that these three genes are not involved in the cause of Sotos syndrome, or alternatively, mutations could not be identified in the small number of patients studied. PMID:11426446

Lin, A E; Liu, Q; Mannheim, G B; Darras, B T

2001-01-01

169

Prevalence of Mutations in eyeGENE Probands With a Diagnosis of Autosomal Dominant Retinitis Pigmentosa  

PubMed Central

Purpose. To screen samples from patients with presumed autosomal dominant retinitis pigmentosa (adRP) for mutations in 12 disease genes as a contribution to the research and treatment goals of the National Ophthalmic Disease Genotyping and Phenotyping Network (eyeGENE). Methods. DNA samples were obtained from eyeGENE. A total of 170 probands with an intake diagnosis of adRP were tested through enrollment in eyeGENE. The 10 most common genes causing adRP (IMPDH1, KLHL7, NR2E3, PRPF3/RP18, PRPF31/RP11, PRPF8/RP13, PRPH2/RDS, RHO, RP1, and TOPORS) were chosen for PCR-based dideoxy sequencing, along with the two X-linked RP genes, RPGR and RP2. RHO, PRPH2, PRPF31, RPGR, and RP2 were completely sequenced, while only mutation hotspots in the other genes were analyzed. Results. Disease-causing mutations were identified in 52% of the probands. The frequencies of disease-causing mutations in the 12 genes were consistent with previous studies. Conclusions. The Laboratory for Molecular Diagnosis of Inherited Eye Disease at the University of Texas in Houston has thus far received DNA samples from 170 families with a diagnosis of adRP from the eyeGENE Network. Disease-causing mutations in autosomal genes were identified in 48% (81/170) of these families while mutations in X-linked genes accounted for an additional 4% (7/170). Of the 55 distinct mutations detected, 19 (33%) have not been previously reported. All diagnostic results were returned by eyeGENE to participating patients via their referring clinician. These genotyped samples along with their corresponding phenotypic information are also available to researchers who may request access to them for further study of these ophthalmic disorders. (ClinicalTrials.gov number, NCT00378742.) PMID:23950152

Sullivan, Lori S.; Bowne, Sara J.; Reeves, Melissa J.; Blain, Delphine; Goetz, Kerry; NDifor, Vida; Vitez, Sally; Wang, Xinjing; Tumminia, Santa J.; Daiger, Stephen P.

2013-01-01

170

Phenylalanine hydroxylase gene mutations in the United States: Report from the maternal PKU collaborative study  

SciTech Connect

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{r_arrow}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 {le}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 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. 47 refs., 1 fig., 5 tabs.

Guldberg, P.; Henriksen, K.F.; Guettler, F. [John F. Kennedy Inst., Glostrup (Denmark)] [and others

1996-07-01

171

DNA repair genes are selectively mutated in diffuse large B cell lymphomas  

PubMed Central

DNA repair mechanisms are fundamental for B cell development, which relies on the somatic diversification of the immunoglobulin genes by V(D)J recombination, somatic hypermutation, and class switch recombination. Their failure is postulated to promote genomic instability and malignant transformation in B cells. By performing targeted sequencing of 73 key DNA repair genes in 29 B cell lymphoma samples, somatic and germline mutations were identified in various DNA repair pathways, mainly in diffuse large B cell lymphomas (DLBCLs). Mutations in mismatch repair genes (EXO1, MSH2, and MSH6) were associated with microsatellite instability, increased number of somatic insertions/deletions, and altered mutation signatures in tumors. Somatic mutations in nonhomologous end-joining (NHEJ) genes (DCLRE1C/ARTEMIS, PRKDC/DNA-PKcs, XRCC5/KU80, and XRCC6/KU70) were identified in four DLBCL tumors and cytogenetic analyses revealed that translocations involving the immunoglobulin-heavy chain locus occurred exclusively in NHEJ-mutated samples. The novel mutation targets, CHEK2 and PARP1, were further screened in expanded DLBCL cohorts, and somatic as well as novel and rare germline mutations were identified in 8 and 5% of analyzed tumors, respectively. By correlating defects in a subset of DNA damage response and repair genes with genomic instability events in tumors, we propose that these genes play a role in DLBCL lymphomagenesis. PMID:23960188

de Miranda, Noel FCC; Peng, Roujun; Georgiou, Konstantinos; Wu, Chenglin; Sorqvist, Elin Falk; Berglund, Mattias; Chen, Longyun; Gao, Zhibo; Lagerstedt, Kristina; Lisboa, Susana; Roos, Fredrik; van Wezel, Tom; Teixeira, Manuel R.; Rosenquist, Richard; Sundstrom, Christer; Enblad, Gunilla; Nilsson, Mats; Zeng, Yixin; Kipling, David

2013-01-01

172

Novel ABCC8 (SUR1) gene mutations in Asian Indian children with congenital hyperinsulinemic hypoglycemia.  

PubMed

Congenital hyperinsulinemic hypoglycemia (HI) is a heterogeneous genetic disorder of insulin secretion characterized by persistent hypoglycemia, most commonly associated with inactivating mutations of the ?-cell ATP-sensitive K(+) channel (K(ATP) channel) genes ABCC8 (encoding SUR1) and KCNJ11(encoding Kir6.2). This study aimed to screen the mutations in the genes associated with congenital HI in Asian Indian children. Recessive mutations of these genes cause hyperinsulinism that is unresponsive to treatment with channel agonists like diazoxide. Dominant K(ATP) mutations have been associated with diazoxide-responsive disease. The KCNJ11, ABCC8, GCK, HNF4A, and GLUD1 genes were analyzed by sequence analysis in 22 children with congenital HI. We found 10 novel mutations (c.1delA, c.61delG, c.267delT, c.619-629delCCCGAGGACCT, Gln444*, Leu724Pro, Ala847Thr, Trp898*, IVS30-2A>C, and Leu1454Arg) and two known mutations (Gly111Arg and Arg598*) in the ABCC8 gene. This study describes novel and known ABCC8 gene mutations in children with congenital HI. This is the first large genetic screening study on HI in India and our results will help clinicians in providing optimal treatment for patients with hyperinsulinemia and in assisting affected families with genetic counseling. PMID:25117148

Jahnavi, Suresh; Poovazhagi, Varadarajan; Kanthimathi, Sekar; Balamurugan, Kandasamy; Bodhini, Dhanasekaran; Yadav, Jaivinder; Jain, Vandana; Khadgawat, Rajesh; Sikdar, Mahuya; Bhavatharini, Ayurchelvan; Das, Ashok Kumar; Kaur, Tanvir; Mohan, Viswanathan; Radha, Venkatesan

2014-09-01

173

Hybrid curation of gene-mutation relations combining automated extraction and crowdsourcing  

PubMed Central

Background: This article describes capture of biological information using a hybrid approach that combines natural language processing to extract biological entities and crowdsourcing with annotators recruited via Amazon Mechanical Turk to judge correctness of candidate biological relations. These techniques were applied to extract gene– mutation relations from biomedical abstracts with the goal of supporting production scale capture of gene–mutation–disease findings as an open source resource for personalized medicine. Results: The hybrid system could be configured to provide good performance for gene–mutation extraction (precision ?82%; recall ?70% against an expert-generated gold standard) at a cost of $0.76 per abstract. This demonstrates that crowd labor platforms such as Amazon Mechanical Turk can be used to recruit quality annotators, even in an application requiring subject matter expertise; aggregated Turker judgments for gene–mutation relations exceeded 90% accuracy. Over half of the precision errors were due to mismatches against the gold standard hidden from annotator view (e.g. incorrect EntrezGene identifier or incorrect mutation position extracted), or incomplete task instructions (e.g. the need to exclude nonhuman mutations). Conclusions: The hybrid curation model provides a readily scalable cost-effective approach to curation, particularly if coupled with expert human review to filter precision errors. We plan to generalize the framework and make it available as open source software. Database URL: http://www.mitre.org/publications/technical-papers/hybrid-curation-of-gene-mutation-relations-combining-automated PMID:25246425

Burger, John D.; Doughty, Emily; Khare, Ritu; Wei, Chih-Hsuan; Mishra, Rajashree; Aberdeen, John; Tresner-Kirsch, David; Wellner, Ben; Kann, Maricel G.; Lu, Zhiyong; Hirschman, Lynette

2014-01-01

174

p53 and K-ras gene mutations in carcinoma of the rectum among Finnish women  

PubMed Central

Aims/Background—The aim of this study was to identify p53 and K-ras gene mutations in carcinoma of the rectum among Finnish women. Mutation patterns might give clues to aetiological factors when comparisons are made with other human tumours. Methods—Of 134 women with carcinoma of the rectum, paraffin wax embedded specimens of the tumour tissue were obtained from 118 patients. Genomic DNA was extracted, and exons 4–8 of the p53 gene and codons 12/13 and 61 of the K-ras gene were amplified, and analysed for mutations by single strand conformation polymorphism and direct sequencing. The production of p53 and K-ras proteins was studied by immunohistochemistry. Results—The overall crude frequency for mutations in the p53 gene was 35% but the true frequency appears to be higher (up to 56%). In the K-ras gene, the mutation frequency (15%) was significantly lower than that reported for colon cancer. In the p53 gene, the mutation frequency increased significantly with patient age. In a high proportion of patients (14%) the rectal tumours contained small subclones of tumour cells that displayed extremely rare mutations at codons 110 and 232 of the p53 gene. Hot spot codon 175 mutations were significantly less common in rectal cancer than in cancer of the colon. Conclusions—Rectal cancer among Finnish women has characteristics in the mutations of the p53 and K-ras genes that are uncommon in other human tumours, including cancer of the colon. A biological explanation of these findings is not clear at present, but might be associated with an unidentified genetic factor in Finland. PMID:10884918

Servomaa, K; Kiuru, A; Kosma, V-M; Hirvikoski, P; Rytomaa, T

2000-01-01

175

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

176

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. PMID:20558140

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

177

Mutations of the CYP1B1 gene in congenital anterior staphylomas  

PubMed Central

Purpose Here, we present two patients with congenital anterior staphyloma, with mutations in the CYP1B1 gene. Methods We reviewed the medical records, including the genetic analysis. Results Two unrelated patients presented with congenital anterior staphylomas. Both patients showed mutations in the CYP1B1 gene. The first patient, the product of a consanguineous marriage, showed a homozygous misssense mutation g.3987G>A (p.G61E). The second patient had compound heterozygous misssense mutations [g.4160 G>T (p.A119S) and g.8131 C>G (p.L432V)]. Conclusion CYP1B1 gene mutation may be associated with congenital anterior staphylomas. PMID:24591815

Al Judaibi, Ramzi; Abu-Amero, Khaled K; Morales, Jose; Al Shahwan, Sami; Edward, Deepak P

2014-01-01

178

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

179

Homozygous tyrosinase gene mutation in an American black with tyrosinase-negative (type IA) oculocutaneous albinism.  

PubMed Central

We have identified a tyrosinase gene mutation in an American black with classic, tyrosinase-negative oculocutaneous albinism. This mutation results in an amino acid substitution (Cys----Arg) at codon 89 of the tyrosinase polypeptide. The proband is homozygous for the substitution, suggesting that this mutation may be frequently associated with tyrosinase-negative oculocutaneous albinism in blacks. Images Figure 1 Figure 2 Figure 3 PMID:1899321

Spritz, R A; Strunk, K M; Hsieh, C L; Sekhon, G S; Francke, U

1991-01-01

180

Somatic Mutations of the Protein Kinase Gene Family in Human Lung Cancer  

Microsoft Academic Search

Protein kinases are frequently mutated in human cancer and inhibitors of mutant protein kinases have proven to be effective anticancer drugs. We screened the coding sequences of 518 protein kinases (f1.3 Mb of DNA per sample) for somatic mutations in 26 primary lung neoplasms and seven lung cancer cell lines. One hundred eighty-eight somatic mutations were detected in 141 genes.

Helen Davies; Chris Hunter; Raffaella Smith; Philip Stephens; Chris Greenman; Graham Bignell; Jon Teague; Adam Butler; Sarah Edkins; Claire Stevens; Adrian Parker; Sarah O'Meara; Syd Barthorpe; Lisa Brackenbury; Jody Clements; Jennifer Cole; Ed Dicks; Ken Edwards; Simon Forbes; Matthew Gorton; Kristian Gray; Kelly Halliday; Rachel Harrison; Katy Hills; Jonathon Hinton; David Jones; Vivienne Kosmidou; Ross Laman; Richard Lugg; Andrew Menzies; Janet Perry; Robert Petty; Keiran Raine; Rebecca Shepherd; Alexandra Small; Helen Solomon; Yvonne Stephens; Calli Tofts; Jennifer Varian; Anthony Webb; Sofie West; Sara Widaa; Andrew Yates; Francis Brasseur; Colin S. Cooper; Adrienne M. Flanagan; Anthony Green; Maggie Knowles; Suet Y. Leung; Leendert H. J. Looijenga; Bruce Malkowicz; Marco A. Pierotti; Siu T. Yuen; Sunil R. Lakhani; Douglas F. Easton; Barbara L. Weber; Peter Goldstraw; Andrew G. Nicholson; Richard Wooster; Michael R. Stratton; P. Andrew Futreal

2005-01-01

181

Absence of BRAF gene mutations in uveal melanomas in contrast to cutaneous melanomas  

Microsoft Academic Search

The recent discovery of activating mutations in the BRAF gene in many cutaneous melanomas led us to screen the genomic sequence of BRAF exons 11 and 15 in a series of 48 intraocular (uveal) melanomas, together with control samples from three cutaneous melanomas and the SK-Mel-28 cell line, which has a BRAF mutation. The same mutation was detected in two-thirds

S. C. Edmunds; I. A. Cree; F. Di Nicolantonio; J. L. Hungerford; J. S. Hurren; D. P. Kelsell

2003-01-01

182

Mutation analysis of the G4.5 gene in patients with isolated left ventricular noncompaction  

Microsoft Academic Search

Mutations in the gene G4.5, originally associated with Barth syndrome, have been reported to result in a wide spectrum of severe infantile X-linked cardiomyopathies. The purpose of this study was to investigate patients with isolated left ventricular noncompaction (LVNC) for disease-causing mutations in G4.5. In 27 patients including 10 families with isolated LVNC, mutation analysis of G4.5 was performed using

Rui Chen; Tohru Tsuji; Fukiko Ichida; Karla R Bowles; Xianyi Yu; Sayaka Watanabe; Keiichi Hirono; Shinichi Tsubata; Yuji Hamamichi; Jun Ohta; Yasuharu Imai; Neil E Bowles; Toshio Miyawaki; Jeffrey A Towbin

2002-01-01

183

A new de novo mutation in the GCK gene causing MODY2.  

PubMed

Analysis of glucokinase (GCK) gene in a 15-year-old male identified a new frameshift mutation in exon 4 caused by a heterozygous guanine deletion at position 382 (c.382delG, p.E128Xfs). No mutation was detected in the parents. Polymorphic markers' study excluded false paternity indicating that c.382delG is a novel de novo mutation. PMID:21514682

Cappelli, Alessia; Silvestri, Serena; Tumini, Stefano; Carinci, Silvia; Cipriano, Paola; Massi, Luciano; Staffolani, Paolo; Pianese, Luigi

2011-07-01

184

Low Frequency of PIK3CA Gene Mutations in Hepatocellular Carcinoma in Chinese Population  

Microsoft Academic Search

PI3K\\/AKT constitutes an important pathway regulating the signaling of multiple biological processes and plays a critical role\\u000a in carcinogenesis. PIK3CA gene missense mutations have been reported in many human cancer types. The mutation of it in hepatocellular carcinoma cases\\u000a varies with different races and regions. In this study, we investigated PIK3CA mutation in Chinese hepatocellular carcinoma patients. A total 90

Xun Li; Quanbao Zhang; Wenting He; Wenbo Meng; Jun Yan; Lei Zhang; Xiaoliang Zhu; Tao Liu; Yumin Li; Zhongtian Bai

185

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

186

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

187

Polymorphisms in Drug Metabolism Genes, Smoking, and p53 Mutations in Breast Cancer  

PubMed Central

Polymorphisms in phase I and phase II enzymes may enhance the occurrence of mutations at critical tumor suppressor genes, such as p53, and increase breast cancer risk by either increasing the activation or detoxification of carcinogens and/or endogenous estrogens. We analyzed polymorphisms in CYP1B1, GSTM1, GSTT1, and GSTP1 and p53 mutations in 323 breast tumor samples. Approximately 11% of patients exhibited mutations in p53. Women with mutations had a significantly younger age of diagnosis (P = 0.01) and a greater incidence of tumors classified as stage II or higher (P = 0.002). More women with mutations had a history of smoking (55%) compared to women without mutations (39%). Although none of the genotypes alone were associated with p53 mutations, positive smoking history was associated with p53 mutations in women with the GSTM1 null allele [OR = 3.54; 95% CI = 0.97–12.90 P = 0.06] compared to women with the wild-type genotype and smoking history [OR = 0.62, 95% CI = 0.19–2.07], although this association did not reach statistical significance. To test for gene–gene interactions, our exploratory analysis in the Caucasian cases suggested that individuals with the combined GSTP1 105 VV, CYP1B1 432 LV/VV, and GSTM1 positive genotype were more likely to harbor mutations in p53 [OR = 4.94; 95% CI = 1.11–22.06]. Our results suggest that gene–smoking and gene–gene interactions may impact the prevalence of p53 mutations in breast tumors. Elucidating the etiology of breast cancer as a consequence of common genetic polymorphisms and the genotoxic effects of smoking will enable us to improve the design of prevention strategies, such as lifestyle modifications, in genetically susceptible subpopulations. PMID:17683074

Van Emburgh, Beth O.; Hu, Jennifer J.; Levine, Edward A.; Mosley, Libyadda J.; Case, L. Douglas; Lin, Hui-Yi; Knight, Sommer N.; Perrier, Nancy D.; Rubin, Peter; Sherrill, Gary B.; Shaw, Cindy S.; Carey, Lisa A.; Sawyer, Lynda R.; Allen, Glenn O.; Milikowski, Clara; Willingham, Mark C.; Miller, Mark Steven

2013-01-01

188

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

189

Two missense mutations of the IRF6 gene in two Japanese families with popliteal pterygium syndrome.  

PubMed

Mutations in the interferon regulatory factor 6 gene (IRF6) cause either popliteal pterygium syndrome (PPS) or Van der Woude syndrome (VWS), allelic autosomal dominant orofacial clefting conditions. To further investigate the IRF6 mutation profile in PPS, we performed mutation analysis of patients from two unrelated Japanese families with PPS and identified mutations in IRF6: c.251G>T (R84L) and c.1271C>T (S424L). We also found R84L, which together with previous reports on R84 mutations, provided another line of evidence that both syndromes could result from the same mutation probably under an influence of a modifier gene(s). This supports the idea that the R84 residue in the DNA binding domain of IRF6 is a mutational hot spot for PPS. A luciferase assay of the S424L protein in the other family demonstrated that the mutation decreased the IRF6 transcriptional activity significantly to 6% of that of the wild-type. This finding suggests that the C-terminus region of IRF6 could have an important function in phosphorylation or protein interaction. To our knowledge, this is the first report of mutations observed in Japanese PPS patients. PMID:20803643

Matsuzawa, Noriko; Kondo, Shinji; Shimozato, Kazuo; Nagao, Toru; Nakano, Motoi; Tsuda, Masayoshi; Hirano, Akiyoshi; Niikawa, Norio; Yoshiura, Koh-Ichiro

2010-09-01

190

Dominance Effects of Deleterious and Beneficial Mutations in a Single Gene of the RNA Virus ?6  

PubMed Central

Most of our knowledge of dominance stems from studies of deleterious mutations. From these studies we know that most deleterious mutations are recessive, and that this recessivity arises from a hyperbolic relationship between protein function (i.e., protein concentration or activity) and fitness. Here we investigate whether this knowledge can be used to make predictions about the dominance of beneficial and deleterious mutations in a single gene. We employed a model system – the bacteriophage ?6 – that allowed us to generate a collection of mutations in haploid conditions so that it was not biased toward either dominant beneficial or recessive deleterious mutations. Screening for the ability to infect a bacterial host that does not permit infection by the wildtype ?6, we generated a collection of mutations in P3, a gene involved in attachment to the host and in phage particle assembly. The resulting collection contained mutations with both deleterious and beneficial effects on fitness. The deleterious mutations in our collection had additive effects on fitness and the beneficial mutations were recessive. Neither of these observations were predicted from previous studies of dominance. This pattern is not consistent with the hyperbolic (diminishing returns) relationship between protein function and fitness that is characteristic of enzymatic genes, but could have resulted from a curve of increasing returns. PMID:24945910

Joseph, Sarah B.; Peck, Kayla M.; Burch, Christina L.

2014-01-01

191

Mutational status of VHL gene and its clinical importance in renal clear cell carcinoma.  

PubMed

The most common subtype of renal cell carcinoma is the clear cell type (ccRCC), accounting for 75 % of cases. Inactivation of VHL gene is thought to be an early event in ccRCC carcinogenesis. Our intention was to assess whether VHL mutational status might provide useful predictive or prognostic information in patients with ccRCC. VHL messenger RNA (mRNA) expression was analyzed by in situ hybridization and its protein by immunohistochemistry on a tissue microarray containing samples from 148 cases. This was validated by qRT-PCR on 62 cases, for which RNA was available. The mutation status was assessed in 91 cases by Sanger sequencing. VHL was found mutated in 57 % of cases, with missense mutations in 26 %, nonsense in 5 %, splice site in 13 %, deletions in 39 %, indels in 8 %, duplications in 8 %, and insertions in 2 % of the cases. The prevalence of mutations by exon was the following: exon 1, 47 %; exon 2, 27 %; and exon 3, 13 %. VHL protein was expressed in a high number of cases (80 %), but significant correlations were not found between protein expression, clinical data, and survival. Importantly, of the 91 samples evaluated by sequencing, 45 were mutated, and 87 % of those were strongly positive. We found 32 novel mutations in the VHL gene in ccRCC. The presence of mutations was not concordant with mRNA or protein expression. Nonsense mutations of the VHL gene appear to be related with poorer prognosis and survival. PMID:25027579

Alves, Mariana Rezende; Carneiro, Felipe Cavalcanti; Lavorato-Rocha, André Mourăo; da Costa, Walter Henriques; da Cunha, Isabela Werneck; de Cássio Zequi, Stęnio; Guimaraes, Gustavo Cardoso; Soares, Fernando Augusto; Carraro, Dirce Maria; Rocha, Rafael Malagoli

2014-09-01

192

Isolation and Characterization of Point Mutations in Mismatch Repair Genes That Destabilize Microsatellites in Yeast  

Microsoft Academic Search

The stability of simple repetitive DNA sequences (microsatellites) is a sensitive indicator of the ability of a cell to repair DNA mismatches. In a genetic screen for yeast mutants with elevated microsatellite instability, we identified strains containing point mutations in the yeast mismatch repair genes, MSH2, MSH3, MLH1, and PMS1. Some of these mutations conferred phenotypes significantly different from those

ELAINE AYRES SIA; MARGARET DOMINSKA; LELA STEFANOVIC; THOMAS D. PETES

2001-01-01

193

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

194

Detection of point mutation in the p53 gene using a peptide nucleic acid biosensor  

Microsoft Academic Search

A 17-mer peptide nucleic acid (PNA) is used as the recognition layer of an electrochemical biosensor for detecting a specific mutation in the p53 gene. The performance of the PNA-derived biosensor is compared with that of its DNA counterpart. The significantly higher specificity of the PNA probe greatly improves the detection of a single point mutation, found in many types

Joseph Wang; Gustavo Rivas; Xiaohua Cai; Manuel Chicharro; Concepcion Parrado; Narasaiah Dontha; Asher Begleiter; Michael Mowat; Emil Palecek; Peter E. Nielsen

1997-01-01

195

Low prevalence of glucokinase gene mutations in gestational diabetic patients with good glycemic control.  

PubMed

Glucokinase (GCK) plays a key role in glucose homeostasis. Gestational diabetes mellitus increases the risk of gestational complications in pregnant women and fetuses. We screened for mutations in coding and flanking regions of the GCK gene in pregnant women with or without gestational diabetes in a Brazilian population. A sample of 200 pregnant women classified as healthy (control, N = 100) or with gestational diabetes (N = 100) was analyzed for mutations in the GCK gene. All gestational diabetes mellitus patients had good glycemic control maintained by diet alone and no complications during pregnancy. Mutations were detected by single-strand conformation polymorphism and DNA sequencing. Thirteen of the 200 subjects had GCK gene mutations. The mutations detected were in intron 3 (c.43331A>G, new), intron 6 (c.47702T>C, rs2268574), intron 9 (c.48935C>T, rs2908274), and exon 10 (c.49620G>A, rs13306388). None of these GCK mutations were found to be significantly associated with gestational diabetes mellitus. In summary, we report a low frequency of GCK mutations in a pregnant Brazilian population and describe a new intronic variation (c.43331A>G, intron 3). We conclude that mutations in GCK introns and in non-translatable regions of the GCK gene do not affect glycemic control and are not correlated with gestational diabetes mellitus. PMID:22653590

Frigeri, H R; Santos, I C R; Réa, R R; Almeida, A C R; Fadel-Picheth, C M T; Pedrosa, F O; Souza, E M; Rego, F G M; Picheth, G

2012-01-01

196

A Cluster of Mutations within a Short Triplet Repeat in the C1 Inhibitor Gene  

Microsoft Academic Search

Mutations in the C1 inhibitor gene that result in low functional levels of C1 inhibitor protein cause hereditary angioneurotic edema. This disease is characterized by episodic edema leading to considerable morbidity and death. Among 60 unreported kindred with the disease, four patients were discovered to have mutations clustered within a 12-bp segment of exon 5 from nucleotide 8449 to nucleotide

John J. Bissler; Marco Cicardi; Virginia H. Donaldson; Paul A. Gatenby; Fred S. Rosen; Albert L. Sheffer; Alvin E. Davis III

1994-01-01

197

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

198

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

199

Missense mutation in the Chlamydomonas chloroplast gene that encodes the Rubisco large subunit  

SciTech Connect

The 69-12Q mutant of Chlamydomonas reinhardtii lacks ribulose-1,5-bisphosphate carboxylase activity, but retains holoenzyme protein. It results from a mutation in the chloroplast large-subunit gene that causes an isoleucine-for-threonine substitution at amino-acid residue 173. Considering that lysine-175 is involved in catalysis, it appears that mutations cluster at the active site.

Spreitzer, R.J.; Brown, T.; Chen, Zhixiang; Zhang, Donghong; Al-Abed, S.R. (Univ. of Nebraska, Lincoln (USA))

1988-04-01

200

Spectrum of hemojuvelin gene mutations in 1q-linked juvenile hemochromatosis  

Microsoft Academic Search

expression identical to the 1q-linked form, is due to inactivation of hepcidin, the key regulator of iron homeostasis. Here we report the spectrum of mutations of the hemojuvelin gene (HJV) in 34 patients who did not show hepcidin mutations. This represents the largest cohort of pa- tients with JH collected worldwide. We identified 17 different (16 novel) muta- tions of

Carmela Lanzara; Antonella Roetto; Filomena Daraio; Silvain Rivard; Romina Ficarella; Hervey Simard; Timothy M. Cox; Mario Cazzola; Alberto Piperno; Anne-Paule Gimenez-Roqueplo; Paola Grammatico; Stefano Volinia; Paolo Gasparini; Clara Camaschella

2004-01-01

201

Identification of mutation sites on omega3 desaturase genes from Mortierella alpina 1S-4 mutants.  

PubMed

The mutation sites on omega3 desaturase genes in two omega3 desaturase-defective mutants derived from arachidonic acid-producing Mortierella alpina 1S-4 were identified. The mutations each resulted in an amino acid replacement (W232Stop or W386Stop) which caused a lack of omega3 desaturase activity in these mutants. PMID:19147101

Sakuradani, Eiji; Abe, Takahiro; Shimizu, Sakayu

2009-01-01

202

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

203

Preliminary mutation analysis in the phenylanaline hydroxylase gene in Greek PKU and HPA patients  

Microsoft Academic Search

The presence of nine mutations in the phenylalanine hydroxlase (PAH) gene, previously described in phenylketonuria (PKU) patients of other Mediterranean and European populations, was assessed in 47 Greek PKU and 3 hyperphenylalaninaemia (HPA) patients. Of the nine mutations investigated, only five were detected, characterizing 31 % of the PKU alleles in our patients.

J. Traeger-Synodinos; E. Kanavakis; M. Kalogerakou; K. Soulpi; S. Missiou-Tsangaraki; C. Kattamis

1994-01-01

204

High accuracy mutation detection in leukemia on a selected panel of cancer genes.  

PubMed

With the advent of whole-genome and whole-exome sequencing, high-quality catalogs of recurrently mutated cancer genes are becoming available for many cancer types. Increasing access to sequencing technology, including bench-top sequencers, provide the opportunity to re-sequence a limited set of cancer genes across a patient cohort with limited processing time. Here, we re-sequenced a set of cancer genes in T-cell acute lymphoblastic leukemia (T-ALL) using Nimblegen sequence capture coupled with Roche/454 technology. First, we investigated how a maximal sensitivity and specificity of mutation detection can be achieved through a benchmark study. We tested nine combinations of different mapping and variant-calling methods, varied the variant calling parameters, and compared the predicted mutations with a large independent validation set obtained by capillary re-sequencing. We found that the combination of two mapping algorithms, namely BWA-SW and SSAHA2, coupled with the variant calling algorithm Atlas-SNP2 yields the highest sensitivity (95%) and the highest specificity (93%). Next, we applied this analysis pipeline to identify mutations in a set of 58 cancer genes, in a panel of 18 T-ALL cell lines and 15 T-ALL patient samples. We confirmed mutations in known T-ALL drivers, including PHF6, NF1, FBXW7, NOTCH1, KRAS, NRAS, PIK3CA, and PTEN. Interestingly, we also found mutations in several cancer genes that had not been linked to T-ALL before, including JAK3. Finally, we re-sequenced a small set of 39 candidate genes and identified recurrent mutations in TET1, SPRY3 and SPRY4. In conclusion, we established an optimized analysis pipeline for Roche/454 data that can be applied to accurately detect gene mutations in cancer, which led to the identification of several new candidate T-ALL driver mutations. PMID:22675565

Kalender Atak, Zeynep; De Keersmaecker, Kim; Gianfelici, Valentina; Geerdens, Ellen; Vandepoel, Roel; Pauwels, Daphnie; Porcu, Michaël; Lahortiga, Idoya; Brys, Vanessa; Dirks, Willy G; Quentmeier, Hilmar; Cloos, Jacqueline; Cuppens, Harry; Uyttebroeck, Anne; Vandenberghe, Peter; Cools, Jan; Aerts, Stein

2012-01-01

205

Quantification of the paternal allele bias for new germline mutations in the retinoblastoma gene  

SciTech Connect

New germline mutations in the human retinoblastoma gene preferentially arise on a paternally derived allele. In nonhereditary retinoblastoma, the initial somatic mutation seems to have no such bias. The few previous reports of these phenomena included relatively few cases (less than a dozen new germline or initial somatic mutations), so that the magnitude of the paternal allele bias for new germline mutations is not known. Knowledge of the magnitude of the bias is valuable for genetic counseling, since, for example, patients with new germline mutations who reproduce transmit risk for retinoblastoma according to the risk that the transmitted allele has a germline mutation. We sought to quantitate the paternal allele bias and to determine whether paternal age is a factor possibly accounting for it. We studied 311 families with retinoblastoma (261 simplex, 50 multiplex) that underwent clinical genetic testing and 5 informative families recruited from earlier research. Using RFLPs and polymorphic microsatellites in the retinoblastoma gene, we could determine the parental origin of 45 new germline mutations and 44 probable initial somatic mutations. Thirty-seven of the 45 new germline mutations, or 82%, arose on a paternal allele while only 24 of the 44 initial somatic mutations (55%) did so. Increased paternal age does not appear to account for the excess of new paternal germline mutations, since the average age of fathers of children with new germline mutations (29.4 years, n=26, incomplete records on 11) was not significantly different from the average age of fathers of children with maternal germline mutations or somatic initial mutations (29.8 years, n=35, incomplete records on 17).

Morrow, J.F.; Rapaport, J.M.; Dryia, T.P. [Massachusetts Eye & Ear Infirmary, Boston, MA (United States)

1994-09-01

206

Aberrant transmembrane signal transduction in Dictyostelium cells expressing a mutated ras gene.  

PubMed Central

Dictyostelium discoideum cells contain a single ras gene (Dd-ras) that is highly homologous to mammalian ras genes. Cell transformation with a vector carrying a ras gene with a (glycine----threonine) missense mutation at position 12 causes an altered morphogenesis. Extracellular cAMP signals regulate morphogenesis and induce chemotaxis and the activation and subsequent desensitization of adenylate and guanylate cyclase. cAMP signal transduction was investigated in Dd-ras-transformed cells. Transformants that overexpress the mutated Dd-ras-Thr12 gene show normal activation and desensitization of adenylate cyclase and normal activation of guanylate cyclase. However, cAMP induces a stronger desensitization of guanylate cyclase stimulation in the Dd-ras-Thr12 transformant than in transformants overexpressing the Dd-ras-Gly12 wild-type gene or in untransformed cells. This effect was correlated with a reduced chemotactic sensitivity of the transformant expressing the mutated Dd-ras-Thr12 gene. PMID:2885843

Van Haastert, P J; Kesbeke, F; Reymond, C D; Firtel, R A; Luderus, E; Van Driel, R

1987-01-01

207

UCSD scientists find gene mutation for aggressive form of pancreatic cancer  

Cancer.gov

Researchers at the University of California, San Diego School of Medicine have identified a mutated gene common to adenosquamous carcinoma tumors – the first known unique molecular signature for this rare, but particularly virulent, form of pancreatic cancer.

208

Methods for the identification of mutations in the human phenylalanine hydroxylase gene using DNA probes  

SciTech Connect

This patent describes a method of detecting a mutation in a phenylalanine hydroxylase gene of human genomic DNA. Also described is an automated method of detecting PKU affected, PKU helerozgotes and normals in fetal to adult human samples.

Woo, S.L.C.; Dilella, A.G.

1990-10-23

209

Mutation profile of the MYO7A gene in Spanish patients with Usher syndrome type I.  

PubMed

Usher syndrome type I is the most severe form of Usher syndrome. It is an autosomal recessive disorder characterized by profound congenital sensorineural deafness, retinitis pigmentosa, and vestibular abnormalities. Mutations in the myosin VIIA gene (MYO7A) are responsible for Usher syndrome type 1B (USH1B). This gene is thought to bear greatest responsibility for USH1 and, depending on the study, has been reported to account for between 24% and 59% of USH1 cases. In this report a mutation screening of the MYO7A gene was carried out in a series of 48 unrelated USH1 families using single strand conformation polymorphism analysis (SSCP) and direct sequencing of those fragments showed an abnormal electrophoretic pattern. Twenty-five mutations were identified in 23 out of the 48 families studied (47.9%). Twelve of these mutations were novel, including five missense mutations, three premature stop codons, three frameshift, and one putative splice-site mutation. Based on our results we can conclude there is an absence of hot spot mutations in the MYO7A gene and that this gene plays a major role in Usher syndrome. PMID:16470552

Jaijo, T; Aller, E; Oltra, S; Beneyto, M; Nájera, C; Ayuso, C; Baiget, M; Carballo, M; Antińolo, G; Valverde, D; Moreno, F; Vilela, C; Perez-Garrigues, H; Navea, A; Millán, J M

2006-03-01

210

1/9/09 2:14 PMResearchers Pinpoint Spontaneous Gene Mutations Responsible for 10 Percent of Non-Familial Cases of Schizophrenia Page 1 of 3http://cumc.columbia.edu/news/press_releases/gene-mutation-schizophrenia.html  

E-print Network

-Familial Cases of Schizophrenia Page 1 of 3http://cumc.columbia.edu/news/press_releases/gene-mutation-schizophrenia Gene Mutations Responsible for 10 Percent of Non-Familial Cases of Schizophrenia NEW YORK (May 30, 2008) ­ Scans of the genome of patients with schizophrenia have revealed rare spontaneous copy number mutations

211

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. PMID:20618940

2010-01-01

212

A Network of Cancer Genes with Co-Occurring and Anti-Co-Occurring Mutations  

Microsoft Academic Search

Certain cancer genes contribute to tumorigenesis in a manner of either co-occurring or mutually exclusive (anti-co-occurring) mutations; however, the global picture of when, where and how these functional interactions occur remains unclear. This study presents a systems biology approach for this purpose. After applying this method to cancer gene mutation data generated from large-scale and whole genome sequencing of cancer

Qinghua Cui

2010-01-01

213

Familiar ochronotic arthropathy–caused by a gene mutation traced three hundred years  

Microsoft Academic Search

Authors trace an ochronotic Hungarian family, which moved from Slovakia to Hungary 300 years ago. As the family members lived in a relatively close village community the gene mutation had been survived silently for ages before the clinical symptoms developed. Family tree analysis could detect with the use of allele specific PCR amplification–the p.G161R mutation of the homogentisic acid 1,2-dioxygenase (HGD) gene,

Kálmán Tóth; Zsuzsanna Kiss-Láaszló; Endre Lénárt; Katalin Juhász; Katalin Takács; Tamas Bender; Janos Szabó

2010-01-01

214

A splicing mutation in the ?5(IV) collagen gene of a family with Alport's syndrome  

Microsoft Academic Search

A splicing mutation in the ?5(IV) collagen gene of a family with Alport's syndrome. DNA sequence analysis of the ?5(IV) collagen chain gene (COL4A5) was carried out between exon 47 and 51, which encode the noncollagenous (NC) domain, in eight Japanese families with Alport's syndrome. In one family with X-linked inheritance of the disease, a point mutation (G to C)

Shinsuke Nomura; Gengo Osawa; Tetsujun Sai; Teruo Harano; Keiko Harano

1993-01-01

215

Novel Gene Mutations in Patients With Left Ventricular Noncompaction or Barth Syndrome  

Microsoft Academic Search

Background—Mutations in the gene G4.5 result in a wide spectrum of severe infantile cardiomyopathic phenotypes, including isolated left ventricular noncompaction (LVNC), as well as Barth syndrome (BTHS) with dilated cardiomyopathy (DCM). The purpose of this study was to investigate patients with LVNC or BTHS for mutations in G4.5 or other novel genes. Methods and Results—DNA was isolated from 2 families

Fukiko Ichida; Shinichi Tsubata; Karla R. Bowles; Noriyuki Haneda; Keiichiro Uese; Toshio Miyawaki; W. Jeffrey Dreyer; John Messina; Hua Li; Neil E. Bowles; Jeffrey A. Towbin

2010-01-01

216

Mutation Analysis of 3 Genes in Patients With Leber Congenital Amaurosis  

Microsoft Academic Search

Methods: Samples were screened with single-strand con- formation polymorphism analysis followed by DNA se- quencing of 3 genes (CRX, GUCY2D, and RPE65) known to be associated with LCA. Results: Of the 176 probands, 28 (15.9%) harbored pos- sible disease-causing mutations. The relative contribu- tion of each gene to the total number of mutations was as follows: CRX, 2.8%; GUCY2D, 6.3%;

Andrew J. Lotery; P. Namperumalsamy; Samuel G. Jacobson; Richard G. Weleber; Gerald A. Fishman; Maria A. Musarella; Creig S. Hoyt; Elise Heon; Alex Levin; James Jan; Byron Lam; Ronald E. Carr; Alan Franklin; S. Radha; Jeaneen L. Andorf; Val C. Sheffield; Edwin M. Stone

2000-01-01

217

RPE65 gene: Multiplex PCR and mutation screening in patients from India with retinal degenerative diseases  

Microsoft Academic Search

We used multiplex PCR followed by sequencing to screen for mutations in the 14 exons of theRPE65 gene in early-hildhood-onset autosomal recessive retinitis pigmentosa (arRP) and Leber’s congenital amaurosis (LCA) patients.\\u000a The RPE65 protein is believed to play an important role in the metabolism of vitamin A in the visual cycle and mutations identified\\u000a in the gene could have implications

Biju Joseph; Anuradha Srinivasan; Nagasamy Soumittra; Authiappan Vidhya; Nitin Shridhara Shetty; Satagopan Uthra; Govindasamy Kumaramanickavel

2002-01-01

218

Genotype\\/Phenotype Correlation of Multiple Endocrine Neoplasia Type 1 Gene Mutations in Sporadic Gastrinomas  

Microsoft Academic Search

Multiple endocrine neoplasia type 1 (MEN1) gene mutations are reported in some gastrinomas occurring in patients without MEN1 as well as in some other pancreatic endocrine tumors (PETs). In some inherited syndromes phenotype-genotype correlations exist for dis- ease severity, location, or other manifestations. The purpose of the present study was to correlate mutations of the MEN1 gene in a large

STEPHAN U. GOEBEL; CHRISTINA HEPPNER; A. LEE BURNS; STEPHEN J. MARX; ALLEN M. SPIEGEL; ZHENGPING ZHUANG; IRINA A. LUBENSKY; FATHIA GIBRIL; ROBERT T. JENSEN

2010-01-01

219

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

220

Mutations in genes encoding subunits of RNA polymerases I and III cause Treacher Collins syndrome  

Microsoft Academic Search

We identified a deletion of a gene encoding a subunit of RNA polymerases I and III, POLR1D, in an individual with Treacher Collins syndrome (TCS). Subsequently, we detected 20 additional heterozygous mutations of POLR1D in 252 individuals with TCS. Furthermore, we discovered mutations in both alleles of POLR1C in three individuals with TCS. These findings identify two additional genes involved

J. G. Dauwerse; J. Dixon; S. Seland; C. A. Ruivenkamp; A. van Haeringen; L. H. Hoefsloot; D. J. Peters; A. C. Boers; C. Daumer-Haas; R. Maiwald; C. Zweier; B. Kerr; A. M. Cobo; J. F. Toral; A. J. M. Hoogeboom; D. R. Lohmann; U. Hehr; M. J. Dixon; M. H. Breuning; D. Wieczorek

2011-01-01

221

Whole exome sequencing reveals concomitant mutations of multiple FA genes in individual Fanconi anemia patients  

PubMed Central

Background Fanconi anemia (FA) is a rare inherited genetic syndrome with highly variable clinical manifestations. Fifteen genetic subtypes of FA have been identified. Traditional complementation tests for grouping studies have been used generally in FA patients and in stepwise methods to identify the FA type, which can result in incomplete genetic information from FA patients. Methods We diagnosed five pediatric patients with FA based on clinical manifestations, and we performed exome sequencing of peripheral blood specimens from these patients and their family members. The related sequencing data were then analyzed by bioinformatics, and the FANC gene mutations identified by exome sequencing were confirmed by PCR re-sequencing. Results Homozygous and compound heterozygous mutations of FANC genes were identified in all of the patients. The FA subtypes of the patients included FANCA, FANCM and FANCD2. Interestingly, four FA patients harbored multiple mutations in at least two FA genes, and some of these mutations have not been previously reported. These patients’ clinical manifestations were vastly different from each other, as were their treatment responses to androstanazol and prednisone. This finding suggests that heterozygous mutation(s) in FA genes could also have diverse biological and/or pathophysiological effects on FA patients or FA gene carriers. Interestingly, we were not able to identify de novo mutations in the genes implicated in DNA repair pathways when the sequencing data of patients were compared with those of their parents. Conclusions Our results indicate that Chinese FA patients and carriers might have higher and more complex mutation rates in FANC genes than have been conventionally recognized. Testing of the fifteen FANC genes in FA patients and their family members should be a regular clinical practice to determine the optimal care for the individual patient, to counsel the family and to obtain a better understanding of FA pathophysiology. PMID:24885126

2014-01-01

222

Mutational Analysis of Thirty-two Double-Strand DNA Break Repair Genes in Breast and Pancreatic Cancers  

Microsoft Academic Search

Inactivating mutations in several genes that encode compo- nents of the DNA repair machinery have been associated with an increased risk of breast cancer. To assess whether alterations in other DNA repair genes contribute to breast cancer and to further determine the relevance of these genes to pancreatic cancer, we performed mutational analysis of 32 DNA double-strand break repair genes

Xianshu Wang; Csilla Szabo; Chiping Qian; Peter G. Amadio; Stephen N. Thibodeau; James R. Cerhan; Gloria M. Petersen; Wanguo Liu

2008-01-01

223

Distribution of ?-Globin Gene Mutations in Thalassemia Minor Population of Kerman Province, Iran  

PubMed Central

Background: Mutations in ?-globin gene may result in ?-thalassemia major, which is one of the most common genetic disorders in Iran and some other countries. Knowing the beta-globin mutation spectrum improves the efficiency of prenatal diagnosis in the affected fetuses (major ?-thalassemia) of heterozygote couples. Methods: Couples with high hemoglobin A2 and low mean corpuscular volume were studied as suspicious of ?-thalassemia carriers in Genetic Laboratory of Afzalipour Hospital, Kerman, Iran. We used amplification refractory mutation system, reverse hybridization, and DNA sequencing to determine the spectrum of ?-globin gene mutation in the people who involved with ?-thalassemia minor in this province. Results: Among the 266 subjects, 17 different types of mutation in ?-globin gene were identified. Three of the mutations account for 77.1% of the studied cases. IVSI-5(G> C) was the most frequent mutation (66.2%) followed by IVSII-I (G> A) (6%) and Fr 8–9 (+G) (4.9%). The less frequent mutations include: IVSI-6(T> C), codon 15 (G>A), codon 44 (-C), codon 39 (C>T), codon 8 (-AA), codon30 (G> C), IVSI-110 (G > A), codon 36–37 (-T), 619bp deletion, codon 5 (-CT), IVSI-25bp del, codon 41–42(-TTCT), IVSI-I (G> A), and ?nt30 (T>A) were accounted for 19.5%. Unknown alleles comprised 3.4% of the mutations. Conclusion: However, the frequencies of different mutations reported here are significantly different from those found in other part of the world and even other Iranian provinces. Reporting a number of these mutations in the neighboring countries such as Pakistan can be explained by gene flow phenomenon. PMID:23113009

Saleh-Gohari, N; Bazrafshani, MR

2010-01-01

224

Detection of Heterozygous Truncating Mutations in the BRCA1 and APC Genes by Using a Rapid Screening Assay in Yeast  

Microsoft Academic Search

The detection of inactivating mutations in tumor suppressor genes is critical to their characterization, as well as to the development of diagnostic testing. Most approaches for mutational screening of germ-line specimens are complicated by the fact that mutations are heterozygous and that missense mutations are difficult to interpret in the absence of information about protein function. We describe a novel

Chikashi Ishioka; Takao Suzuki; Michael Fitzgerald; Michael Krainer; Hideki Shimodaira; Akira Shimada; Tadashi Nomizu; Kurt J. Isselbacher; Daniel Haber; Ryunosuke Kanamaru

1997-01-01

225

Three novel PHEX gene mutations in four Chinese families with X-linked dominant hypophosphatemic rickets  

SciTech Connect

Highlights: Black-Right-Pointing-Pointer In our study, all of the patients were of Han Chinese ethnicity, which were rarely reported. Black-Right-Pointing-Pointer We identified three novel PHEX gene mutations in four unrelated families with XLH. Black-Right-Pointing-Pointer We found that the relationship between the phenotype and genotype of the PHEX gene was not invariant. Black-Right-Pointing-Pointer We found that two PHEX gene sites, p.534 and p.731, were conserved. -- Abstract: Background: X-linked hypophosphatemia (XLH), the most common form of inherited rickets, is a dominant disorder that is characterized by renal phosphate wasting with hypophosphatemia, abnormal bone mineralization, short stature, and rachitic manifestations. The related gene with inactivating mutations associated with XLH has been identified as PHEX, which is a phosphate-regulating gene with homologies to endopeptidases on the X chromosome. In this study, a variety of PHEX mutations were identified in four Chinese families with XLH. Methods: We investigated four unrelated Chinese families who exhibited typical features of XLH by using PCR to analyze mutations that were then sequenced. The laboratory and radiological investigations were conducted simultaneously. Results: Three novel mutations were found in these four families: one frameshift mutation, c.2033dupT in exon 20, resulting in p.T679H; one nonsense mutation, c.1294A > T in exon 11, resulting in p.K432X; and one missense mutation, c.2192T > C in exon 22, resulting in p.F731S. Conclusions: We found that the PHEX gene mutations were responsible for XLH in these Chinese families. Our findings are useful for understanding the genetic basis of Chinese patients with XLH.

Kang, Qing-lin [Department of Orthopedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233 (China)] [Department of Orthopedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233 (China); Xu, Jia [Department of Orthopedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233 (China) [Department of Orthopedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233 (China); Metabolic Bone Disease and Genetic Research Unit, Department of Osteoporosis and Bone Diseases, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233 (China); Medical College of Soochow University, Suzhou, Jiangsu province 215000 (China); Zhang, Zeng [Department of Orthopedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233 (China) [Department of Orthopedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233 (China); Metabolic Bone Disease and Genetic Research Unit, Department of Osteoporosis and Bone Diseases, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233 (China); He, Jin-wei [Metabolic Bone Disease and Genetic Research Unit, Department of Osteoporosis and Bone Diseases, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233 (China)] [Metabolic Bone Disease and Genetic Research Unit, Department of Osteoporosis and Bone Diseases, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233 (China); Lu, Lian-song [Department of Orthopedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233 (China) [Department of Orthopedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233 (China); Medical College of Soochow University, Suzhou, Jiangsu province 215000 (China); Fu, Wen-zhen [Metabolic Bone Disease and Genetic Research Unit, Department of Osteoporosis and Bone Diseases, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233 (China)] [Metabolic Bone Disease and Genetic Research Unit, Department of Osteoporosis and Bone Diseases, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233 (China); Zhang, Zhen-lin, E-mail: zzl2002@medmail.com.cn [Metabolic Bone Disease and Genetic Research Unit, Department of Osteoporosis and Bone Diseases, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233 (China)] [Metabolic Bone Disease and Genetic Research Unit, Department of Osteoporosis and Bone Diseases, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233 (China)

2012-07-13

226

Overexpression of genes involved in miRNA biogenesis in medullary thyroid carcinomas with RET mutation.  

PubMed

Abnormal expression of non-coding micro RNA (miRNA) has been described in medullary thyroid carcinoma (MTC). Expression of genes encoding factors involved in miRNA biogenesis results often deregulated in human cancer and correlates with aggressive clinical behavior. In this study, expression of four genes involved in miRNA biogenesis (DICER, DROSHA, DCGR8, and XPO5) was investigated in 54 specimens of MTC. Among them, 33 and 13 harbored RET and RAS mutations, respectively. DICER, DGCR8, and XPO5 mRNA levels were significantly overexpressed in MTC harboring RET mutations, in particular, in the presence of RET634 mutation. When MTCs with RET and RAS mutations were compared, only DGCR8 displayed a significant difference, while MTCs with RAS mutations did not show significant differences with respect to non-mutated tumors. We then attempted to correlate expression of miRNA biogenesis genes with tumor aggressiveness. According to the TNM status, MTCs were divided in two groups and compared (N0 M0 vs. N1 and/or M1): for all four genes no significant difference was detected. Cell line experiments, in which expression of a RET mutation is silenced by siRNA, suggest the existence of a causal relationship between RET mutation and overexpression of DICER, DGCR8, and XPO5 genes. These findings demonstrate that RET- but not RAS-driven tumorigenic alterations include abnormalities in the expression of some important genes involved in miRNA biogenesis that could represent new potential markers for targeted therapies in the treatment of RET-mutated MTCs aimed to restore the normal miRNA expression profile. PMID:24569963

Puppin, Cinzia; Durante, Cosimo; Sponziello, Marialuisa; Verrienti, Antonella; Pecce, Valeria; Lavarone, Elisa; Baldan, Federica; Campese, Antonio Francesco; Boichard, Amelie; Lacroix, Ludovic; Russo, Diego; Filetti, Sebastiano; Damante, Giuseppe

2014-11-01

227

Characterization of in vivo somatic mutations at the hypoxanthine phosphoribosyltransferase gene of a human control population  

SciTech Connect

The ability to recognize a change in mutation spectrum after an exposure to a toxic substance and then relate that exposure to health risk depends on the knowledge of mutations that occur in the absence of exposure. The authors have been studying both the frequency and molecular nature of mutations of the hypoxanthine phosphoribosyltransferase (hprt) gene in peripheral blood lymphocytes as surrogate reporters of genetic damage. The authors have analyzed mutants, one per donor to ensure independence, from a control population in which the quantitative effect of smoking and age on mutant frequency have been well defined. Analyses of cDNA and genomic DNA by polymerase chain reaction and sequencing have identified the mutations in 63 mutants, 45 from males and 18 from females, of which 34 were smokers and 29 were nonsmokers. Slightly less than half of the mutations were base substitutions (28); they were predominantly at GC base pairs (19). Different mutations at the same site indicated that there are features of the hprt polypeptide that affect the mutation spectrum. Two pairs of identical mutations indicated that there may be hot spots. Mutations not previously reported have been detected, indicating that the mutation spectrum is only partly defined. The remainder of the mutations were deletions (32) or insertions/duplications (3); deletions ranged from one base pair to complete loss of the locus. Despite a small average increase in mutant frequency for smokers, an increased proportion of base substitutions at AT base pairs in smokers (p = 0.2) hinted at a smoking-associated shift in the mutation spectrum. Expanding the study to include individuals with larger, smoking-associated increases of mutant frequency will determine the significance of this observation. This background mutation study provides insight into factors that determine the mutation spectra of the hprt locus and provides data for comparison with mutation spectra of other populations. 44 refs., 7 tabs.

Burkhart-Schultz, K.; Thomas, C.B.; Brinson, E.; Jones, I.M. (Lawrence Livermore National Lab., CA (United States)); Thompson, C.L.; Strout, C.L. (National Inst. of Environmental Health Sciences, Research Triangle Park, NC (United States))

1993-04-22

228

Two novel mutations in the myophosphorylase gene in a patient with McArdle disease.  

PubMed

We identified two novel mutations in exon 2 of the myophosphorylase gene in a 33-year-old German women with McArdle disease. The patient was compound heterozygous for a novel nonsense mutation at codon 84 changing tyrosine to stop codon (Y84X) and for a novel missense mutation at codon 93 changing arginine to tryptophan (R93W). These mutations are the first to be described in exon 2 and expand the genetic heterogeneity in patients with McArdle disease. PMID:12508303

Deschauer, Marcus; Hertel, Kathrin; Zierz, Stephan

2003-01-01

229

"20209C-T" a variant mutation of prothrombin gene mutation in a patient with recurrent pregnancy loss.  

PubMed

Recurrent pregnancy loss is considered when a female undergoes at least two consecutive, spontaneous abortions or more than two alternatively. This condition affects approximately 5% of women in reproductive age. Several causes of recurrent abortion have been established, but nevertheless, approximately half of all cases remain unexplained. Thrombophilic disorders have been suggested as a possible cause of recurrent miscarriage. A single 20210 G-A mutation of the 3'-untranslated region of (F2) has been reported as a cause of inherited thrombophilia. The F2 G-A mutation affects 1% to 4% of the US population, and its prevalence is higher among Caucasian women of Southern European descendants. Studies of G20210A polymorphism have also shown conflicting associations with recurrent abortions. In addition to G20210A polymorphism, other mutations affecting the F2 gene have been associated with thrombosis and/or pregnancy complications. PMID:25117109

Prat, Maria; Morales-Indiano, Cristian; Jimenez, Carme; Mas, Virgina; Besses, Carles; Checa, Miguel A; Carreras, Ramon

2014-01-01

230

Genetic characterization of Swedish patients with familial hypercholesterolemia: a heterogeneous pattern of mutations in the LDL receptor gene  

Microsoft Academic Search

Familial hypercholesterolemia (FH) is an autosomal codominant disease, caused by mutations in the LDL receptor gene. To characterize the distribution of genetic aberrations in Swedish FH-patients fulfilling the clinical criteria of FH, we have investigated 150 unrelated Swedish patients for mutations in the LDL receptor gene and for the most common mutation causing familial ligand defective apo B-100 (FDB). Of

S. Lind; E. Rystedt; M. Eriksson; O. Wiklund; B. Angelin; G. Eggertsen

2002-01-01

231

Cellular and molecular aspects of familial hypertrophic cardiomyopathy caused by mutations in the cardiac troponin I gene  

Microsoft Academic Search

Mutations in the cardiac troponin I (CTnI) gene occur in ~5% of families with familial hypertrophic cardiomyopathy (FHC) and 20 mutations in this gene that cause FHC have now been described. The clinical manifestations of CTnI mutations that cause FHC are diverse, ranging from asymptomatic with high life expectancy to severe heart failure and sudden cardiac death. Most of these

Aldrin V. Gomes; James D. Potter

2004-01-01

232

Mutation screening of the PTEN gene in patients with autism spectrum disorders and macrocephaly.  

PubMed

Mutations in the PTEN gene are associated with a broad spectrum of disorders, including Cowden syndrome (CS), Bannayan-Riley-Ruvalcaba syndrome, Proteus syndrome, and Lhermitte-Duclos disease. In addition, PTEN mutations have been described in a few patients with autism spectrum disorders (ASDs) and macrocephaly. In this study, we screened the PTEN gene for mutations and deletions in 88 patients with ASDs and macrocephaly (defined as >or=2 SD above the mean). Mutation analysis was performed by direct sequencing of all exons and flanking regions, as well as the promoter region. Dosage analysis of PTEN was carried out using multiplex ligation-dependent probe amplification (MLPA). No partial or whole gene deletions were observed. We identified a de novo missense mutation (D326N) in a highly conserved amino acid in a 5-year-old boy with autism, mental retardation, language delay, extreme macrocephaly (+9.6 SD) and polydactyly of both feet. Polydactyly has previously been described in two patients with Lhermitte-Duclos disease and CS and is thus likely to be a rare sign of PTEN mutations. Our findings suggest that PTEN mutations are a relatively infrequent cause of ASDs with macrocephaly. Screening of PTEN mutations is warranted in patients with autism and pronounced macrocephaly, even in the absence of other features of PTEN-related tumor syndromes. PMID:17427195

Buxbaum, Joseph D; Cai, Guiqing; Chaste, Pauline; Nygren, Gudrun; Goldsmith, Juliet; Reichert, Jennifer; Anckarsäter, Henrik; Rastam, Maria; Smith, Christopher J; Silverman, Jeremy M; Hollander, Eric; Leboyer, Marion; Gillberg, Christopher; Verloes, Alain; Betancur, Catalina

2007-06-01

233

Heterozygosity Loss at 22q and Lack of INI1 Gene Mutation in Gastrointestinal Stromal Tumor  

Microsoft Academic Search

Objectives: Gastrointestinal stromal tumor (GIST) is characterized by KIT or PDGFRA gene mutation. Although chromosomal losses of 22q are frequent in GIST, it is unclear which tumor suppressor genes might be inactivated in association with such losses. The INI1 gene, located at 22q11.23, is a tumor suppressor gene that is frequently altered in malignant rhabdoid tumor. Methods: To elucidate the

Hidetaka Yamamoto; Kenichi Kohashi; Masazumi Tsuneyoshi; Yoshinao Oda

2011-01-01

234

Novel mutation of the notch3 gene in arabic family with CADASIL  

PubMed Central

Mutations in the NOTCH3 gene are responsible for cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), an adult onset hereditary angiopathy leading to ischemic stroke, vascular dementia and psychiatric disorders. All mutation of NOTCH3 described so far are striking stereotyped leading to the gain or loss of cystiene residue in a given epidermal growth factor (EGF), like repeat. We report an Arabic family affected with CADASIL mutation, G1790 C, in Exon 11 of the NOTCH3 gene. This is the first novel mutation reported in Arabic CADASIL patients. This finding confirms that mutations in NOTCH3 are associated with the pathogenesis of CADASIL across different ethnic background. PMID:22053260

Bohlega, Saeed

2011-01-01

235

Inferring the Temporal Order of Cancer Gene Mutations in Individual Tumor Samples  

PubMed Central

The temporal order of cancer gene mutations in tumors is essential for understanding and treating the disease. Existing methods are unable to infer the order of mutations that are identified at the same time in individual tumor samples, leaving the heterogeneity of the order unknown. Here, we show that through a complex network-based approach, which is based on the newly defined statistic –carcinogenesis information conductivity (CIC), the temporal order in individual samples can be effectively inferred. The results suggest that tumor-suppressor genes might more frequently initiate the order of mutations than oncogenes, and every type of cancer might have its own unique order of mutations. The initial mutations appear to be dedicated to acquiring the function of evading apoptosis, and some order constraints might reflect potential regularities. Our approach is completely data-driven without any parameter settings and can be expected to become more effective as more data will become available. PMID:24586626

Guo, Jun; Guo, Hanliang; Wang, Zhanyi

2014-01-01

236

A frameshift mutation in exon 2 of the phenylalanine hydroxylase gene linked to RFLP haplotype 1.  

PubMed

A deletion of a single base in codon 55 (exon 2) of the phenylalanine hydroxylase (PAH) gene has been identified by direct DNA sequencing of 94 phenylketonuria (PKU) chromosomes. This mutation alters the reading frame so that a stop signal (TAA) is generated in codon 60 of the PAH gene. Haplotype analysis revealed that all PKU alleles showing the codon 55 frameshift mutation exhibited haplotype 1. In our panel of DNA probes 13% of all mutant haplotype 1 alleles carry this particular mutation. Patients who were compound heterozygotes for this deletion and R408W in exon 12, or the splice mutation in intron 12, were affected by severe PKU. Thus, the clinical data provide additional evidence that haplotype 1 PKU alleles carry molecular defects which confer a null phenotype. In addition, we were able to show that the newly detected mutation occurs on alleles of different ethnic background. PMID:1682235

Eigel, A; Dworniczak, B; Kalaydjieva, L; Horst, J

1991-10-01

237

Distribution of Gene Mutations Associated with Familial Normosmic Idiopathic Hypogonadotropic Hypogonadism  

PubMed Central

Objective: Normosmic idiopathic hypogonadotropic hypogonadism (nIHH) is characterized by failure of initiation or maintenance of puberty due to insufficient gonadotropin release, which is not associated with anosmia/hyposmia. The objective of this study was to determine the distribution of causative mutations in a hereditary form of nIHH. Methods: In this prospective collaborative study, 22 families with more than one affected individual (i.e. multiplex families) with nIHH were recruited and screened for genes known or suspected to be strong candidates for nIHH. Results: Mutations were identified in five genes (GNRHR, TACR3, TAC3, KISS1R, and KISS1) in 77% of families with autosomal recessively inherited nIHH. GNRHR and TACR3 mutations were the most common two causative mutations occurring with about equal frequency. Conclusions: Mutations in these five genes account for about three quarters of the causative mutations in nIHH families with more than one affected individual. This frequency is significantly greater than the previously reported rates in all inclusive (familial plus sporadic) cohorts. GNRHR and TACR3 should be the first two genes to be screened for diagnostic purposes. Identification of causative mutations in the remaining families will shed light on the regulation of puberty. Conflict of interest:None declared. PMID:22766261

Gurbuz, Fatih; Kotan, L. Damla; Mengen, Eda; S?klar, Zeynep; Berberoglu, Merih; Dokmetas, Sebila; K?l?cl?, Mehmet Fatih; Guven, Ayla; Kirel, Birgul; Saka, Nurcin; Poyrazoglu, Sukran; Cesur, Yasar; Dogan, Murat; Ozen, Samim; Ozbek, Mehmet Nuri; Demirbilek, Huseyin; Kekil, M. Burcu; Temiz, Fatih; Onenli Mungan, Neslihan; Yuksel, Bilgin; Topaloglu, Ali Kemal

2012-01-01

238

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. PMID:20585624

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

239

Novel missense mutations in the FOXC2 gene alter transcriptional activity.  

PubMed

Mutations in the FOXC2 gene that codes for a forkhead transcription factor are associated with primary lymphedema that usually develops around puberty. Associated abnormalities include distichiasis and, very frequently, superficial and deep venous insufficiency. Most mutations reported so far either truncate the protein or are missense mutations in the forkhead domain causing a loss of function. The haplo-insufficient state is associated with lymphatic hyperplasia in mice as well as in humans. We analyzed the FOXC2 gene in 288 patients with primary lymphedema and found 11 pathogenic mutations, of which 9 are novel. Of those, 5 were novel missense mutations of which 4 were located outside of the forkhead domain. To examine their pathogenic potential we performed a transactivation assay using a luciferase reporter construct driven by FOXC1 response elements. We found that the mutations outside the forkhead domain cause a gain of function as measured by luciferase activity. Patient characteristics conform to previous reports with the exception of distichiasis, which was found in only 2 patients out of 11. FOXC2 mutations causing lymphedema-distichiasis syndrome reported thus far result in haplo-insufficiency and lead to lymphatic hyperplasia. Our results suggest that gain-of-function mutations may also cause lymphedema. One would expect that in this case, lymphatic hypoplasia would be the underlying abnormality. Patients with activating mutations might present with Meige disease. PMID:19760751

van Steensel, M A M; Damstra, R J; Heitink, M V; Bladergroen, R S; Veraart, J; Steijlen, Peter M; van Geel, M

2009-12-01

240

Analysis of gene mutations in children with cholestasis of undefined etiology  

PubMed Central

Introduction The discovery of genetic mutations in children with inherited syndromes of intrahepatic cholestasis allows for diagnostic specificity despite similar clinical phenotypes. Here, we aimed to determine whether mutation screening of target genes can assign a molecular diagnosis in children with idiopathic cholestasis. Methods DNA samples were obtained from 51 subjects with cholestasis of undefined etiology and surveyed for mutations in the genes SERPINA1, JAG1, ATP8B1, ABCB11, and ABCB4 by a high-throughput gene chip. Then, the sequence readouts for all five genes were analyzed for mutations and correlated with clinical phenotypes. Healthy subjects served as controls. Results Sequence analysis of the genes identified 14 (or 27%) subjects with missense, nonsense, deletion, and splice site variants associated with disease phenotypes based on the type of mutation and/or biallelic involvement in the JAG1, ATP8B1, ABCB11, or ABCB4 genes. These patients had no syndromic features and could not be differentiated by biochemical markers or histopathology. Among the remaining subjects, 10 (or ~20%) had sequence variants in ATP8B1 or ABCB11 that involved only one allele, 8 had variants not likely to be associated with disease phenotypes, and 19 had no variants that changed amino acid composition. Conclusion Gene sequence analysis assigned a molecular diagnosis in 27% of subjects with idiopathic cholestasis based on the presence of variants likely to cause disease phenotypes. PMID:20683201

Miethke, Alexander; Liu, Cong; Kauffmann, Gregory; Moyer, Katie; Zhang, Kejian; Bezerra, Jorge A.

2014-01-01

241

Recombination and spontaneous mutation at the major cluster of resistance genes in lettuce (Lactuca sativa).  

PubMed Central

Two sets of overlapping experiments were conducted to examine recombination and spontaneous mutation events within clusters of resistance genes in lettuce. Multiple generations were screened for recombinants using PCR-based markers flanking Dm3. The Dm3 region is not highly recombinagenic, exhibiting a recombination frequency 18-fold lower than the genome average. Recombinants were identified only rarely within the cluster of Dm3 homologs and no crossovers within genes were detected. Three populations were screened for spontaneous mutations in downy mildew resistance. Sixteen Dm mutants were identified corresponding to spontaneous mutation rates of 10(-3) to 10(-4) per generation for Dm1, Dm3, and Dm7. All mutants carried single locus, recessive mutations at the corresponding Dm locus. Eleven of the 12 Dm3 mutations were associated with large chromosome deletions. When recombination could be analyzed, deletion events were associated with exchange of flanking markers, consistent with unequal crossing over; however, although the number of Dm3 paralogs was changed, no novel chimeric genes were detected. One mutant was the result of a gene conversion event between Dm3 and a closely related homolog, generating a novel chimeric gene. In two families, spontaneous deletions were correlated with elevated levels of recombination. Therefore, the short-term evolution of the major cluster of resistance genes in lettuce involves several genetic mechanisms including unequal crossing over and gene conversion. PMID:11157000

Chin, D B; Arroyo-Garcia, R; Ochoa, O E; Kesseli, R V; Lavelle, D O; Michelmore, R W

2001-01-01

242

Mutational landscape of gingivo-buccal oral squamous cell carcinoma reveals new recurrently-mutated genes and molecular subgroups  

PubMed Central

Gingivo-buccal oral squamous cell carcinoma (OSCC-GB), an anatomical and clinical subtype of head and neck squamous cell carcinoma (HNSCC), is prevalent in regions where tobacco-chewing is common. Exome sequencing (n=50) and recurrence testing (n=60) reveals that some significantly and frequently altered genes are specific to OSCC-GB (USP9X, MLL4, ARID2, UNC13C and TRPM3), while some others are shared with HNSCC (for example, TP53, FAT1, CASP8, HRAS and NOTCH1). We also find new genes with recurrent amplifications (for example, DROSHA, YAP1) or homozygous deletions (for example, DDX3X) in OSCC-GB. We find a high proportion of C>G transversions among tobacco users with high numbers of mutations. Many pathways that are enriched for genomic alterations are specific to OSCC-GB. Our work reveals molecular subtypes with distinctive mutational profiles such as patients predominantly harbouring mutations in CASP8 with or without mutations in FAT1. Mean duration of disease-free survival is significantly elevated in some molecular subgroups. These findings open new avenues for biological characterization and exploration of therapies. PMID:24292195

Maitra, Arindam; Biswas, Nidhan K.; Amin, Kishore; Kowtal, Pradnya; Kumar, Shantanu; Das, Subrata; Sarin, Rajiv; Majumder, Partha P.; Bagchi, I; Bairagya, B. B.; Basu, A.; Bhan, M. K.; Chaturvedi, P.; Das, D.; D'Cruz, A.; Dhar, R.; Dutta, D.; Ganguli, D.; Gera, P.; Gupta, T.; Mahapatra, S.; Mujawar, M. H. K.; Mukherjee, S.; Nair, S.; Nikam, S.; Nobre, M.; Patil, A.; Patra, S.; Rama-Gowtham, M.; Rao, T. S.; Roy, B.; Roychowdhury, B.; Sarkar, D.; Sarkar, S.; Sarkar-Roy, N.; Sutradhar, D.

2013-01-01

243

Phenotype variability and neonatal diabetes in a large family with heterozygous mutation of the glucokinase gene.  

PubMed

Monogenic diabetes caused by mutations in the glucokinase gene (GCK-MODY) is usually characterized by a mild clinical phenotype. The clinical course of diabetes may be, however, highly variable. The authors present a child with diabetes manifesting with ketoacidosis during the neonatal period, born in a large family with ten members bearing a heterozygous p.Gly223Ser mutation in GCK. DNA sequencing and multiplex ligation-dependent probe amplification were used to confirm GCK mutation and exclude other de novo mutations in other known genes associated with monogenic diabetes. Continuous glucose monitoring (CGM) was used to assess daily glycemic profiles. At the onset of diabetes the child had hyperglycemia 765 mg/dl with pH 7.09. Her glycated hemoglobin level was 8.6% (70.5 mmol/mol). The C-peptide level was below normal range (<0.5 pmol/ml) at onset, and the three- and 6-month follow-up examinations. Current evaluation at age 3 still showed unsatisfactory metabolic control with HbA1c level equal to 8.1% (65.0 mmol/mol). CGM data showed glucose concentrations profile similar to poorly controlled type 1 diabetes. The patient was confirmed to be heterozygous for the p.Gly223Ser mutation and did not show any point mutations or deletions within other monogenic diabetes genes. Other family members with p.Gly223Ser mutation had retained C-peptide levels and mild diabetes manageable with diet (five individuals), oral hypoglycemizing agents (five patients), or insulin (one patient). This mutation was absent within all healthy family members. Heterozygous mutations of the GCK gene may result in neonatal diabetes similar to type 1 diabetes, the cause of such phenotype variety is still unknown. The possibility of other additional, unknown mutations seems to be the most likely explanation for the unusual presentation of GCK-MODY. PMID:21437567

Borowiec, Maciej; Mysliwiec, Malgorzata; Fendler, Wojciech; Antosik, Karolina; Brandt, Agnieszka; Malecki, Maciej; Mlynarski, Wojciech

2011-09-01

244

Identification of photoreceptor genes affected by PRPF31 mutations associated with autosomal dominant retinitis pigmentosa.  

PubMed

Several ubiquitously expressed genes encoding pre-mRNA splicing factors have been associated with autosomal dominant retinitis pigmentosa (adRP), including PRPF31, PRPF3 and PRPF8. Molecular mechanisms by which defects in pre-mRNA splicing factors cause photoreceptor degeneration are not clear. To investigate the role of pre-mRNA splicing in photoreceptor gene expression and function, we have begun to search for photoreceptor genes whose pre-mRNA splicing is affected by mutations in PRPF31. Using an immunoprecipitation-coupled-microarray method, we identified a number of transcripts associated with PRPF31-containing complexes, including peripherin/RDS, FSCN2 and other photoreceptor-expressed genes. We constructed minigenes to study the effects of PRPF31 mutations on the pre-mRNA splicing of these photoreceptor specific genes. Our experiments demonstrated that mutant PRPF31 significantly inhibited pre-mRNA splicing of RDS and FSCN2. These observations suggest a functional link between ubiquitously expressed and retina-specifically expressed adRP genes. Our results indicate that PRPF31 mutations lead to defective pre-mRNA splicing of photoreceptor-specific genes and that the ubiquitously expressed adRP gene, PRPF31, is critical for pre-mRNA splicing of a subset of photoreceptor genes. Our results provide an explanation for the photoreceptor-specific phenotype of PRPF31 mutations. PMID:17350276

Mordes, Daniel; Yuan, Liya; Xu, Lili; Kawada, Mariko; Molday, Robert S; Wu, Jane Y

2007-05-01

245

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

246

Characterization of Usher syndrome type I gene mutations in an Usher syndrome patient population.  

PubMed

Usher syndrome type I (USH1), the most severe form of this syndrome, is characterized by profound congenital sensorineural deafness, vestibular dysfunction, and retinitis pigmentosa. At least seven USH1 loci, USH1A-G, have been mapped to the chromosome regions 14q32, 11q13.5, 11p15, 10q21-q22, 21q21, 10q21-q22, and 17q24-25, respectively. Mutations in five genes, including MYO7A, USH1C, CDH23, PCDH15 and SANS, have been shown to be the cause of Usher syndrome type 1B, type 1C, type 1D, type 1F and type 1G, respectively. In the present study, we carried out a systematic mutation screening of these genes in USH1 patients from USA and from UK. We identified a total of 27 different mutations; of these, 19 are novel, including nine missense, two nonsense, four deletions, one insertion and three splicing defects. Approximatelly 35-39% of the observed mutations involved the USH1B and USH1D genes, followed by 11% for USH1F and 7% for USH1C in non-Acadian alleles and 7% for USH1G. Two of the 12 MYO7A mutations, R666X and IVS40-1G > T accounted for 38% of the mutations at that locus. A 193delC mutation accounted for 26% of CDH23 (USH1D) mutations, confirming its high frequency. The most common PCDH15 (USH1F) mutation in this study, 5601-5603delAAC, accounts for 33% of mutant alleles. Interestingly, a novel SANS mutation, W38X, was observed only in the USA cohort. The present study suggests that mutations in MYO7A and CDH23 are the two major components of causes for USH1, while PCDH15, USH1C, and SANS are less frequent causes. PMID:15660226

Ouyang, Xiao Mei; Yan, Denise; Du, Li Lin; Hejtmancik, J Fielding; Jacobson, Samuel G; Nance, Walter E; Li, An Ren; Angeli, Simon; Kaiser, Muriel; Newton, Valerie; Brown, Steve D M; Balkany, Thomas; Liu, Xue Zhong

2005-03-01

247

Mutations in Gcr1, a Transcriptional Activator of Saccharomyces Cerevisiae Glycolytic Genes, Function as Suppressors of Gcr2 Mutations  

PubMed Central

The Saccharomyces cerevisiae GCR1 and GCR2 genes affect expression of most of the glycolytic genes. Evidence for Gcr1p/Gcr2p interaction has been presented earlier and is now supported by the isolation of mutations in Gcr1p suppressing gcr2, as assessed by growth and enzyme assay. Four specific mutation sites were identified. Together with use of the two-hybrid system of FIELDS and SONG, they show that Gcr1p in its N-terminal half has a potential transcriptional activating function as well as elements for interaction with Gcr2p, which perhaps acts normally to expose an otherwise cryptic activation domain on Gcr1p. Complementation of various gcr1 mutant alleles and results with the two-hybrid system also indicate that Gcr1p itself normally functions as an oligomer. PMID:7713414

Uemura, H.; Jigami, Y.

1995-01-01

248

Mutation analysis of the phenylalanine hydroxylase gene using heteroduplex analysis with synthetic DNA constructs.  

PubMed

Using heteroduplex analysis generated with synthetic PCR-amplifiable DNA we have screened the PKU populations of southwest England and Wales, western Scotland, and southeast and central England for mutations in exons 3, 7 and 12 of the phenylalanine hydroxylase (PAH) gene. The technique characterized three mutations in exon 12, two in exon 3 and five in exon 7. Altogether over 370 PKU chromosomes were screened. In all geographical regions exon 12 mutations (R408W, IVS12nt1g- > a and Y414C) accounted for about 40% of mutant chromosomes. Exon 3 mutations (principally I65T) were found on between 9 and 12% of mutant alleles and exon 7 mutations accounted for a further 5-7%. Heteroduplex analysis is rapid, simple and safe and three constructs covering three exons can identify between 55 and 60% of mutations in various PKU populations of the UK. PMID:7766958

Tyfield, L A; Stephenson, A; Bidwell, J L; Wood, N A; Cockburn, F; Harvie, A; Smith, I

1994-12-01

249

Spectrum of rhodopsin gene mutations in Chinese patients with retinitis pigmentosa  

PubMed Central

Purpose This study was to analyze the spectrum and frequency of rhodopsin gene (RHO) mutations in Chinese patients with retinitis pigmentosa (RP). Methods Patients were given physical examinations, and blood samples were collected for DNA extraction. The RHO mutations were screened with direct sequencing. Results Eight heterozygous nucleotide changes were detected in eight of 300 probands with RP, including six novel mutations and two known mutations. p.R21C, p.C110S, p.G182V, p.C187G, c.409–426delGTGGTGGTGTGTAAGCCC, and p.P347L were found in six autosomal dominant families. p.T92I and p.Y178C were found in two isolated cases. Conclusions The results reveal the spectrum and frequency of RHO mutations in Chinese patients with different forms of RP and demonstrate that RHO mutations account for a high proportion of autosomal dominant RP (adRP) cases.

Yang, Guoxing; Xie, Shipeng; Feng, Na; Yuan, Zhifeng; Zhang, Minglian

2014-01-01

250

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

251

Mutations of 3c and spike protein genes correlate with the occurrence of feline infectious peritonitis.  

PubMed

The genes encoding accessory proteins 3a, 3b, 3c, 7a and 7b, the S2 domain of the spike (S) protein gene and the membrane (M) protein gene of feline infectious peritonitis virus (FIPV) and feline enteric coronavirus (FECV) samples were amplified, cloned and sequenced. For this faeces and/or ascites samples from 19 cats suffering from feline infectious peritonitis (FIP) as well as from 20 FECV-infected healthy cats were used. Sequence comparisons revealed that 3c genes of animals with FIP were heavily affected by nucleotide deletions and point mutations compared to animals infected with FECV; these alterations resulted either in early termination or destruction of the translation initiation codon. Two ascites-derived samples of cats with FIP which displayed no alterations of ORF3c harboured mutations in the S2 domain of the S protein gene which resulted in amino acid exchanges or deletions. Moreover, changes in 3c were often accompanied by mutations in S2. In contrast, in samples obtained from faeces of healthy cats, the ORF3c was never affected by such mutations. Similarly ORF3c from faecal samples of the cats with FIP was mostly intact and showed only in a few cases the same mutations found in the respective ascites samples. The genes encoding 3a, 3b, 7a and 7b displayed no mutations linked to the feline coronavirus (FCoV) biotype. The M protein gene was found to be conserved between FECV and FIPV samples. Our findings suggest that mutations of 3c and spike protein genes correlate with the occurrence of FIP. PMID:25150756

Bank-Wolf, Barbara Regina; Stallkamp, Iris; Wiese, Svenja; Moritz, Andreas; Tekes, Gergely; Thiel, Heinz-Jürgen

2014-10-10

252

A novel fibrillin 1 gene mutation leading to marfan syndrome with minimal cardiac features.  

PubMed

Marfan syndrome is an autosomal dominant disorder of the connective tissue, characterized by early development of thoracic aortic aneurysms and/or dissections, accompanied by ocular and/or skeletal involvement, and is caused by mutations in the fibrillin 1 (FBN1) gene. We report on a patient with ectopia lentis and a nonprogressive aortic root dilatation who presented with a novel mutation affecting a conserved cysteine residue present in a calcium-binding epidermal growth factor-like domain of FBN1 (ENSP00000325527, p.Cys538Phe; Chr15:48,805,751 G>T), as revealed by complete sequencing of the FBN1 gene exons and flanking sequences. Identification of the mutation led to genetic screening of apparently asymptomatic family members, allowing the detection of characteristic ocular phenotypes in the absence of typical cardiac Marfan features. This finding stresses the importance of genetic screening of asymptomatic relatives for FBN1 gene mutation carriers. PMID:25337071

Martínez-Quintana; Rodríguez-González; Garay-Sánchez; Tugores

2014-08-01

253

A Novel Fibrillin 1 Gene Mutation Leading to Marfan Syndrome with Minimal Cardiac Features  

PubMed Central

Marfan syndrome is an autosomal dominant disorder of the connective tissue, characterized by early development of thoracic aortic aneurysms and/or dissections, accompanied by ocular and/or skeletal involvement, and is caused by mutations in the fibrillin 1 (FBN1) gene. We report on a patient with ectopia lentis and a nonprogressive aortic root dilatation who presented with a novel mutation affecting a conserved cysteine residue present in a calcium-binding epidermal growth factor-like domain of FBN1 (ENSP00000325527, p.Cys538Phe; Chr15:48,805,751 G>T), as revealed by complete sequencing of the FBN1 gene exons and flanking sequences. Identification of the mutation led to genetic screening of apparently asymptomatic family members, allowing the detection of characteristic ocular phenotypes in the absence of typical cardiac Marfan features. This finding stresses the importance of genetic screening of asymptomatic relatives for FBN1 gene mutation carriers.

Martinez-Quintana; Rodriguez-Gonzalez; Garay-Sanchez; Tugores

2014-01-01

254

A common FGFR3 gene mutation is present in achondroplasia but not in hypochondroplasia  

SciTech Connect

Achondroplasia is the most common type of genetic dwarfism. It is characterized by disproportionate short stature and other skeletal anomalies resulting from a defect in the maturation of the chondrocytes in the growth plate of the cartilage. Recent studies mapped the achondroplasia gene on chromosome region 4p16.3 and identified a common mutation in the gene encoding the fibroblast growth factor receptor 3 (FGFR3). In an analysis of 19 achondroplasia families from a variety of ethnic backgrounds we confirmed the presence of the G380R mutation in 21 of 23 achondroplasia chromosomes studied. In contrast, the G380R mutation was not found in any of the 8 hypochondroplasia chromosomes studied. Futhermore, linkage studies in a 3-generation family with hypochondroplasia show discordant segregation with markers in the 4p16.3 region suggesting that at least some cases of hypochondroplasia are caused by mutations in a gene other than FGFR3. 27 refs., 2 figs.

Stoilov, I.; Kilpatrick, M.W.; Tsipouras, P. [Univ. of Connecticut Health Center, Farmington, CT (United States)

1995-01-02

255

Novel polymerase gamma (POLG1) gene mutation in the linker domain associated with parkinsonism  

PubMed Central

Background Mutations in the POLG1 gene have variable phenotypic presentations and a high degree of clinical suspicion is necessary for their recognition. Parkinsonism and ataxia are the most common movement disorders associated with POLG1 mutations but no phenotype-genotype correlation has been established. Case presentation We identified a male patient with progressive external ophthalmoplegia who also developed a progressive bradykinesia, rigidity and camptocormia in the third decade. Parkinsonism was partially responsive to dopaminegic replacement. His father and brother had reportedly similar clinical problems. Genetic analysis identified a novel mutation p.K512M in the POLG1 gene. Conclusion This report further expands the spectrum of POLG1-associated neurologic problems with the report of a novel mutation in the linker region of the gene, which are rarely associated with parkinsonism. PMID:23865558

2013-01-01

256

[Search for frequently encountered mutations in genes predisposing to breast cancer].  

PubMed

DNA of oncological patients, including Ashkenazi Jews and Slavs, living in St. Petersburg was collected, and the resultant collection was screened for three common mutations of genes BRCA1 and BRCA2 by means of heteroduplex analysis. The mutation 5382insC in exon 20 of the BRCA1 gene was found in four unrelated patients, including three Slavs and one Ashkenazi Jew, with a positive family history of breast cancer. The mutations 185delAG and 6174delT in the BRCA1 and BRCA2 genes, respectively, which are typical of Ashkenazi Jewish patients with breast cancer, were not found in the patients of either ethnicity living in St. Petersburg, although the 6174delT mutation was found in the control group of Ashkenazi Jews. A new 12-nucleotide duplication g.71741ins12nt found in intron 20 of the BRCA1 gene was described. The high frequency of the 5382insC mutation in the BRCA1 gene in patients with familial breast cancer in both St. Petersburg and Moscow indicates that Russian families with the history of breast cancer should be primarily tested for this mutation. PMID:11785296

Mandel'shtam, M Iu; Golubkov, V I; Lamber, E P; Shapiro, I M; Brezhneva, T V; Semiglazov, V F; Lipovetski?, B M; Hanson, K P; Ga?tskhoki, V S

2001-12-01

257

Four novel cases of permanent neonatal diabetes mellitus caused by homozygous mutations in the glucokinase gene.  

PubMed

Permanent neonatal diabetes mellitus (PNDM) caused by homozygous mutations in the glucokinase gene (GCK) is rare and only eight homozygous GCK mutations have been reported so far. Heterozygous GCK mutations cause maturity-onset diabetes of the young (MODY). We report four patients with growth retardation from two separate families (with three siblings in one family and one patient in another family) presenting with persistent hyperglycaemia within the first two days of life. We found one homozygous non-sense mutation (Q98X) in GCK in three siblings from one family and a homozygous missense GCK mutation (G261R) in one patient from another family. Both mutations have been identified previously in GCK-MODY in the heterozygous state. However, this is the first study to report the homozygous forms of these mutations in PNDM. We report four novel cases of PNDM caused by homozygous GCK mutations, including a non-sense mutation in exon 3 (Q98X) and a missense mutation in exon 7 (G261R). PMID:21518409

Bennett, Kate; James, Chela; Mutair, Angham; Al-Shaikh, Hala; Sinani, Aisha; Hussain, Khalid

2011-05-01

258

Mutations of the tyrosinase gene in Indo-Pakistani patients with type I (tyrosinase-deficient) oculocutaneous albinsm (OCA)  

SciTech Connect

Oculocutaneous albinism (OCA) is a group of autosomal recessive disorders characterized by deficient synthesis of melanin pigment. Type I (tyrosinase-deficient) OCA results from mutations of the tyrosinase gene (TYR gene) encoding tyrosinase, the enzyme that catalyzes the first two steps of melanin biosynthesis. Mutations of the TYR gene have been identified in a large number of patients, most of Caucasian ethnic origin, with various forms of type I OCA. The authors present an analysis of the TYR gene in eight Indo-Pakistani patients with type I OCA. The authors describe four novel TYR gene mutations and a fifth mutation previously observed in a Caucasian patient. 16 refs., 6 figs.

Tripathi, R.K.; Droetto, S.; Strunk, K.M.; Holmes, S.A.; Spritz, R.A. (Univ. of Wisconsin, Madison, WI (United States)); Bundey, S.; Musarella, M.A.

1993-12-01

259

The Phenotype of a Germline Mutation in PIGA: The Gene Somatically Mutated in Paroxysmal Nocturnal Hemoglobinuria  

PubMed Central

Phosphatidylinositol glycan class A (PIGA) is involved in the first step of glycosylphosphatidylinositol (GPI) biosynthesis. Many proteins, including CD55 and CD59, are anchored to the cell by GPI. Loss of CD55 and CD59 on erythrocytes causes complement-mediated lysis in paroxysmal nocturnal hemoglobinuria (PNH), a disease that manifests after clonal expansion of hematopoietic cells with somatic PIGA mutations. Although somatic PIGA mutations have been identified in many PNH patients, it has been proposed that germline mutations are lethal. We report a family with an X-linked lethal disorder involving cleft palate, neonatal seizures, contractures, central nervous system (CNS) structural malformations, and other anomalies. An X chromosome exome next-generation sequencing screen identified a single nonsense PIGA mutation, c.1234C>T, which predicts p.Arg412?. This variant segregated with disease and carrier status in the family, is similar to mutations known to cause PNH as a result of PIGA dysfunction, and was absent in 409 controls. PIGA-null mutations are thought to be embryonic lethal, suggesting that p.Arg412? PIGA has residual function. Transfection of a mutant p.Arg412? PIGA construct into PIGA-null cells showed partial restoration of GPI-anchored proteins. The genetic data show that the c.1234C>T (p.Arg412?) mutation is present in an affected child, is linked to the affected chromosome in this family, is rare in the population, and results in reduced, but not absent, biosynthesis of GPI anchors. We conclude that c.1234C>T in PIGA results in the lethal X-linked phenotype recognized in the reported family. PMID:22305531

Johnston, Jennifer J.; Gropman, Andrea L.; Sapp, Julie C.; Teer, Jamie K.; Martin, Jodie M.; Liu, Cyndi F.; Yuan, Xuan; Ye, Zhaohui; Cheng, Linzhao; Brodsky, Robert A.; Biesecker, Leslie G.

2012-01-01

260

Mutation analysis of pre-mRNA splicing genes in Chinese families with retinitis pigmentosa  

PubMed Central

Purpose Seven genes involved in precursor mRNA (pre-mRNA) splicing have been implicated in autosomal dominant retinitis pigmentosa (adRP). We sought to detect mutations in all seven genes in Chinese families with RP, to characterize the relevant phenotypes, and to evaluate the prevalence of mutations in splicing genes in patients with adRP. Methods Six unrelated families from our adRP cohort (42 families) and two additional families with RP with uncertain inheritance mode were clinically characterized in the present study. Targeted sequence capture with next-generation massively parallel sequencing (NGS) was performed to screen mutations in 189 genes including all seven pre-mRNA splicing genes associated with adRP. Variants detected with NGS were filtered with bioinformatics analyses, validated with Sanger sequencing, and prioritized with pathogenicity analysis. Results Mutations in pre-mRNA splicing genes were identified in three individual families including one novel frameshift mutation in PRPF31 (p.Leu366fs*1) and two known mutations in SNRNP200 (p.Arg681His and p.Ser1087Leu). The patients carrying SNRNP200 p.R681H showed rapid disease progression, and the family carrying p.S1087L presented earlier onset ages and more severe phenotypes compared to another previously reported family with p.S1087L. In five other families, we identified mutations in other RP-related genes, including RP1 p. Ser781* (novel), RP2 p.Gln65* (novel) and p.Ile137del (novel), IMPDH1 p.Asp311Asn (recurrent), and RHO p.Pro347Leu (recurrent). Conclusions Mutations in splicing genes identified in the present and our previous study account for 9.5% in our adRP cohort, indicating the important role of pre-mRNA splicing deficiency in the etiology of adRP. Mutations in the same splicing gene, or even the same mutation, could correlate with different phenotypic severities, complicating the genotype–phenotype correlation and clinical prognosis. PMID:24940031

Pan, Xinyuan; Chen, Xue; Liu, Xiaoxing; Gao, Xiang; Kang, Xiaoli; Xu, Qihua; Chen, Xuejuan; Zhao, Kanxing; Zhang, Xiumei; Chu, Qiaomei; Wang, Xiuying

2014-01-01

261

Distinct gene expression patterns associated with FLT3- and NRAS-activating mutations in acute myeloid leukemia with normal karyotype  

Microsoft Academic Search

In acute myeloid leukemia (AML), constitutive activation of the FLT3 receptor tyrosine kinase, either by internal tandem duplications (FLT3-ITD) of the juxtamembrane region or by point mutations in the second tyrosine kinase domain (FLT3-TKD), as well as point mutations of the NRAS gene (NRAS-PM) are among the most frequent somatic gene mutations. To elucidate whether these mutations cause aberrant signal

Kai Neben; Susanne Schnittger; Benedikt Brors; Björn Tews; Felix Kokocinski; Torsten Haferlach; Jasmin Müller; Meinhard Hahn; Wolfgang Hiddemann; Roland Eils; Peter Lichter; Claudia Schoch

2005-01-01

262

Investigation of Underlying Reasons of Factor VIII Deficiency in Hemophilia A Patients with Undetectable Mutations in the F8 Gene  

Microsoft Academic Search

Hemophilia A (HA) is an X-linked bleeding disorder caused by heterogeneous mutations in the coagulation factor VIII (F8) gene [4]. Despite applying sensitive methods for mutation detection, and after excluding the inversions mutations a causative mutation\\u000a is not identified in F8 gene in about 2.5% of severe HA patients (53 patients out of 2350 German patients) (unpublished data). Analysis of

O. El-Maarri; C. Klein; J. Schröder; A. Pavlova; J. Junen; J. Müller; M. Watzka; R. Schwaab; A. Goodeve; C. Negrier; A. R. Thompson; A. Srivastava; J. Oldenburg

263

Variation in mutation rate and polymorphism among mitochondrial genes of Silene vulgaris.  

PubMed

The prevailing wisdom of the plant mitochondrial genome is that it has very low substitution rates, thus it is generally assumed that nucleotide diversity within species will also be low. However, recent evidence suggests plant mitochondrial genes may harbor variable and sometimes high levels of within-species polymorphism, a result attributed to variance in the influence of selection. However, insufficient attention has been paid to the effect of among-gene variation in mutation rate on varying levels of polymorphism across loci. We measured levels of polymorphism in seven mitochondrial gene regions across a geographically wide sample of the plant Silene vulgaris to investigate whether individual mitochondrial genes accumulate polymorphisms equally. We found that genes vary significantly in polymorphism. Tests based on coalescence theory show that the genes vary significantly in their scaled mutation rate, which, in the absence of differences among genes in effective population size, suggests these genes vary in their underlying mutation rate. Further evidence that among-gene variance in polymorphism is due to variation in the underlying mutation rate comes from a significant positive relationship between the number of segregating sites and silent site divergence from an outgroup. Contrary to recent studies, we found unconvincing evidence of recombination in the mitochondrial genome, and generally confirm the standard model of plant mitochondria characterized by low substitution rates and no recombination. We also show no evidence of significant variation in the strength or direction of selection among genes; this result may be expected if there is no recombination. The present study provides some of the most thorough data on plant mitochondrial polymorphism, and provides compelling evidence for mutation rate variation among genes. The study also demonstrates the difficulty in establishing a null model of mitochondrial genome polymorphism, and thus the difficulty, in the absence of a comparative approach, in testing the assumption that low substitution rates in plant mitochondria lead to low polymorphism. PMID:17533174

Barr, Camille M; Keller, Stephen R; Ingvarsson, Pär K; Sloan, Daniel B; Taylor, Douglas R

2007-08-01

264

Mutations in the muscle LIM protein and ?-actinin-2 genes in dilated cardiomyopathy and endocardial fibroelastosis  

Microsoft Academic Search

Dilated cardiomyopathy (DCM) is a major cause of morbidity and mortality. Two genes have been identified for the X-linked forms (dystrophin and tafazzin), while mutations in multiple genes cause autosomal dominant DCM. Muscle LIM protein (MLP) is a member of the cysteine-rich protein (CRP) family and has been implicated in both myogenesis and sarcomere assembly. In the latter role, it

Bhagyalaxmi Mohapatra; Shinawe Jimenez; Jiuann Huey Lin; Karla R Bowles; Karen J Coveler; Joseph G Marx; Michele A Chrisco; Ross T Murphy; Paul R Lurie; Robert J Schwartz; Perry M Elliott; Matteo Vatta; William McKenna; Jeffrey A Towbin; Neil E Bowles

2003-01-01

265

Identification of photoreceptor genes affected by PRPF31 mutations associated with autosomal dominant retinitis pigmentosa  

E-print Network

RP), autosomal recessive (arRP) and X-linked (xlRP). Many RP genes are expressed specifically or predominantlyIdentification of photoreceptor genes affected by PRPF31 mutations associated with autosomal been associated with autosomal dominant retinitis pigmentosa (adRP), including PRPF31, PRPF3 and PRPF8

Wu, Jane Y.

266

Mutations in the CEP290 ( NPHP6) Gene Are a Frequent Cause of Leber Congenital Amaurosis  

Microsoft Academic Search

Leber congenital amaurosis (LCA) is one of the main causes of childhood blindness. To date, mutations in eight genes have been described, which together account for approximately 45% of LCA cases. We localized the genetic defect in a consanguineous LCA-affected family from Quebec and identified a splice defect in a gene encoding a centrosomal protein (CEP290). The defect is caused

Anneke I. den Hollander; Robert K. Koenekoop; Suzanne Yzer; Irma Lopez; Maarten L. Arends; Krysta E. J. Voesenek; Marijke N. Zonneveld; Tim M. Strom; Thomas Meitinger; Han G. Brunner; Carel B. Hoyng; L. Ingeborgh van den Born; Klaus Rohrschneider; Frans P. M. Cremers

2006-01-01

267

Study on the Evolution of Genes Mutation Related With Gastrointestinal Stromal Tumors  

ClinicalTrials.gov

Full Gene Sequences of c-KIT?PDGFRA and DOG1 Are Analyzed With the Screening-sequencing Approach; Investigate the Characteristics and Variations Associated With the Different Gene Mutations of c-KIT?PDGFRA and DOG1 in GIST Patients

2012-01-05

268

Screening for NOTCH3 gene mutations among 151 consecutive Korean patients with acute ischemic stroke  

Microsoft Academic Search

BackgroundCerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a single gene disorder of cerebral small blood vessels caused by mutations in the NOTCH3 gene. The initial detection of CADASIL may be more difficult among Asian populations because common clinical phenotypes and neuroimaging findings are not frequently found in these populations. The purpose of this study was to

Jay Chol Choi; Keun-Hwa Lee; Sook-Keun Song; Jung Seok Lee; Sa-Yoon Kang; Ji-Hoon Kang

269

Glutaric acidemia type II: gene structure and mutations of the electron transfer flavoprotein:ubiquinone oxidoreductase (ETF:QO) gene  

Microsoft Academic Search

Glutaric acidemia type II is a human inborn error of metabolism which can be due to defects in either subunit of electron transfer flavoprotein (ETF) or in ETF:ubiquinone oxidoreductase (ETF:QO), but few disease-causing mutations have been described. The ETF:QO gene is located on 4q33, and contains 13 exons. Primers to amplify these exons are presented, together with mutations identified by

Stephen I Goodman; Robert J Binard; Michael R Woontner; Frank E Frerman

2002-01-01

270

Mutation Screening of the PTEN Gene in Patients With Autism Spectrum Disorders and Macrocephaly  

PubMed Central

Mutations in the PTEN gene are associated with a broad spectrum of disorders, including Cowden syndrome (CS), Bannayan–Riley–Ruvalcaba syndrome, Proteus syndrome, and Lhermitte–Duclos disease. In addition, PTENmutations have been described in a few patients with autism spectrum disorders (ASDs) and macrocephaly. In this study, we screened the PTEN gene for mutations and deletions in 88 patients with ASDs and macrocephaly (defined as ?2 SD above the mean). Mutation analysis was performed by direct sequencing of all exons and flanking regions, as well as the promoter region. Dosage analysis of PTEN was carried out using multiplex ligation-dependent probe amplification (MLPA). No partial or whole gene deletions were observed. We identified a de novo missense mutation (D326N) in a highly conserved amino acid in a 5-year-old boy with autism, mental retardation, language delay, extreme macrocephaly (+9.6 SD) and polydactyly of both feet. Polydactyly has previously been described in two patients with Lhermitte–Duclos disease and CS and is thus likely to be a rare sign of PTEN mutations. Our findings suggest that PTEN mutations are a relatively infrequent cause of ASDs with macrocephaly. Screening of PTEN mutations is warranted in patients with autism and pronounced macrocephaly, even in the absence of other features of PTEN-related tumor syndromes. PMID:17427195

Buxbaum, Joseph D.; Cai, Guiqing; Chaste, Pauline; Nygren, Gudrun; Goldsmith, Juliet; Reichert, Jennifer; Anckarsater, Henrik; Rastam, Maria; Smith, Christopher J.; Silverman, Jeremy M.; Hollander, Eric; Leboyer, Marion; Gillberg, Christopher; Verloes, Alain; Betancur, Catalina

2010-01-01

271

Novel mutations of the APC gene and genetic consequences of splicing mutations in the Czech FAP families.  

PubMed

Familial adenomatous polyposis (FAP) is an autosomal dominant syndrome with almost 100 % risk of colorectal cancer. The typical FAP is characterized by hundreds to thousands of colorectal adenomatous polyps and by extracolonic manifestations, later onset and lower number of polyps in colon is characteristic of an attenuated form (AFAP). We analyzed the APC gene for germline mutations in 90 FAP/AFAP patients. Mutation screening was performed using Denaturing Gradient Gel Electrophoresis. DNA fragments showing an aberrant electrophoretic banding pattern were sequenced. APC-mutation-negative probands were screened for large deletions of the APC gene using multiplex ligation dependent probe amplification. Analysis of mRNA variants followed in probands with possible splicing mutation by PCR amplification of target site flanking exons and sequencing the normal and aberrant products. We identified 30 germline variants among 36 unrelated probands including large deletions. Eleven APC variants detected last two years have not been reported yet. At all, fifteen of them are expected to cause errors in mRNA splicing. Analysis of mRNA in ten of these patients revealed exon skipping in seven cases, exonisation of intron in one of these as well, change of the amount of alternatively spliced product in one case, and no effect was found in three cases. In two of the patients, the biopsy of colon mucosa and polyp enabled us to examine the effect of the mutation on splicing pattern in colon cells directly. The comparison of alternative and standard transcript amount showed similar transcription pattern of exon 14 in control colon mucosa tissue (9 samples) as in 51 blood control samples. PMID:22987206

Schwarzová, Lucie; Štekrová, Jitka; Florianová, Martina; Novotný, Aleš; Schneiderová, Michaela; Ln?ni?ka, Petr; Kebrdlová, V?ra; Kotlas, Jaroslav; Veselá, Kamila; Kohoutová, Milada

2013-03-01

272

UGT1A1 Gene Mutation due to Crigler-Najjar Syndrome in Iranian Patients: Identification of a Novel Mutation  

PubMed Central

Crigler-Najjar syndrome (CNS) type I and type II are inherited as autosomal recessive conditions that are caused by mutations in the UGT1A1 gene. We present the analysis of UGT1A1 gene in 12 individuals from three different families. This analysis allowed us to identify one novel mutation, which was not previously described. In this study, three families with clinically diagnosed CNS referred from Khuzestan province, southwest Iran, were screened. After signing the informed consent, peripheral blood samples from the patients and their parents were collected in EDTA-containing tube followed by DNA extraction using a routine phenol-chloroform method. All five coding exons and the flanking intronic regions of the bilirubin-UGT were amplified by polymerase chain reaction (PCR) followed by DNA sequencing by Sanger method. From the first family, a 9-month-old boy was homozygous for a deletion mutation of two adjacent nucleotides including one adenosine (A) and one glutamine (G) between nucleotides 238 and 239 in exon 1 (c.238_240 del AG). In the second family, there were two affected individuals, an 11-year-old girl and a fetus, found to be homozygous for the same mutation. The third family showed a mutation at nucleotide 479 in exon 1 (Val160Glu) that has been reported previously. Molecular analysis can significantly help confirm the diagnosis of CNS, without any need for the liver biopsy, and may help the therapeutic management by ruling out more harmful causes of hyperbilirubinemia. PMID:24286076

Mohammadi Asl, Javad; Tabatabaiefar, Mohammad Amin; Galehdari, Hamid; Riahi, Kourosh; Masbi, Mohammad Hosein; Zargar Shoshtari, Zohre; Rahim, Fakher

2013-01-01

273

Identification of new mutations in the NF2 tumor suppressor gene in schwannomas  

SciTech Connect

Neurofibromatosis type 2 (NF2) is a severe genetic disorder with an incidence of approximately 1 in 40,000 individuals and is characterized by the formation of multiple benign nervous system tumors. The clinical hallmark of NF2 is the bilateral occurrence of schwannomas on the eighth cranial nerve (vestibular schwannomas). Recently, it has been shown that loss or inactivation of a tumor suppressor gene located in chromosome band 22q12 is the molecular cause of NF2 tumorigenesis. Also, mutations in the NF2 gene have now been identified in patients with sporadic vestibular schwannomas (unilateral schwannomas). We have completed the screening of 80% of the NF2 coding sequence of DNA from 13 sporadic schwannomas and 2 schwannomas from NF2 patients. Using heteroduplex analysis and direct sequencing, we found 13 novel mutations located in 7 different exons with a small cluster (46% of the mutations) located in the central portion of the gene. All of the mutations were unique to single patients. In three tumors, both NF2 alleles were mutated. The types of mutations found include: small deletions ranging from 1 to 30 base pairs, nonsense mutations, a single missense mutation and a splice donor site alteration. It appears that small deletions are the most common type of NF2 gene mutation. We also have developed a dosage test based on quantitative PCR and hybridization with specific probes to detect the loss of heterozygosity. We found that 7 out of 15 schwannomas (47%) show loss of heterozygosity. We are currently extending the analysis to all of the NF2 exons and DNA from 60 additional schwannomas.

Guida, M.; Welling, B.; Prior, T.W. [Ohio State Univ., Columbus, OH (United States)

1994-09-01

274

Novel mutations of the PRKAR1A gene in patients with acrodysostosis.  

PubMed

Acrodysostosis is characterized by a peripheral dysostosis that is accompanied by short stature, midface hypoplasia, and developmental delay. Recently, it was shown that heterozygous point mutations in the PRKAR1A gene cause acrodysostosis with hormone resistance. By mutational analysis of the PRKAR1A gene we detected four different mutations (p.Arg368Stop, p.Ala213Thr, p.Tyr373Cys, and p.Arg335Cys) in four of seven affected patients with acrodysostosis. The combination of clinical results, endocrinological parameters and in silico mutation analysis gives evidence to suppose a pathogenic effect of each mutation. This assumption is supported by the de novo origin of these mutations. Apart from typical radiological abnormalities of the hand bones, elevated thyroid stimulating hormone and parathyroid hormone values as well as short stature are the most common findings. Less frequent features are characteristic facial dysmorphisms, sensorineural hearing loss and mild intellectual disability. These results lead to the conclusion that mutations of PKRAR1A are the major molecular cause for acrodysostosis with endocrinological abnormalities. In addition, in our cohort of 44 patients affected with brachydactyly type E (BDE) we detected only one sequence variant of PRKAR1A (p.Asp227Asn) with an unclear effect on protein function. Thus, we conclude that PRKAR1A mutations may play no major role in the pathogenesis of BDE. PMID:23425300

Muhn, F; Klopocki, E; Graul-Neumann, L; Uhrig, S; Colley, A; Castori, M; Lankes, E; Henn, W; Gruber-Sedlmayr, U; Seifert, W; Horn, D

2013-12-01

275

Central hypothyroidism reveals compound heterozygous mutations in the Pit-1 gene.  

PubMed

Mutations in the gene encoding the Pit-1 transcriptional activator interfere with the embryologic determination and ultimate functions of anterior pituitary cells that produce growth hormone (GH), prolactin (Prl) and thyroid-stimulating hormone (TSH). Central hypothyroidism is often the presenting feature of combined pituitary hormone deficiency (CPHD), but it is not detected in screening programs that rely upon elevation of TSH. We report a child whose hypothyroidism was recognized clinically at age 6 weeks, and subsequently found to have GH and Prl as well as TSH deficiency. With thyroxine and GH replacement he has reached the 70th percentile for height and has normal intelligence. Molecular analysis of genomic DNA for Pit-1 revealed the presence of compound heterozygous recessive mutations: a nonsense mutation in codon 172 and a novel missense mutation substituting glycine for glutamate at codon 174. This case is the first demonstration of CPHD due to compound heterozygous Pit-1 point mutations, as most reported cases of the CPHD phenotype involve either the dominant negative R271W allele or homozygosity for recessive Pit-1 mutations. Therefore, in cases of CPHD, the possibilities of compound heterozygosity for two different Pit-1 mutations, or homozygosity for mutations in the epigenetic gene, Prop-1, should be considered. PMID:9485179

Brown, M R; Parks, J S; Adess, M E; Rich, B H; Rosenthal, I M; Voss, T C; VanderHeyden, T C; Hurley, D L

1998-01-01

276

Insight into the biochemical characteristics of a novel glucokinase gene mutation.  

PubMed

Glucokinase (GCK) acts as a glucose sensor and regulates ?-cell insulin secretion. The heterozygous mutations in the gene encoding GCK cause a reduction of the enzyme activity, which results in a monogenic form of diabetes, maturity-onset diabetes of the young. In the present study, we identified and functionally characterized a novel missense mutation in the GCK gene, which results in a protein mutation Glu(339)?Lys (E339K), from a Chinese family with hyperglycemia. The same GCK mutation that co-segregated with diabetes phenotype was identified in five members of this family but was not found in 200 healthy control individuals. We expressed and affinity-purified the GCK proteins from bacterial expression system that carries mutation (E339K) and fused to glutathione S-transferase. The expressed GCK protein was subjected to the measurement of its biochemical effects of the missense mutation on GCK activity. Our results showed that the mutation reduced the GCK protein yield. The enzymatic kinetics and the thermal stability analysis on the recombinant GCK proteins revealed that the mutation inactivates enzyme kinetics and severely impaired the GCK protein stability. PMID:21104275

Shen, Yunfeng; Cai, Mengyin; Liang, Hua; Wang, Hongwei; Weng, Jianping

2011-03-01

277

De novo gene mutations highlight patterns of genetic and neural complexity in schizophrenia  

PubMed Central

To evaluate evidence for de novo etiologies in schizophrenia, we sequenced at high coverage the exomes of families recruited from two populations with distinct demographic structure and history. We sequenced a total of 795 exomes from 231 parent-proband trios enriched for sporadic schizophrenia cases, as well as 34 unaffected trios. We observed in cases an excess of non-synonymous single nucleotide variants as well as a higher prevalence of gene-disruptive de novo mutations. We found four genes (LAMA2, DPYD, TRRAP and VPS39) affected by recurrent de novo events within or across the two populations, a finding unlikely to have occurred by chance. We show that de novo mutations affect genes with diverse functions and developmental profiles but we also find a substantial contribution of mutations in genes with higher expression in early fetal life. Our results help define the pattern of genomic and neural architecture of schizophrenia. PMID:23042115

Xu, Bin; Ionita-Laza, Iuliana; Roos, J. Louw; Boone, Braden; Woodrick, Scarlet; Sun, Yan; Levy, Shawn; Gogos, Joseph A.; Karayiorgou, Maria

2013-01-01

278

Mutation screening of TSC1 and TSC2 genes in Chinese Han children with tuberous sclerosis complex.  

PubMed

Tuberous sclerosis complex (TSC) is an autosomal dominant neurogenetic disorder caused by mutations in the TSC1 or TSC2 genes and is frequently associated with hamartoma formation in multiple organ systems. Here, we report two novel mutations in the TSC2 gene, including a splicing mutation (IVS 29 +1G>C) in intron 29 and a deletion/insertion mutation (C.5090-5092delCCA- inAG) in exon 39 in two Chinese Han children with TSC whose first clinical manifestation was seizure. The identification of these two mutations confirmed the diagnosis of TSC and expands the spectrum of TSC2 mutations causing TSC. PMID:24737435

Mi, C R; Wang, H; Jiang, H; Sun, R P; Wang, G X

2014-01-01

279

Specific mutation screening of TP53 gene by low-density DNA microarray  

PubMed Central

TP53 is the most commonly mutated gene in human cancers. Approximately 90% of mutations in this gene are localized between domains encoding exons 5 to 8. The aim of this investigation was to examine the ability of the low density DNA microarray with the assistance of double tandem hybridization platform to characterize TP53 mutational hotspots in exons 5, 7, and 8 of the TP53. Nineteen capture probes specific to each potential mutation site were designed to hybridize to specific site. Virtual hybridization was used to predict the stability of hybridization of each capture probe with the target. Thirty-three DNA samples from different sources were analyzed for mutants in these exons. A total of 32 codon substitutions were found by DNA sequencing. 24 of them a showed a perfect correlation with the hybridization pattern system and DNA sequencing analysis of the regions scanned. Although in this work we directed our attention to some of the most representative mutations of the TP53 gene, the results suggest that this microarray system proved to be a rapid, reliable, and effective method for screening all the mutations in TP53 gene. PMID:24198462

Rangel-Lopez, Angelica; Mendez-Tenorio, Alfonso; Beattie, Kenneth L; Maldonado, Rogelio; Mendoza, Patricia; Vazquez, Guelaguetza; Perez-Plasencia, Carlos; Sanchez, Martha; Navarro, Guillermo; Salcedo, Mauricio

2009-01-01

280

Beyond the cardiac myofilament: hypertrophic cardiomyopathy- associated mutations in genes that encode calcium-handling proteins.  

PubMed

Traditionally regarded as a genetic disease of the cardiac sarcomere, hypertrophic cardiomyopathy (HCM) is the most common inherited cardiovascular disease and a significant cause of sudden cardiac death. While the most common etiologies of this phenotypically diverse disease lie in a handful of genes encoding critical contractile myofilament proteins, approximately 50% of patients diagnosed with HCM worldwide do not host sarcomeric gene mutations. Recently, mutations in genes encoding calcium-sensitive and calcium-handling proteins have been implicated in the pathogenesis of HCM. Among these are mutations in TNNC1- encoded cardiac troponin C, PLN-encoded phospholamban, and JPH2-encoded junctophilin 2 which have each been associated with HCM in multiple studies. In addition, mutations in RYR2-encoded ryanodine receptor 2, CASQ2-encoded calsequestrin 2, CALR3-encoded calreticulin 3, and SRI-encoded sorcin have been associated with HCM, although more studies are required to validate initial findings. While a relatively uncommon cause of HCM, mutations in genes that encode calcium-handling proteins represent an emerging genetic subset of HCM. Furthermore, these naturally occurring disease-associated mutations have provided useful molecular tools for uncovering novel mechanisms of disease pathogenesis, increasing our understanding of basic cardiac physiology, and dissecting important structure-function relationships within these proteins. PMID:22515980

Landstrom, A P; Ackerman, M J

2012-06-01

281

Inherited bone marrow failure associated with germline mutation of ACD, the gene encoding telomere protein TPP1  

PubMed Central

Telomerase is a ribonucleoprotein enzyme that is necessary for overcoming telomere shortening in human germ and stem cells. Mutations in telomerase or other telomere-maintenance proteins can lead to diseases characterized by depletion of hematopoietic stem cells and bone marrow failure (BMF). Telomerase localization to telomeres requires an interaction with a region on the surface of the telomere-binding protein TPP1 known as the TEL patch. Here, we identify a family with aplastic anemia and other related hematopoietic disorders in which a 1-amino-acid deletion in the TEL patch of TPP1 (?K170) segregates with disease. All family members carrying this mutation, but not those with wild-type TPP1, have short telomeres. When introduced into 293T cells, TPP1 with the ?K170 mutation is able to localize to telomeres but fails to recruit telomerase to telomeres, supporting a causal relationship between this TPP1 mutation and bone marrow disorders. ACD/TPP1 is thus a newly identified telomere-related gene in which mutations cause aplastic anemia and related BMF disorders. PMID:25205116

Guo, Yiran; Kartawinata, Melissa; Li, Jiankang; Pickett, Hilda A.; Teo, Juliana; Kilo, Tatjana; Barbaro, Pasquale M.; Keating, Brendan; Chen, Yulan; Tian, Lifeng; Al-Odaib, Ahmad; Reddel, Roger R.; Christodoulou, John; Xu, Xun; Hakonarson, Hakon

2014-01-01

282

Missense mutation of the {beta}-cardiac myosin heavy-chain gene in hypertrophic cardiomyopathy  

SciTech Connect

Hypertrophic cardiomyopathy occurs as an autosomal dominant familial disorder or as a sporadic disease without familial involvement. We describe a missense mutation of the {beta}-cardiac myosin heavy chain (MHC) gene, a G to T transversion (741 Gly{r_arrow}Trp) identified by direct sequencing of exon 20 in four individuals affected with familial hypertrophic cardiomyopathy. Three individuals with sporadic hypertrophic cardiomyopathy, whose parents are clinically and genetically unaffected, had sequence variations of exon 34 of the {alpha}-cardiac MHC gene (a C to T transversion, 1658 Asp{r_arrow}Asp, resulting in FokI site polymorphism), of intron 33 of the {alpha}-cardiac MHC gene (a G to A and an A to T transversion), and also of intron 14 of the {beta}-cardiac MHC gene (a C to T transversion in a patient with Noonan syndrome). Including our case, 30 missense mutations of the {beta}-cardiac MHC gene in 49 families have been reported thus far worldwide. Almost all are located in the region of the gene coding for the globular head of the molecule, and only one mutation was found in both Caucasian and Japanese families. Missense mutations of the {Beta}-cardiac MHC gene in hypertrophic cardiomyopathy may therefore differ according to race. 29 refs., 6 figs., 3 tabs.

Arai, Shoichi; Matsuoka, Rumiko; Hirayama, Kenji; Sakurai, Hisanao [Heart Inst. of Japan, Tokyo (Japan)] [and others

1995-09-11

283

A Novel POLG Gene Mutation in 4 Children With Alpers-like Hepatocerebral Syndromes  

PubMed Central

Objective To describe a novel POLG missense mutation (c.3218C>T; p.P1073L) that, in association with 2 previously described mutations, caused an Alpers-like hepatocerebral syndrome in 4 children. Design Genotype-phenotype correlation. Setting Tertiary care universities. Patients Four children, 2 related and 2 unrelated, with the novel p.P1073L mutation (all patients) and either the p.A467T (2 patients), p.G848S (1 patient), or p.W748S (1 patient) mutation presented with psychomotor delay, encephalopathy, and liver failure. Interventions Detailed clinical and laboratory examinations including brain magnetic resonance imaging, muscle biopsy, measurement of mitochondrial DNA, and sequencing of the POLG gene. Main Outcome Measures Definition of clinical variability. Results All 4 patients had psychomotor delay, seizures, and liver disease. Three patients had severe gastrointestinal dysmotility, which may be associated with the new p.P1073L mutation. Conclusions The heterozygous presence of the novel p.P1073L mutation in trans with another recessive POLG mutation causes a hepatocerebral disorder identical or very similar to Alpers syndrome. This adds to the already striking clinical heterogeneity of POLG mutations. In the Belgian patients, the familial occurrence without consanguinity is related to the high frequency of the recessive p.A467T and p.W748S mutations in northwestern Europe and reveals a pitfall for diagnosis and genetic counseling. PMID:20142534

Kurt, Bulent; Jaeken, Jaak; Van Hove, Johan; Lagae, Lieven; Löfgren, Ann; Everman, David B.; Jayakar, Parul; Naini, Ali; Wierenga, Klaas J.; Van Goethem, Gert; Copeland, William C.; DiMauro, Salvatore

2013-01-01

284

Genomic approaches for the discovery of genes mutated in inherited retinal degeneration.  

PubMed

In view of their high degree of genetic heterogeneity, inherited retinal diseases (IRDs) pose a significant challenge for identifying novel genetic causes. Thus far, more than 200 genes have been found to be mutated in IRDs, which together contain causal variants in >80% of the cases. Accurate genetic diagnostics is particularly important for isolated cases, in which X-linked and de novo autosomal dominant variants are not uncommon. In addition, new gene- or mutation-specific therapies are emerging, underlining the importance of identifying causative mutations in each individual. Sanger sequencing of selected genes followed by cost-effective targeted next-generation sequencing (NGS) can identify defects in known IRD-associated genes in the majority of the cases. Exome NGS in combination with genetic linkage or homozygosity mapping studies can aid the identification of the remaining causal genes. As these are thought to be mutated in <1% of the cases, validation through functional modeling in, for example, zebrafish and/or replication through the genotyping of large patient cohorts is required. In the near future, whole genome NGS in combination with transcriptome NGS may reveal mutations that are currently hidden in the noncoding regions of the human genome. PMID:24939053

Siemiatkowska, Anna M; Collin, Rob W J; den Hollander, Anneke I; Cremers, Frans P M

2014-08-01

285

Mutation Spectrum of Six Genes in Chinese Phenylketonuria Patients Obtained through Next-Generation Sequencing  

PubMed Central

Background The identification of gene variants plays an important role in the diagnosis of genetic diseases. Methodology/Principal Findings To develop a rapid method for the diagnosis of phenylketonuria (PKU) and tetrahydrobiopterin (BH4) deficiency, we designed a multiplex, PCR-based primer panel to amplify all the exons and flanking regions (50 bp average) of six PKU-associated genes (PAH, PTS, GCH1, QDPR, PCBD1 and GFRP). The Ion Torrent Personal Genome Machine (PGM) System was used to detect mutations in all the exons of these six genes. We tested 93 DNA samples from blood specimens from 35 patients and their parents (32 families) and 26 healthy adults. Using strict bioinformatic criteria, this sequencing data provided, on average, 99.14% coverage of the 39 exons at more than 70-fold mean depth of coverage. We found 23 previously documented variants in the PAH gene and six novel mutations in the PAH and PTS genes. A detailed analysis of the mutation spectrum of these patients is described in this study. Conclusions/Significance These results were confirmed by Sanger sequencing. In conclusion, benchtop next-generation sequencing technology can be used to detect mutations in monogenic diseases and can detect both point mutations and indels with high sensitivity, fidelity and throughput at a lower cost than conventional methods in clinical applications. PMID:24705691

Cen, Zhong; Yu, Li; Lin, Lin; Hao, Jing; Yang, Zhigang; Peng, Jiabao; Cui, Shujian; Huang, Jian

2014-01-01

286

Mutations that alter the timing and pattern of cubitus interruptus gene expression in Drosophila melanogaster  

SciTech Connect

The cubitus interruptus (ci) gene is a member of the Drosophila segment polarity gene family and encodes a protein with a zinc finger domain homologous to the vertebrate Gli genes and the nematode tra-1 gene. Three classes of existing mutations in the ci locus alter the regulation of ci expression and can be used to examine ci function during development. The first class of ci mutations causes interruptions in wing veins four and five due to inappropriate expression of the ci product in the posterior compartment of imaginal discs. The second class of mutations eliminates ci protein early in embryogenesis and causes the deletion of structures that are derived from the region including and adjacent to the engrailed expressing cells. The third class of mutations eliminates ci protein later in embryogenesis and blocks the formation of the ventral naked cuticle. The loss of ci expression at these two different stages in embryonic development correlates with the subsequent elimination of wingless expression. Adults heterozygous for the unique ci{sup Ce} mutation have deletions between wing veins three and four. A similar wing defect is present in animals mutant for the segment polarity gene fused that encodes a putative serine/threonine kinase. In ci{sup Ce}/+ and fused mutants, the deletions between wing veins three and four correlate with increased ci protein levels in the anterior compartment. Thus, proper regulation of both the ci mRNA and protein appears to be critical for normal Drosophila development. 47 refs., 9 figs., 1 tab.

Slusarski, D.C.; Motzny, C.K.; Holmgren, R. [Northwestern Univ., Evanston, IL (United States)

1995-01-01

287

GeneChip{sup {trademark}} screening assay for cystic fibrosis mutations  

SciTech Connect

GeneChip{sup {trademark}} assays are based on high density, carefully designed arrays of short oligonucleotide probes (13-16 bases) built directly on derivatized silica substrates. DNA target sequence analysis is achieved by hybridizing fluorescently labeled amplification products to these arrays. Fluorescent hybridization signals located within the probe array are translated into target sequence information using the known probe sequence at each array feature. The mutation screening assay for cystic fibrosis includes sets of oligonucleotide probes designed to detect numerous different mutations that have been described in 14 exons and one intron of the CFTR gene. Each mutation site is addressed by a sub-array of at least 40 probe sequences, half designed to detect the wild type gene sequence and half designed to detect the reported mutant sequence. Hybridization with homozygous mutant, homozygous wild type or heterozygous targets results in distinctive hybridization patterns within a sub-array, permitting specific discrimination of each mutation. The GeneChip probe arrays are very small (approximately 1 cm{sup 2}). There miniature size coupled with their high information content make GeneChip probe arrays a useful and practical means for providing CF mutation analysis in a clinical setting.

Cronn, M.T.; Miyada, C.G.; Fucini, R.V. [Affymetrix, Santa Clara, CA (United States)] [and others

1994-09-01

288

Identification of two poorly prognosed ovarian carcinoma subtypes associated with CHEK2 germ-line mutation and non-CHEK2 somatic mutation gene signatures.  

PubMed

High-grade serous ovarian cancer (HG-SOC), a major histologic type of epithelial ovarian cancer (EOC), is a poorly-characterized, heterogeneous and lethal disease where somatic mutations of TP53 are common and inherited loss-of-function mutations in BRCA1/2 predispose to cancer in 9.5-13% of EOC patients. However, the overall burden of disease due to either inherited or sporadic mutations is not known. We performed bioinformatics analyses of mutational and clinical data of 334 HG-SOC tumor samples from The Cancer Genome Atlas to identify novel tumor-driving mutations, survival-significant patient subgroups and tumor subtypes potentially driven by either hereditary or sporadic factors. We identified a sub-cluster of high-frequency mutations in 22 patients and 58 genes associated with DNA damage repair, apoptosis and cell cycle. Mutations of CHEK2, observed with the highest intensity, were associated with poor therapy response and overall survival (OS) of these patients (P = 8.00e-05), possibly due to detrimental effect of mutations at the nuclear localization signal. A 21-gene mutational prognostic signature significantly stratifies patients into relatively low or high-risk subgroups with 5-y OS of 37% or 6%, respectively (P = 7.31e-08). Further analysis of these genes and high-risk subgroup revealed 2 distinct classes of tumors characterized by either germline mutations of genes such as CHEK2, RPS6KA2 and MLL4, or somatic mutations of other genes in the signature. Our results could provide improvement in prediction and clinical management of HG-SOC, facilitate our understanding of this complex disease, guide the design of targeted therapeutics and improve screening efforts to identify women at high-risk of hereditary ovarian cancers distinct from those associated with BRCA1/2 mutations. PMID:24879340

Ow, Ghim Siong; Ivshina, Anna V; Fuentes, Gloria; Kuznetsov, Vladimir A

2014-07-15

289

A mutation in a dog gene opens new research into the defensin protein  

NSDL National Science Digital Library

Researchers who were trying to find the mutated gene that controls coat color in dogs now report that they found the gene, and have also discovered that it has an unexpected additional role. The gene also sends a signal to a member of a protein family that is responsible for defending the body against infection. The proteins are called defensins, because their job is to defend the body.

American Association for the Advancement of Science (AAAS;)

2007-10-18

290

Retinal dystrophies caused by mutations in the ABCA4 gene : an evaluation of the clinical spectrum  

Microsoft Academic Search

In the past seven years, the ABCA4 gene has emerged as the most prominent gene in inherited retinal disease. Pathogenic ABCA4 mutations are the cause of all cases of Stargardt disease, and a portion of the cases of autosomal recessive retinitis pigmentosa and cone-rod dystrophy. Moreover, specific heterozygous alterations in this gene have been associated with age-related macular degeneration, although

Bert Jeroen Klevering

2004-01-01

291

Effects of p51\\/p63 Missense Mutations on Transcriptional Activities of p53 Downstream Gene Promoters1  

Microsoft Academic Search

The p51\\/p63 gene is a homologue of p53, the product of which acts as a transcriptional activator by binding to p53-responsive elements in the promoter regions of several p53 downstream genes. Recently, we identi- fied four distinct mutations in the p51\\/p63 gene after screening >200 human tumors and cell lines. Because all of the detected p51\\/p63 mutations were missense mutations,

Shunsuke Kato; Akira Shimada; Motonobu Osada; Shuntaro Ikaw; Masuo Obinata; Akira Nakagawara; Ryunosuke Kanamaru; Chikashi Ishioka

1999-01-01

292

Mutational analysis of the VCP gene in Parkinson’s Disease  

PubMed Central

Mutations in the valosin-containing protein gene (VCP) have been identified in neurological disorders (IBMPFD and ALS) and are thought to play a role in the clearance of abnormally folded proteins. Parkinsonism has been noted in kindreds with VCP mutations. Based on this, we hypothesized that mutations in VCP may also contribute to idiopathic PD. We screened the coding region of the VCP gene in a large cohort of 768 late onset PD cases (average age at onset = 70 years), both sporadic and with positive family history. We identified a number of rare single nucleotide changes, including a variant previously described to be pathogenic, but no clear disease-causing variants. We conclude that mutations in VCP are not a common cause for idiopathic PD. PMID:21920633

Majounie, Elisa; Traynor, Bryan J.; Chiň, Adriano; Restagno, Gabriella; Mandrioli, Jessica; Benatar, Michael; Taylor, J. Paul; Singleton, Andrew B.

2011-01-01

293

A novel CHSY1 gene mutation underlies Temtamy preaxial brachydactyly syndrome in a Pakistani family.  

PubMed

Temtamy preaxial brachydactyly syndrome (TPBS) is an autosomal recessive rare disorder characterized by hyperphalangism of digits, facial dysmorphism, dental anomalies, sensorineural hearing loss, delayed motor and mental development, and growth retardation. Loss of function mutations have been recently reported in the CHSY1 gene to cause the TPBS. Here, we report a novel missense mutation (c.1897 G > A) in the CHSY1 gene in two TPBS patients from a consanguineous Pakistani family. The mutation predicted substitution of a highly conserved aspartate amino acid residue to asparagine at position 633 in the protein (D633N). Polyphen analysis supported the pathogenicity of D36N mutation. Our finding extends the body of recent evidence that supports the role of CHSY1 as a potential mediator of BMP signaling. PMID:24269551

Sher, Gulab; Naeem, Muhammad

2014-01-01

294

Mutations of the NOG gene in individuals with proximal symphalangism and multiple synostosis syndrome.  

PubMed

Proximal symphalangism is an autosomal-dominant disorder with ankylosis of the proximal interphalangeal joints, carpal and tarsal bone fusion, and conductive deafness. These symptoms are shared by another disorder of joint morphogenesis, multiple synostoses syndrome. Recently, it was reported that both disorders were caused by heterozygous mutations of the human noggin gene (NOG). To date, seven mutations of NOG have been identified from unrelated families affected with joint morphogenesis. To characterize the molecular lesions of proximal symphalangism, we performed analyses of NOG in three Japanese individuals with proximal symphalangism. We found three novel mutations: g.551G>A (C184Y) in a sporadic case of symphalangism, g.386T>A (L129X) in a familial case of symphalangism, and a g.58delC (frameshift) in a family with multiple synostosis syndrome. Characteristic genotype-phenotype correlations have not been recognized from the mutations in the NOG gene. PMID:11846737

Takahashi, T; Takahashi, I; Komatsu, M; Sawaishi, Y; Higashi, K; Nishimura, G; Saito, H; Takada, G

2001-12-01

295

A novel nonsense mutation of the KAL1 gene (p.Trp204*) in Kallmann syndrome  

PubMed Central

Objective To describe a novel KAL1 mutation in patients affected by Kallmann syndrome. Setting Endocrinology Clinic of the Joăo de Barros Barreto University Hospital – Federal University of Pará, Brazil. Methods Clinical examination, hormone assays and sequencing of exons 5, 6 and 9 of the KAL1 gene in four Brazilian brothers with Kallmann syndrome. Results Detected a novel KAL1 mutation, c.612G.A/p.Trp204*, in four hemizygous brothers with Kallmann syndrome, and five heterozygous female family members. Conclusion The novel p.Trp204* mutation of the KAL1 gene results in the production of a truncated anosmin-1 enzyme in patients with Kallmann syndrome. This finding broadens the spectrum of pathogenic mutations for this disease. PMID:25328414

El Husny, Antonette Souto; Raiol-Moraes, Milene; Fernandes-Caldato, Milena Coelho; Ribeiro-dos-Santos, Andrea

2014-01-01

296

Ribosomal Protein S24 Gene Is Mutated in Diamond-Blackfan Anemia  

PubMed Central

Diamond-Blackfan anemia (DBA) is a rare congenital red-cell aplasia characterized by anemia, bone-marrow erythroblastopenia, and congenital anomalies and is associated with heterozygous mutations in the ribosomal protein (RP) S19 gene (RPS19) in ?25% of probands. We report identification of de novo nonsense and splice-site mutations in another RP, RPS24 (encoded by RPS24 [10q22-q23]) in ?2% of RPS19 mutation–negative probands. This finding strongly suggests that DBA is a disorder of ribosome synthesis and that mutations in other RP or associated genes that lead to disrupted ribosomal biogenesis and/or function may also cause DBA. PMID:17186470

Gazda, Hanna T.; Grabowska, Agnieszka; Merida-Long, Lilia B.; Latawiec, Elzbieta; Schneider, Hal E.; Lipton, Jeffrey M.; Vlachos, Adrianna; Atsidaftos, Eva; Ball, Sarah E.; Orfali, Karen A.; Niewiadomska, Edyta; Da Costa, Lydie; Tchernia, Gil; Niemeyer, Charlotte; Meerpohl, Joerg J.; Stahl, Joachim; Schratt, Gerhard; Glader, Bertil; Backer, Karen; Wong, Carolyn; Nathan, David G.; Beggs, Alan H.; Sieff, Colin A.

2006-01-01

297

The interplay of mutations and electronic properties in disease-related genes  

NASA Astrophysics Data System (ADS)

Electronic properties of DNA are believed to play a crucial role in many phenomena in living organisms, for example the location of DNA lesions by base excision repair (BER) glycosylases and the regulation of tumor-suppressor genes such as p53 by detection of oxidative damage. However, the reproducible measurement and modelling of charge migration through DNA molecules at the nanometer scale remains a challenging and controversial subject even after more than a decade of intense efforts. Here we show, by analysing 162 disease-related genes from a variety of medical databases with a total of almost 20,000 observed pathogenic mutations, a significant difference in the electronic properties of the population of observed mutations compared to the set of all possible mutations. Our results have implications for the role of the electronic properties of DNA in cellular processes, and hint at the possibility of prediction, early diagnosis and detection of mutation hotspots.

Shih, Chi-Tin; Wells, Stephen A.; Hsu, Ching-Ling; Cheng, Yun-Yin; Römer, Rudolf A.

2012-02-01

298

The interplay of mutations and electronic properties in disease-related genes  

E-print Network

Electronic properties of DNA are believed to play a crucial role in many phenomena in living organisms, for example the location of DNA lesions by base excision repair (BER) glycosylases and the regulation of tumor-suppressor genes such as p53 by detection of oxidative damage. However, the reproducible measurement and modelling of charge migration through DNA molecules at the nanometer scale remains a challenging and controversial subject even after more than a decade of intense efforts. Here we show, by analysing 162 disease-related genes from a variety of medical databases with a total of almost 20,000 observed pathogenic mutations, a significant difference in the electronic properties of the population of observed mutations compared to the set of all possible mutations. Our results have implications for the role of the electronic properties of DNA in cellular processes, and hint at the possibility of prediction, early diagnosis and detection of mutation hotspots.

Shih, Chi-Tin; Hsu, Ching-Ling; Cheng, Yun-Yin; Römer, Rudolf A

2011-01-01

299

[Multiplex minisequencing applied in detection of human functional CYP21 gene mutations].  

PubMed

We analyzed seven most common mutations within the CYP21B gene, responsible for congenital adrenal hyperplasia (CAH), using the minisequencing method. Functional CYP21B gene sequences were amplified with the pair of specific primers that pevented amplification of pseudogene CYP21P or pseudogene CYP21P/active CYP21 hybrids. Multiplex minisequencing (SNaPShot PCR) assay was performed with fluorescent dideoxynucleotides ([F]ddNTPs) and originally designed primers, claiming seven most common mutation sites responsible for the CAH symptoms. Using the method we detected five novel substitutions of unknown effect on the CAH course in five out of seven analyzed mutation sites. Compared to classic SNPs analyzing methods, especially single SNP detection, multiplex minisequencing is the same highly specific and sensitive but much faster one. The method is recommended for any population screened for known mutations. PMID:18042312

Tokarska, Ma?gorzata; Barg, Ewa; Wikiera, Beata; Dobosz, Tadeusz; Zo?edziewska, Magdalena; Brzezi?ska, Katarzyna; Jonkisz, Anna; Kosowska, Barbara

2007-01-01

300

The stop mutation R553X in the CFTR gene results in exon skipping  

SciTech Connect

Stop or nonsense mutations are known to disrupt gene function in a number of different ways. The authors have studied the effects of the stop mutation R553X in exon 11 of the CFTR gene by analyzing mRNA extracted from nasal epithelial cells harvested from patients with cystic fibrosis. Four patients who were compound heterozygotes for the R553X mutation were studied. Ten non-CF control subjects were also studied. In all four patients, full-length CFTR mRNA was identified, but only a very small proportion of this was derived from the R553X allele. A smaller transcript, lacking exon 11, was also seen in the R553X patients but not in the controls. Most of this transcript was derived from the R553X allele. These results suggest that the R553X mutation results in skipping of the exon in which it is located. 14 refs., 3 figs.

Hull, J.; Shackleton, S.; Harris, A. (Institute of Molecular Medicine, Oxford (United Kingdom))

1994-01-15

301

Identification of a germ-line mutation in the p53 gene in a patient with an intracranial ependymoma  

SciTech Connect

The authors detected a germ-line mutation of the p53 gene in a patient with a malignant ependymoma of the posterior fossa. This mutation, which was found at codon 242, resulted in an amino acid substitution in a highly conserved site of exon 7 of the p53 gene; the same mutation was found in both the germ-line and tumor tissue. This is the most common region of previously described somatic p53 mutations in tumor specimens and of the germ-line p53 mutations in patients with the Li-Fraumeni cancer syndrome. Evaluation of the patient's family revealed several direct maternal and paternal relatives who had died at a young age from different types of cancer. The association of a germ-line p53 mutation with an intracranial malignancy and a strong family history of cancer suggests that p53 gene mutations predispose a person to malignancy and, like retinoblastoma mutations, may be inherited.

Metzger, A.K.; Duyk, G.; Daneshvar, L.; Edwards, M.S.B.; Cogen, P.H. (Univ. of California, San Francisco (United States)); Sheffield, V.C. (Univ. of Iowa, Iowa City (United States))

1991-09-01

302

2004 Annual Meeting - Genes, Mutations and Disease: The Environmental Connection  

SciTech Connect

The Meeting consisted of 9 Symposia, 4 Keynote Lectures, 3 Platform Sessions and 4 Poster Sessions. In addition there were Breakfast Meetings for Special Interest Groups designed to inform attendees about the latest advances in environmental mutagenesis research. Several of the topics to be covered at this broad meeting will be of interest to the Department of Energy, Office of Science. The relevance of this meeting to the DOE derives from the fact that low dose radiation may represent one of the most significant sources of human mutations that are attributable to the environment. The EMS membership, and those who attended the EMS Annual Meeting were interested in both chemical and radiation induced biological effects, such as cell death, mutation, teratogenesis, carcinogenesis and aging. These topics thate were presented at the 2004 EMS Annual meeting that were of clear interest to DOE include: human variation in cancer susceptibility, unusual mechanisms of mutation, germ and stem cell mutagenesis, recombination and the maintenance of genomic stability, multiple roles for DNA mismatch repair, DNA helicases, mutation, cancer and aging, Genome-wide transcriptional responses to environmental change, Telomeres and genomic stability: when ends don?t meet, systems biology approach to cell phenotypic decision processes, and the surprising biology of short RNAs. Poster and platform sessions addressed topics related to environmental mutagen exposure, DNA repair, mechanisms of mutagenesis, epidemiology, genomic and proteomics and bioinformatics. These sessions were designed to give student, postdocs and more junior scientists a chance to present their workl.

Leona D. Samson, Ph.D.

2004-08-23

303

NF1 gene mutations and loss of heterozygosity in constitutional and tumor tissues  

SciTech Connect

Neurofibromatosis type 1 (NF1) is a common autosomal dominant disorder characterized by neurofibromas, cafe-au-lait spots, and Lisch nodules. NF1 patients are at increased risk for certain types of malignancies such as brain tumors, sarcomas, and leukemias. NF1 is caused by disrupting mutations of the NF1 gene (17q11.2), with half of cases caused by new mutation. Less than 50 constitutional mutations have thus far been reported, with only one recurring. We are pursuing mutation analysis in germline and tumor tissues from NF1 patients (and non-NF1 tumors) by heteroduplex analysis (HDA) and SSCP, simultaneously testing for large deletions by Southern blots and loss-of-heterozygosity (LOH) studies. HDA has so far identified 18 exon mutations/variants in 110 unrelated patients (3/4 of exons tested), including splice mutations, insertions, deletions, and point changes. RT-PCR analysis in our four clearly-inactivating mutations showed that all four mutant alleles are expressed. This suggests that aberrant forms of the protein (neurofibromin) may be produced, which may shed light on yet-unknown functions. In a study of 10 new-mutations parent-child sets, one very mildly-affected patient showed LOH of an entire NF1 allele, in contrast to other patients reported who have similar deletions and a severe phenotype. This mutation is materally-derived, which is unusual given that over 90% of new mutations are thought to be of paternal origin. Preliminary LOH studies in one new-mutation patient indicate large independent somatic deletions involving the maternal NF1 allele in several neurofibromas, implicating the two-hit tumor suppressor system in neurofibroma formation. no other losses on chromosome 17 are evident, and blood and tumor karyotypes are normal. We are attempting to identify the germline mutation, confirm the somatic findings, and find the boundaries of the deletions.

Abernathy, C.R.; Colman, S.D.; Ho, V.T. [Univ. of Florida, Gainesville, FL (United States)] [and others

1994-09-01

304

Four new mutations in the BCHE gene of human butyrylcholinesterase in a Brazilian blood donor sample.  

PubMed

The genetic variation of human butyrylcholinesterase has been associated with height, body mass index, Alzheimer's disease, and response to xenobiotic agents. The present study reports four new mutations, found in the exon 2 of the BCHE gene, in a sample from 3001 Brazilian blood donors. The three nonsynonymous mutations and one synonymous mutation detected are: 223G-->C, G75R; 270A-->C, E90 D; 297T-->G, I99 M; 486T-->C, A162 A, respectively. All these variants are rare: 0.093+/-0.093% for the missense mutations and 0.137+/-0.137% for the synonymous mutation. A table with the 58 non-usual variants of butyrylcholinesterase is also presented. PMID:15781196

Souza, Ricardo L R; Mikami, Liya R; Maegawa, Rodrigo O B; Chautard-Freire-Maia, Eleidi A

2005-04-01

305

Familial interstitial pneumonia in an adolescent boy with surfactant protein C gene (Y104H) mutation.  

PubMed

Recent studies have suggested that some cases of familial interstitial pneumonia are associated with mutations in the gene encoding surfactant protein C (SFTPC). We report here a case of familial interstitial pneumonia in an adolescent boy whose paternal grandfather and father suffered from idiopathic interstitial pneumonia (IIP). The patient was asymptomatic but showed an abnormal shadow in the chest at his medical check-up. The surgical biopsy of the patient revealed non-specific interstitial pneumonia and showed pathological findings similar to those in his father's autopsy. Genomic DNA from blood leucocytes of the patient was sequenced for the Thy104His (Y104H) SFTPC mutation. Based on these results, he was diagnosed with SFTPC mutation-associated familial interstitial pneumonia. There has been no clinical, physiologic and radiologic progression for 4 years since the diagnosis. The relation between clinical manifestation and the mutation site of the patient may broaden the spectrum of SFTPC mutation-associated interstitial pneumonia. PMID:24003539

Kuse, N; Abe, S; Hayashi, H; Kamio, K; Saito, Y; Azuma, A; Kudoh, S; Kunugi, S; Fukuda, Y; Setoguchi, Y; Gemma, A

2013-03-01

306

Frequent NF2 gene transcript mutations in sporadic meningiomas and vestibular schwannomas  

SciTech Connect

The gene for the hereditary disorder neurofibromatosis type 2 (NF2), which predisposes for benign CNS tumors such as vestibular schwannomas and meningiomas, has been assigned to chromosome 22 and recently has been isolated. Mutations in the NF2 gene were found in both sporadic meningiomas and vestibular schwannomas. However, so far only 6 of the 16 exons of the gene have been analyzed. In order to extend the analysis of an involvement of the NF2 gene in the sporadic counterparts of these NF2-related tumors, the authors have used reverse transcriptase-PCR amplification followed by SSCP and DNA sequence analysis to screen for mutations in the coding region of the NF2 gene. Analysis of the NF2 gene transcript in 53 unrelated patients with meningiomas and vestibular schwannomas revealed mutations in 32% of the sporadic meningiomas (n = 44), in 50% of the sporadic vestibular schwannomas (n = 4), in 100% of the tumors found in NF2 patients (n = 2), and in one of three tumors from multiple-meningioma patients. Of the 18 tumors in which a mutation in the NF2 gene transcript was observed and the copy number of chromosome 22 could be established, 14 also showed loss of (parts of) chromosome 22. This suggests that in sporadic meningiomas and NF2-associated tumors the NF2 gene functions as a recessive tumor-suppressor gene. The mutations detected resulted mostly in frameshifts, predicting truncations starting within the N-terminal half of the putative protein. 23 refs., 2 figs. 3 tabs.

Deprez, R.H.L.; Groen, N.A.; Zwarthoff, E.C.; Hagemeijer, A.; Van Drunen, E.; Bootsma, D.; Koper, J.W.; Avezaat, C.J.J. (Erasmus Univ., Rotterdam (Netherlands)); Bianchi, A.B.; Seizinger, B.R. (Bristol Myers-Squibb Pharmaceutical Research Institute, Princeton, NY (United States))

1994-06-01

307

Mutational Screening of LCA Genes Emphasizing RPE65 in South Indian Cohort of Patients  

PubMed Central

Background Leber congenital amaurosis (LCA) is the most severe form of inherited retinal visual impairment in children. So far, mutations in more than 20 genes have been known to cause LCA and among them, RPE65 is a suitable candidate for gene therapy. The mutational screenings of RPE65 and other LCA genes are requisite in support of emerging gene specific therapy for LCA. Therefore, we have carried out a comprehensive LCA genes screening using a combined approach of direct sequencing and DNA microarray based Asper chip analysis. Methodology/Principal Findings Thirty clinically diagnosed index LCA cases from Southern India were screened for coding and flanking intronic regions of RPE65 through direct sequencing. Among thirty, 25 cases excluded from RPE65 mutations were subjected to Asper chip analysis, testing 784 known pathogenic variations in 15 major LCA genes. In RPE65 screening, four different pathogenic variations including two novel (c.361insT & c.939T>A) and two known (c.394G>A & c.361delT) mutations were identified in five index cases. In the chip analysis, seven known pathogenic mutations were identified in six index cases, involving genes GUCY2D, RPGRIP1, AIPL1, CRX and IQCB1. Overall, 11 out of 30 LCA cases (36.6%) revealed pathogenic variations with the involvement of RPE65 (16.6%), GUCY2D (10%), RPGRIP1 (3.3%), AIPL1 (3.3%) and CRX & IQCB1 (3.3%). Conclusions/Significance Our study suggests that such combined screening approach is productive and cost-effective for mutation detection and can be applied in Indian LCA cohort for molecular diagnosis and genetic counselling. PMID:24066033

Verma, Anshuman; Perumalsamy, Vijayalakshmi; Shetty, Shashikant; Kulm, Maigi; Sundaresan, Periasamy

2013-01-01

308

[Recent advances in the research on mechanisms underlying podocyte-specific gene mutation-related steroid-resistant nephrotic syndrome].  

PubMed

Steroid-resistant nephrotic syndrome poses a significant clinical challenge. Its pathogenesis has not been fully elucidated. In recent years, numerous studies have shown that podocyte-specific gene mutations may play important roles in the development of steroid-resistant nephrotic syndrome. Among the identified genes mutated in podocytes include NPHS2, NPHS1, WT1, TRPC6, MDR1, PLCE1, LMX1B, and LAMB2. This review aims to summarize the characteristics of these mutated genes in podocytes. The putative role for these podocyte-specific mutated genes in the pathogenesis, diagnosis, treatment and prognosis of steroid-resistant nephrotic syndrome is also discussed. PMID:24461191

Zhang, Li-Wen; Wang, Le-Ping

2014-01-01

309

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

SciTech Connect

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

Braun, A.; Ambach, H.; Kammerer, S.; Rolinski, B.; Roscher, A.; Rabl, W. [Univ. of Munich (Germany); Stoeckler, S. [Univ. of Graz (Germany); Gaertner, J. [Univ. of Duesseldorf (Germany); Zierz, S. [Univ. of Bonn (Germany)

1995-04-01

310

The human LMX1B gene: transcription unit, promoter, and pathogenic mutations  

Microsoft Academic Search

LMX1B is a LIM-homeodomain transcription factor required for the normal development of dorsal limb structures, the glomerular basement membrane, the anterior segment of the eye, and dopaminergic and serotonergic neurons. Heterozygous loss-of-function mutations in LMX1B cause nail patella syndrome (NPS). To further understand LMX1B gene regulation and to identify pathogenic mutations within the coding region, a detailed analysis of LMX1B

Jennifer A. Dunston; Jeanette D. Hamlington; Jayshree Zaveri; Elizabeth Sweeney; Julie Sibbring; Catherine Tran; Maria Malbroux; John P. O'Neill; Roger Mountford; Iain McIntosh

2004-01-01

311

Mfrp, a gene encoding a frizzled related protein, is mutated in the mouse retinal degeneration 6  

Microsoft Academic Search

The autosomal recessive mouse mutation retinal degeneration 6 (rd6 ) causes small, white retinal spots and progressive photoreceptor degeneration similar to that observed in human flecked retinal diseases. Using a positional cloning approach, we determined that rd6 mice carry a splice donor mutation in the mouse homolog of the human membrane-type frizzled-related protein (Mfrp) gene that results in the skipping

Shuhei Kameya; Norman L. Hawes; Bo Chang; John R. Heckenlively; J urgen K. Naggert; Patsy M. Nishina

2002-01-01

312

Eight previously unidentified mutations found in the OA1 ocular albinism gene  

PubMed Central

Background Ocular albinism type 1 (OA1) is an X-linked ocular disorder characterized by a severe reduction in visual acuity, nystagmus, hypopigmentation of the retinal pigmented epithelium, foveal hypoplasia, macromelanosomes in pigmented skin and eye cells, and misrouting of the optical tracts. This disease is primarily caused by mutations in the OA1 gene. Methods The ophthalmologic phenotype of the patients and their family members was characterized. We screened for mutations in the OA1 gene by direct sequencing of the nine PCR-amplified exons, and for genomic deletions by PCR-amplification of large DNA fragments. Results We sequenced the nine exons of the OA1 gene in 72 individuals and found ten different mutations in seven unrelated families and three sporadic cases. The ten mutations include an amino acid substitution and a premature stop codon previously reported by our team, and eight previously unidentified mutations: three amino acid substitutions, a duplication, a deletion, an insertion and two splice-site mutations. The use of a novel Taq polymerase enabled us to amplify large genomic fragments covering the OA1 gene. and to detect very likely six distinct large deletions. Furthermore, we were able to confirm that there was no deletion in twenty one patients where no mutation had been found. Conclusion The identified mutations affect highly conserved amino acids, cause frameshifts or alternative splicing, thus affecting folding of the OA1 G protein coupled receptor, interactions of OA1 with its G protein and/or binding with its ligand. PMID:16646960

Mayeur, Helene; Roche, Olivier; Vetu, Christelle; Jaliffa, Carolina; Marchant, Dominique; Dollfus, Helene; Bonneau, Dominique; Munier, Francis L; Schorderet, Daniel F; Levin, Alex V; Heon, Elise; Sutherland, Joanne; Lacombe, Didier; Said, Edith; Mezer, Eedy; Kaplan, Josseline; Dufier, Jean-Louis; Marsac, Cecile; Menasche, Maurice; Abitbol, Marc

2006-01-01

313

Frontotemporal dementia and parkinsonism with the P301S tau gene mutation in a Jewish family  

Microsoft Academic Search

.   Background: Frontotemporal dementia with parkinsonism linked to chromosome 17q21–22 (FTDP-17) is an autosomal dominant tauopathy manifested\\u000a by a variable combination of personality changes, cognitive decline and hypokinetic-rigid movement disorder. Significant clinical\\u000a and pathological heterogeneity of FTDP-17 is related in part to more than 20 different pathogenic mutations identified in\\u000a the tau gene. Among others, the P301S mutation has been

Alexander Lossos; Avinoam Reches; Aya Gal; Joel P. Newman; Dov Soffer; John Moshe Gomori; Moshe Boher; Dana Ekstein; Iftah Biran; Zeev Meiner; Oded Abramsky; Hanna Rosenmann

2003-01-01

314

HFE gene mutations in alcoholic and virus-related cirrhotic patients with hepatocellular carcinoma  

Microsoft Academic Search

OBJECTIVE:The increased risk of developing hepatocellular carcinoma in hereditary hemochromatosis has been associated with cirrhosis and hepatic iron overload. The aim of this study was to investigate the association between HFE gene mutations (C282Y, H63D) and hepatocellular carcinoma in patients with alcoholic and virus-related cirrhosis.METHODS:Serum markers of iron status and HFE mutations were determined in 179 patients with alcoholic cirrhosis

Eugenia Lauret; Manuel Rodríguez; Segundo González; Antonio Linares; Antonio López-Vázquez; Jesú Martínez-Borra; Luis Rodrigo; Carlos López-Larrea

2002-01-01

315

A large-scale gene-trap screen for insertional mutations in developmentally regulated genes in mice  

SciTech Connect

We have used a gene-trap vector and mouse embryonic stem (ES) cells to screen for insertional mutations in genes developmentally regulated at 8.5 days of embryogenesis (dpc). From 38,730 cell lines with vector insertions, 393 clonal integrations had disrupted active transcription units, as assayed by {beta}-galactosidase reporter gene expression. From these lines, 290 clones were recovered and injected into blastocysts to assay for reporter gene expression in 8.5-dpc chimeric mouse embryos. Of these, 279 clones provided a sufficient number of chimeric embryos for analysis. Thirty-six (13%) showed restricted patterns of reporter-gene expression, 88 (32%) showed widespread expression and 155 (55%) failed to show detectable levels of expression. Further analysis showed that approximately one-third of the clones that did not express detectable levels of the reporter gene at 8.5 dpc displayed reporter gene activity at 12.5 dpc. Thus, a large proportion of the genes that are expressed in ES cells are either temporally or spatially regulated during embryogenesis. These results indicate that gene-trap mutageneses in embryonic stem cells provide an effective approach for isolating mutations in a large number of developmentally regulated genes. 40 refs., 5 figs., 4 tabs.

Wurst, W.; Rossant, J.; Prideaux, V.; Kownacka, M.; Hill, D.P.; Guillemot, F.; Auerbach, A.; Cado, D.; Ang, S.L. [Mount Sinai Hospital, Toronto, Ontario (Canada); and others

1995-02-01

316

Novel mutations in the HSN2 gene causing hereditary sensory and autonomic neuropathy type II.  

PubMed

Hereditary sensory and autonomic neuropathy type II (HSAN-II) is caused by recessive mutations in the HSN2 gene assigned to chromosome 12p13.33. The authors report three unrelated HSAN-II families with homozygous or compound heterozygous mutations resulting in the truncation of the HSN2 protein. Genotype-phenotype correlations indicated that HSN2 mutations are associated with an early childhood onset of a predominantly sensory neuropathy, complicated by acromutilations in both upper and lower limbs. PMID:16534117

Coen, K; Pareyson, D; Auer-Grumbach, M; Buyse, G; Goemans, N; Claeys, K G; Verpoorten, N; Laurŕ, M; Scaioli, V; Salmhofer, W; Pieber, T R; Nelis, E; De Jonghe, P; Timmerman, V

2006-03-14

317

Gene encoding a deubiquitinating enzyme is mutated in artesunate- and chloroquine-resistant rodent malaria parasites.  

PubMed

Artemisinin- and artesunate-resistant Plasmodium chabaudi mutants, AS-ART and AS-ATN, were previously selected from chloroquine-resistant clones AS-30CQ and AS-15CQ respectively. Now, a genetic cross between AS-ART and the artemisinin-sensitive clone AJ has been analysed by Linkage Group Selection. A genetic linkage group on chromosome 2 was selected under artemisinin treatment. Within this locus, we identified two different mutations in a gene encoding a deubiquitinating enzyme. A distinct mutation occurred in each of the clones AS-30CQ and AS-ATN, relative to their respective progenitors in the AS lineage. The mutations occurred independently in different clones under drug selection with chloroquine (high concentration) or artesunate. Each mutation maps to a critical residue in a homologous human deubiquitinating protein structure. Although one mutation could theoretically account for the resistance of AS-ATN to artemisinin derivates, the other cannot account solely for the resistance of AS-ART, relative to the responses of its sensitive progenitor AS-30CQ. Two lines of Plasmodium falciparum with decreased susceptibility to artemisinin were also selected. Their drug-response phenotype was not genetically stable. No mutations in the UBP-1 gene encoding the P. falciparum orthologue of the deubiquitinating enzyme were observed. The possible significance of these mutations in parasite responses to chloroquine or artemisinin is discussed. PMID:17581118

Hunt, Paul; Afonso, Ana; Creasey, Alison; Culleton, Richard; Sidhu, Amar Bir Singh; Logan, John; Valderramos, Stephanie G; McNae, Iain; Cheesman, Sandra; do Rosario, Virgilio; Carter, Richard; Fidock, David A; Cravo, Pedro

2007-07-01

318

Somatic mutations of the APC, KRAS, and TP53 genes in nonpolypoid colorectal adenomas.  

PubMed

Colorectal adenomas are macroscopically visible morphological changes of the mucosa that can develop focal carcinoma in the absence of surgical intervention. The successive molecular changes proposed to occur at different stages in the adenoma-carcinoma sequence were primarily based on DNA studies of exophytic, polypoid-type adenomas. Not all colorectal lesions, however, display an exophytic phenotype and a presumed distinct colorectal neoplasm, the nonpolypoid adenoma, was subsequently described as a precursor of colorectal cancer. The low incidence of KRAS mutations in nonpolypoid colorectal adenomas reported previously suggested a different genetic basis for the transformation process in these lesions. We have pursued the identification of genetic changes in benign sporadic nonpolypoid colorectal adenomas in a selected Swedish patient group with no family history of colorectal cancer. Mutation screening of the adenomatous polyposis coli (APC), KRAS, and TP53 genes was conducted using the protein truncation test, heteroduplex-single-strand conformation polymorphism analysis, and denaturing gradient gel electrophoresis on PCR-amplified fragments. Fourteen mutations in the APC gene were characterized in 10/20 samples. Mutations in the KRAS and TP53 genes were identified in 3/57 and 4/51 adenomas, respectively. The mutation frequencies and distribution of mutations in APC correlate with published data on exophytic adenomas. The low mutation frequency of the TP53 gene is consistent with the benign nature of the research material. KRAS activation (an early event in polypoid colorectal adenomas) apparently does not play a significant role in nonpolypoid adenoma development but may result in the development of a polypoid configuration. Genes Chromosomes Cancer 27:202-208, 2000. PMID:10612810

van Wyk, R; Slezak, P; Hayes, V M; Buys, C H; Kotze, M J; de Jong, G; Rubio, C; Dolk, A; Jaramillo, E; Koizumi, K; Grobbelaar, J J

2000-02-01

319

Chromosome alterations and E-cadherin gene mutations in human lobular breast cancer  

PubMed Central

We have studied a set of 40 human lobular breast cancers for loss of heterozygosity (LOH) at various chromosome locations and for mutations in the coding region plus flanking intron sequences of the E-cadherin gene. We found a high frequency of LOH (100%, 31/31) at 16q21–q22.1. A significantly higher level of LOH was detected in ductal breast tumours at chromosome arms 1p, 3p, 9p, 11q, 13q and 18q compared to lobular breast tumours. Furthermore, we found a significant association between LOH at 16 q containing the E-cadherin locus and lobular histological type. Six different somatic mutations were detected in the E-cadherin gene, of which three were insertions, two deletions and one splice site mutation. Mutations were found in combination with LOH of the wild type E-cadherin locus and loss of or reduced E-cadherin expression detected by immunohistochemistry. The mutations described here have not previously been reported. We compared LOH at different chromosome regions with E-cadherin gene mutations and found a significant association between LOH at 13 q and E-cadherin gene mutations. A significant association was also detected between LOH at 13q and LOH at 7q and 11q. Moreover, we found a significant association between LOH at 3 p and high S phase, LOH at 9p and low ER and PgR content, LOH at 17p and aneuploidy. We conclude that LOH at 16q is the most frequent chromosome alteration and E-cadherin is a typical tumour suppressor gene in lobular breast cancer. Š 1999 Cancer Research Campaign PMID:10584868

Huiping, C; Sigurgeirsdottir, J R; Jonasson, J G; Eiriksdottir, G; Johannsdottir, J T; Egilsson, V; Ingvarsson, S

1999-01-01

320

Missense mutation of the cholecystokinin B receptor gene: Lack of association with panic disorder  

SciTech Connect

Cholecystokinin tetrapeptide (CCK{sub 4}) is known to induce panic attacks in patients with panic disorder at a lower dose than in normal controls. Therefore, the cholecystokinin B (CCK{sub B}) receptor gene is a candidate gene for panic disorder. We searched for mutations in the CCK{sub B} gene in 22 probands of panic disorder pedigrees, using single-strand conformation polymorphism (SSCP) analysis. Two polymorphisms were detected. A polymorphism in an intron (2491 C{yields}A) between exons 4 and 5 was observed in 10 of 22 probands. A missense mutation in the extracellular loop of exon 2 (1550 G{yields}A, Val{sup 125}{yields}Ile) was found in only one proband. This mutation was also examined in additional 34 unrelated patients with panic disorder and 112 controls. The prevalence rate of this mutation was 8.8% in patients with panic disorder (3/34) and 4.4% in controls (5/112). The mutation did not segregate with panic disorder in two families where this could be tested. These results suggest no pathophysiological significance of this mutation in panic disorder. 21 refs., 4 figs., 1 tab.

Kato, Tadafumi; Wang, Zhe Wu; Crowe, R.R. [Univ. of Iowa College of Medicine, Iowa City, IA (United States)] [Univ. of Iowa College of Medicine, Iowa City, IA (United States); Zoega, T. [National Univ. Hospital, Reykjavik (Iceland)] [National Univ. Hospital, Reykjavik (Iceland)

1996-07-26

321

Partial ABCC8 gene deletion mutations causing diazoxide-unresponsive hyperinsulinaemic hypoglycaemia.  

PubMed

Inactivating mutations in the pancreatic beta cell ATP-sensitive potassium (K(ATP) ) channel genes are identified by sequencing in approximately 80% of patients with diazoxide-unresponsive hyperinsulinaemic hypoglycaemia (HH). Genetic testing is clinically important as the mode of inheritance of a K(ATP) channel mutation(s) provides information on the histological subtype. For example in patients with a single paternally inherited mutation a focal lesion is possible and once confirmed, the patient can undergo a curative lesionectomy. By contrast, recessive inheritance indicates diffuse disease, which requires near-total pancreatectomy, if medical management is unsuccessful. We investigated ABCC8 and KCNJ11 gene dosage in 29 probands from a cohort of 125 with diazoxide-unresponsive HH where sequencing did not provide a genetic diagnosis. We identified heterozygous partial ABCC8 deletions in four probands. In two cases with focal pancreatic disease, a paternally inherited deletion was found. Two other probands with diffuse pancreatic disease were compound heterozygotes for a deletion and a recessively acting mutation that had been identified by sequencing. Family member studies confirmed compound heterozygosity for the deletion and the missense mutation in two affected siblings of one proband. Heterozygous deletions of the ABCC8 gene are a rare, but important cause of diazoxide-unresponsive HH. Dosage analysis should be undertaken in all patients when sequencing analysis does not confirm the genetic diagnosis as confirmation of the mode of inheritance can guide clinical management and will provide important information regarding recurrence risk. PMID:21978130

Flanagan, Se; Damhuis, A; Banerjee, I; Rokicki, D; Jefferies, C; Kapoor, Rr; Hussain, K; Ellard, S

2012-05-01

322

CEP290, a gene with many faces: mutation overview and presentation of CEP290base.  

PubMed

Ciliopathies are an emerging group of disorders, caused by mutations in ciliary genes. One of the most intriguing disease genes associated with ciliopathies is CEP290, in which mutations cause a wide variety of distinct phenotypes, ranging from isolated blindness over Senior-Loken syndrome (SLS), nephronophthisis (NPHP), Joubert syndrome (related disorders) (JS[RD]), Bardet-Biedl syndrome (BBS), to the lethal Meckel-Grüber syndrome (MKS). Despite the identification of over 100 unique CEP290 mutations, no clear genotype-phenotype correlations could yet be established, and consequently the predictive power of a CEP290-related genotype remains limited. One of the challenges is a better understanding of second-site modifiers. In this respect, there is a growing interest in the potential modifying effects of variations in genes encoding other members of the ciliary proteome that interact with CEP290. Here, we provide an overview of all CEP290 mutations identified so far, with their associated phenotypes. To this end, we developed CEP290base, a locus-specific mutation database that links mutations with patients and their phenotypes (medgen.ugent.be/cep290base). PMID:20690115

Coppieters, Frauke; Lefever, Steve; Leroy, Bart P; De Baere, Elfride

2010-10-01

323

Analysis of mutations in the entire coding sequence of the factor VIII gene  

SciTech Connect

Hemophilia A is a common X-linked recessive disorder of bleeding caused by deleterious mutations in the gene for clotting factor VIII. The large size of the factor VIII gene, the high frequency of de novo mutations and its tissue-specific expression complicate the detection of mutations. We have used a combination of RT-PCR of ectopic factor VIII transcripts and genomic DNA-PCRs to amplify the entire essential sequence of the factor VIII gene. This is followed by chemical mismatch cleavage analysis and direct sequencing in order to facilitate a comprehensive search for mutations. We describe the characterization of nine potentially pathogenic mutations, six of which are novel. In each case, a correlation of the genotype with the observed phenotype is presented. In order to evaluate the pathogenicity of the five missense mutations detected, we have analyzed them for evolutionary sequence conservation and for their involvement of sequence motifs catalogued in the PROSITE database of protein sites and patterns.

Bidichadani, S.I.; Lanyon, W.G.; Connor, J.M. [Glascow Univ. (United Kingdom)] [and others

1994-09-01

324

Mutation analysis of 24 known cancer genes in the NCI-60 cell line set  

PubMed Central

The panel of 60 human cancer cell lines (the NCI-60) assembled by the National Cancer Institute for anticancer drug discovery is a widely used resource. The NCI-60 has been characterized pharmacologically and at the molecular level more extensively than any other set of cell lines. However, no systematic mutation analysis of genes causally implicated in oncogenesis has been reported. This study reports the sequence analysis of 24 known cancer genes in the NCI-60 and an assessment of 4 of the 24 genes for homozygous deletions. One hundred thirty-seven oncogenic mutations were identified in 14 (APC, BRAF, CDKN2, CTNNB1, HRAS, KRAS, NRAS, SMAD4, PIK3CA, PTEN, RB1, STK11, TP53, and VHL) of the 24 genes. All lines have at least one mutation among the cancer genes examined, with most lines (73%) having more than one. Identification of those cancer genes mutated in the NCI-60, in combination with pharmacologic and molecular profiles of the cells, will allow for more informed interpretation of anticancer agent screening and will enhance the use of the NCI-60 cell lines for molecularly targeted screens. PMID:17088437

Ikediobi, Ogechi N.; Davies, Helen; Bignell, Graham; Edkins, Sarah; Stevens, Claire; O'Meara, Sarah; Santarius, Thomas; Avis, Tim; Barthorpe, Syd; Brackenbury, Lisa; Buck, Gemma; Butler, Adam; Clements, Jody; Cole, Jennifer; Dicks, Ed; Forbes, Simon; Gray, Kristian; Halliday, Kelly; Harrison, Rachel; Hills, Katy; Hinton, Jonathan; Hunter, Chris; Jenkinson, Andy; Jones, David; Kosmidou, Vivienne; Lugg, Richard; Menzies, Andrew; Mironenko, Tatiana; Parker, Adrian; Perry, Janet; Raine, Keiran; Richardson, David; Shepherd, Rebecca; Small, Alex; Smith, Raffaella; Solomon, Helen; Stephens, Philip; Teague, Jon; Tofts, Calli; Varian, Jennifer; Webb, Tony; West, Sofie; Widaa, Sara; Yates, Andy; Reinhold, William; Weinstein, John N.; Stratton, Michael R.; Futreal, P. Andrew; Wooster, Richard

2009-01-01

325

A Novel WASP Gene Mutation in a Chinese Boy with Wiskott-Aldrich Syndrome.  

PubMed

Wiskott-Aldrich syndrome (WAS) is a rare inherited X-linked recessive immunodeficiency disease characterized by eczema, thrombocytopenia, immune deficiency, and bloody diarrhea and is caused by WASP gene mutations. This study reports a case of WAS with a novel mutation. A newborn Chinese infant was admitted to the hospital because of intermittent bloody stools, recurrent infections, and persistent thrombocytopenia. Genetic analysis of the coding sequences and flanking splice sites of the WASP gene showed a novel WASP gene deletion mutation (1144delA) at exon 10. Family history showed that both his mother and aunt had a heterozygous genotype of the WASP gene. The infant died at the age of 4 months due to persistent thrombocytopenia and severe pneumonia. A novel WASP gene deletion (1144delA) at exon 10 was identified in a Chinese infant with WAS. This base deletion results in a frame-shift mutation of the gene for an early stop codon at amino acid 444. PMID:25332617

Wu, Hui; Hu, Cheng; Dang, Dan; Guo, Ying-Jie

2014-09-01

326

MEFV gene mutations and cardiac phenotype in children with familial Mediterranean fever: a cohort study  

PubMed Central

Background Familial Mediterranean fever (FMF) is the most common autoinflammatory disorder in the world. It is characterized by recurrent febrile inflammatory attacks of serosal and synovial membranes. MEFV gene mutations are responsible for the disease and its protein product, pyrin or marenostrin, plays an essential role in the regulation of the inflammatory reactions. Although the disease may carry a potential for cardiovascular disorders because of sustained inflammation during its course, the spectrum of cardiac involvement in children with FMF has not been well studied. We aimed at defining the frequency and spectrum of cardiac affection in children with FMF. The correlation between these affections and MEFV gene mutations was searched for to establish the relationship between cardiac phenotype and the patient's genotype in FMF. Methods The present work is a cohort study including 55 patients with the clinical diagnosis of FMF based on the Tel-Hashomere criteria, confirmed by genetic analysis showing homozygous or compound heterozygous mutation of MEFV genes. Fifty age- and sex-matched normal children were included as controls. The entire study group underwent detailed cardiac examination, 12-lead ECG and echocardiography. All data was statistically analysed using SPSS version-15. Results Patients had an average age of 8.5+/?4.2 years; with an average disease duration of 2.1+/?2.2 years; 28 were males. All controls showed no MEVF gene mutations. The most frequent gene mutation of the studied cases was E148Q mutation seen in 34% of cases and the most frequent compound mutation was E148Q/V726A seen in 16.6% of cases. Echocardiographic examination revealed pericardial effusion in nine patients. Twelve had aortic regurgitation; nine had mitral regurgitation and six had pulmonary regurgitation. The most common mutation associated with pericardial effusion was E148Q/V726A in 5/9 of cases. Valvular involvement were significantly more common in FMF patients with gene mutations. Also cardiac involvement was more common in patients with positive consanguinity. However, these cardiac manifestations showed no correlation to age, family history of FMF, or response to therapy or laboratory data. Conclusions In our cohort of children with FMF, cardiac involvement appears to be common. Pericardial effusions are significantly related to presence of mutation types E48Q, P 369S, V726A. These associations may warrant genetic screening of children with FMF to detect cardiac risk. PMID:24433404

2014-01-01

327

A nonsense mutation in the gene ROR2 underlying autosomal dominant brachydactyly type B.  

PubMed

Brachydactyly type B1 (BDB1), an autosomal dominant condition characterized by terminal deficiency of the fingers and toes, results from mutations in the gene ROR2 encoding a receptor tyrosine kinase. In addition to BDB1, mutations in the gene ROR2 also cause a more severe form of skeletal dysplasia, autosomal recessive Robinow syndrome. The present study reports on a large Punjabi-speaking Pakistani family segregating autosomal dominant BDB1. In total, 34 individuals in this family showed features of BDB1. Sequence analysis of the gene ROR2 identified a previously reported nonsense mutation (c.2278C>T, p.Q760X) in all affected individuals of the family. PMID:23238279

Habib, Rabia; Amin-ud-din, Muhammad; Ahmad, Wasim

2013-04-01

328

Sporadic hemiplegic migraine and epilepsy associated with CACNA1A gene mutation.  

PubMed

Familial hemiplegic migraine (FHM) is a clinically and genetically heterogeneous disease most commonly linked to CACNA1A gene mutation. Epilepsy rarely occurs in FHM and is seen predominantly with specific CACNA1A gene mutations. Here we report a sporadic case of FHM1 linked to S218L CACNA1A gene mutation with the triad of prolonged hemiplegic migraine, cerebellar symptoms, and epileptic seizures. Epilepsy in this syndrome follows the pattern of isolated unprovoked seizures occurring only during childhood and hemiplegic migraine-provoked seizures occurring during adulthood. Clinical and electrographic status epilepticus can occur during prolonged migraine attacks. We suggest that patients with seizures, ataxia, and hemiplegic migraine be genetically tested for FHM. Patients with prolonged hemiplegic migraine attacks and confusion should be tested with continuous EEG recording to ascertain whether electrographic status is occurring, as intensive antiepileptic treatment not only resolves status but immediately stops hemiplegic migraine and improves associated neurological deficits. PMID:20071244

Zangaladze, Andro; Asadi-Pooya, Ali A; Ashkenazi, Avi; Sperling, Michael R

2010-02-01

329

Convergence of Mutation and Epigenetic Alterations Identifies Common Genes in Cancer That Predict for Poor Prognosis  

PubMed Central

Background The identification and characterization of tumor suppressor genes has enhanced our understanding of the biology of cancer and enabled the development of new diagnostic and therapeutic modalities. Whereas in past decades, a handful of tumor suppressors have been slowly identified using techniques such as linkage analysis, large-scale sequencing of the cancer genome has enabled the rapid identification of a large number of genes that are mutated in cancer. However, determining which of these many genes play key roles in cancer development has proven challenging. Specifically, recent sequencing of human breast and colon cancers has revealed a large number of somatic gene mutations, but virtually all are heterozygous, occur at low frequency, and are tumor-type specific. We hypothesize that key tumor suppressor genes in cancer may be subject to mutation or hypermethylation. Methods and Findings Here, we show that combined genetic and epigenetic analysis of these genes reveals many with a higher putative tumor suppressor status than would otherwise be appreciated. At least 36 of the 189 genes newly recognized to be mutated are targets of promoter CpG island hypermethylation, often in both colon and breast cancer cell lines. Analyses of primary tumors show that 18 of these genes are hypermethylated strictly in primary cancers and often with an incidence that is much higher than for the mutations and which is not restricted to a single tumor-type. In the identical breast cancer cell lines in which the mutations were identified, hypermethylation is usually, but not always, mutually exclusive from genetic changes for a given tumor, and there is a high incidence of concomitant loss of expression. Sixteen out of 18 (89%) of these genes map to loci deleted in human cancers. Lastly, and most importantly, the reduced expression of a subset of these genes strongly correlates with poor clinical outcome. Conclusions Using an unbiased genome-wide approach, our analysis has enabled the discovery of a number of clinically significant genes targeted by multiple modes of inactivation in breast and colon cancer. Importantly, we demonstrate that a subset of these genes predict strongly for poor clinical outcome. Our data define a set of genes that are targeted by both genetic and epigenetic events, predict for clinical prognosis, and are likely fundamentally important for cancer initiation or progression. PMID:18507500

Chan, Timothy A; Glockner, Sabine; Yi, Joo Mi; Chen, Wei; Van Neste, Leander; Cope, Leslie; Herman, James G; Velculescu, Victor; Schuebel, Kornel E; Ahuja, Nita; Baylin, Stephen B

2008-01-01

330

The 2588G-->C mutation in the ABCR gene is a mild frequent founder mutation in the Western European population and allows the classification of ABCR mutations in patients with Stargardt disease.  

PubMed Central

In 40 western European patients with Stargardt disease (STGD), we found 19 novel mutations in the retina-specific ATP-binding cassette transporter (ABCR) gene, illustrating STGD's high allelic heterogeneity. One mutation, 2588G-->C, identified in 15 (37.5%) patients, shows linkage disequilibrium with a rare polymorphism (2828G-->A) in exon 19, suggesting a founder effect. The guanine at position 2588 is part of the 3' splice site of exon 17. Analysis of the lymphoblastoid cell mRNA of two STGD patients with the 2588G-->C mutation shows that the resulting mutant ABCR proteins either lack Gly863 or contain the missense mutation Gly863Ala. We hypothesize that the 2588G-->C alteration is a mild mutation that causes STGD only in combination with a severe ABCR mutation. This is supported in that the accompanying ABCR mutations in at least five of eight STGD patients are null (severe) and that a combination of two mild mutations has not been observed among 68 STGD patients. The 2588G-->C mutation is present in 1 of every 35 western Europeans, a rate higher than that of the most frequent severe autosomal recessive mutation, the cystic fibrosis conductance regulator gene mutation DeltaPhe508. Given an STGD incidence of 1/10,000, homozygosity for the 2588G-->C mutation or compound heterozygosity for this and other mild ABCR mutations probably does not result in an STGD phenotype. PMID:10090887

Maugeri, A; van Driel, M A; van de Pol, D J; Klevering, B J; van Haren, F J; Tijmes, N; Bergen, A A; Rohrschneider, K; Blankenagel, A; Pinckers, A J; Dahl, N; Brunner, H G; Deutman, A F; Hoyng, C B; Cremers, F P

1999-01-01

331

The importance of arginine mutation for the evolutionary structure and function of phenylalanine hydroxylase gene.  

PubMed

Phenylalanine hydroxylase (PAH) gene mutations were investigated in 23 (46 alleles) unrelated phenylketonuria (PKU) patients in Cukurova region. First, all exons of PAH gene were screened by denaturing high performance liquid chromatography (DHPLC), and then, the suspicious samples were analyzed by direct sequencing technique. Consequently, the following results were obtained: IVS10-11g-->a splicing mutation in 27/46 (58.7%), R261Q mutation in 7/46 (15.2%) and E178G, R243X, R243Q, P281L, Y386C, R408W mutations, each found in the frequency of 2/46 (4.3%). In many countries, Arginine mutations have the highest frequency among PAH gene mutations in PKU patients. Although, CpG dinucleotids are effective in mutations resulting in arginine changes, this finding originated from the studies on the causes of mutations rather than the studies on the importance of arginine amino acid. In our analyses, we have detected that a majority of mutations causing a change in arginine and other amino acids concentrated in exon 7 comprising the catalytic domain (residues 143-410) of PAH gene. Several studies has emphasized the role of arginine amino acid; with the following outcomes; arginine repetition is significant for RNA binding proteins, and for histon proteins in eukaryotic gene expression, and also arginine repetition occurring in the structure of signal recognition particle's (SRPs) as a consequence of post-translational processes is very important in terms of gene expression. Therefore, the role of arginine amino acid in PAH gene is rather remarkable in that it shows the role of amino acids in the protein/RNA interaction that has started in the evolutionary process and is still preserved and maintained in the motif formation of active domain structure due to its strong binding properties. Thus, such properties imply that both arginine amino acid and exon 7 is of great significance with regards to the structure and function of the PheOH enzyme. PMID:16765994

Lüleyap, H Umit; Alptekin, Davut; Pazarba?i, Ayfer; Kasap, Mulkiye; Kasap, Halil; Demirhindi, Hakan; Mungan, Neslihan; Ozer, Güler; Froster, Ursula G

2006-10-10

332

A mutation of the p63 gene in non-syndromic cleft lip  

PubMed Central

Mutations in the p63 gene (TP63) underlie several monogenic malformation syndromes manifesting cleft lip with or without cleft palate (CL/P). We investigated whether p63 mutations also result in non?syndromic CL/P. Specifically, we performed mutation analysis of the 16 exons of the p63 gene for 100 Thai patients with non?syndromic CL/P. In total, 21 variant sites were identified. All were single nucleotide changes, with six in coding regions, including three novel non?synonymous changes: S90L, R313G, and D564H. The R313G was concluded to be pathogenic on the basis of its amino acid change, evolutionary conservation, its occurrence in a functionally important domain, its predicted damaging function, its de novo occurrence, and its absence in 500 control individuals. Our data strongly suggest, for the first time, a causative role of a heterozygous mutation in the p63 gene in non?syndromic CL/P, highlighting the wide phenotypic spectrum of p63 gene mutations. PMID:16740912

Leoyklang, P; Siriwan, P; Shotelersuk, V

2006-01-01

333

Mutation in MEOX1 gene causes a recessive Klippel-Feil syndrome subtype  

PubMed Central

Background Klippel-Feil syndrome (KFS) is characterized by the developmental failure of the cervical spine and has two dominantly inherited subtypes. Affected individuals who are the children of a consanguineous marriage are extremely rare in the medical literature, but the gene responsible for this recessive trait subtype of KFS has recently been reported. Results We identified a family with the KFS phenotype in which their parents have a consanguineous marriage. Radiological examinations revealed that they carry fusion defects and numerical abnormalities in the cervical spine, scoliosis, malformations of the cranial base, and Sprengel’s deformity. We applied whole genome linkage and whole-exome sequencing analysis to identify the chromosomal locus and gene mutated in this family. Whole genome linkage analysis revealed a significant linkage to chromosome 17q12-q33 with a LOD score of 4.2. Exome sequencing identified the G?>?A p.Q84X mutation in the MEOX1 gene, which is segregated based on pedigree status. Homozygous MEOX1 mutations have reportedly caused a similar phenotype in knockout mice. Conclusions Here, we report a truncating mutation in the MEOX1 gene in a KFS family with an autosomal recessive trait. Together with another recently reported study and the knockout mouse model, our results suggest that mutations in MEOX1 cause a recessive KFS phenotype in humans. PMID:24073994

2013-01-01

334

Spectrum of NIPBL gene mutations in Polish patients with Cornelia de Lange syndrome.  

PubMed

Cornelia de Lange syndrome (CdLS) is a rare multi-system genetic disorder characterised by growth and developmental delay, distinctive facial dysmorphism, limb malformations and multiple organ defects. The disease is caused by mutations in genes responsible for the formation and regulation of cohesin complex. About half of the cases result from mutations in the NIPBL gene coding delangin, a protein regulating the initialisation of cohesion. To date, approximately 250 point mutations have been identified in more than 300 CdLS patients worldwide. In the present study, conducted on a group of 64 unrelated Polish CdLS patients, 25 various NIPBL sequence variants, including 22 novel point mutations, were detected. Additionally, large genomic deletions on chromosome 5p13 encompassing the NIPBL gene locus were detected in two patients with the most severe CdLS phenotype. Taken together, 42 % of patients were found to have a deleterious alteration affecting the NIPBL gene, by and large private ones (89 %). The review of the types of mutations found so far in Polish patients, their frequency and correlation with the severity of the observed phenotype shows that Polish CdLS cases do not significantly differ from other populations. PMID:23254390

Kuzniacka, Alina; Wierzba, Jolanta; Ratajska, Magdalena; Lipska, Beata S; Koczkowska, Magdalena; Malinowska, Monika; Limon, Janusz

2013-02-01

335

Electrostatic Surface Modifications to Improve Gene Delivery  

PubMed Central

Importance of the field Gene therapy has the potential to treat a wide variety of diseases including genetic diseases and cancer. Areas covered in this review This review introduces biomaterials used for gene delivery and then focuses on the use of electrostatic surface modifications to improve gene delivery materials. These modifications have been used to stabilize therapeutics in vivo, add cell-specific targeting ligands, and promote controlled release. Coatings of nanoparticles and microparticles as well as non-particulate surface coatings are covered in this review. Electrostatic principles are crucial for the development of multilayer delivery structures fabricated by the layer-by-layer method. What the reader will gain The reader will gain knowledge about the composition of biomaterials used for surface modifications and how these coatings and multilayers can be utilized to improve spatial control and efficiency of delivery. Examples are shown for the delivery of nucleic acids, including DNA and siRNA, to in vitro and in vivo systems. Take home message The versatile and powerful approach of electrostatic coatings and multilayers will lead to the development of enhanced gene therapies. PMID:20201712

Shmueli, Ron B.; Anderson, Daniel G.

2010-01-01

336

Associations between epidermal growth factor receptor gene mutation and serum tumor markers in advanced lung adenocarcinomas: a retrospective study(?).  

PubMed

Objective To investigate the associations between epidermal growth factor receptor (EGFR) gene mutations and serum tumor markers in advanced lung adenocarcinomas. Methods We investigated the association between EGFR gene mutations and clinical features, including serum tumor marker levels, in 97 advanced lung adenocarcinomas patients who did not undergo the treatment of EGFR tyrosine kinase inhibitors. EGFR gene mutation was detected by real-time PCR at exons 18, 19, 20, and 21. Serum tumor marker concentrations were analyzed by chemiluminescence assay kit at the same time. Results EGFR gene mutations were detected in 42 (43%) advanced lung adenocarcinoma patients. Gender (P=0.003), smoking status (P=0.001), and abnormal serum status of carcinoembryonic antigen (CEA, P=0.028) were significantly associated with EGFR gene mutation incidence. Multivariate analysis showed the abnormal CEA level in serum was independently associated with the incidence of EGFR gene mutation (P=0.046) with an odds ratio of 2.613 (95% CI: 1.018-6.710). However, receiver operating characteristic (ROC) curve analysis revealed CEA was not an ideal predictive marker for EGFR gene mutation status in advanced lung adenocarcinoma (the area under the ROC curve was 0.608, P=0.069). Conclusions EGFR gene mutation status is significantly associated with serum CEA status in advanced lung adenocarcinmoas. However, serum CEA is not an ideal predictor for EGFR mutation. PMID:25264883

Pan, Ying-Qiu; Shi, Wei-Wu; Xu, Dan-Ping; Xu, Hui-Hui; Zhou, Mei-Ying; Yan, Wei-Hua

2014-09-29

337

Wilms' tumor suppressor gene mutations in girls with sporadic isolated steroid-resistant nephrotic syndrome.  

PubMed

Mutations in the Wilms' tumor suppressor gene (WT1) can lead to syndromic forms of steroid-resistant nephrotic syndrome (SRNS) such as Denys-Drash or Frasier syndrome and can cause isolated SRNS. A mutation within WT1 is a frequent cause of sporadic isolated SRNS in girls. In a worldwide cohort of girls, the rate of occurrence was 10.8%. Previous reports have indicated that in Chinese girls, the detection rate of WT1 mutations is 16.7% for early onset isolated nephrotic syndrome. The detection rate of WT1 mutations in Chinese girls with sporadic isolated SRNS is unknown. We examined WT1 mutations in 14 Chinese girls with sporadic isolated SRNS using polymerase chain reaction and direct sequencing and studied a control group of 38 boys with sporadic isolated SRNS. We identified a WT1 mutation in 1 of 14 (7.1% detection rate) Chinese girls with sporadic isolated SRNS. No mutations occurred in WT1 in the remaining 13 girls or the control group. Our investigation supports the necessity of genetic examination for mutations in WT1 in girls with sporadic isolated SRNS. PMID:24338413

Yang, Y H; Zhao, F; Feng, D N; Wang, J J; Wang, C F; Huang, J; Nie, X J; Xia, G Z; Chen, G M; Yu, Z H

2013-01-01

338

Somatic Mutations in the Chromatin Remodeling Gene ARID1A Occur in Several Tumor Types  

PubMed Central

Mutations in the chromatin remodeling gene ARID1A have recently been identified in the majority of ovarian clear cell carcinomas (OCCCs). To determine the prevalence of mutations in other tumor types, we evaluated 759 malignant neoplasms including those of the pancreas, breast, colon, stomach, lung, prostate, brain, and blood (leukemias). We identified truncating mutations in 6% of the neoplasms studied; nontruncating somatic mutations were identified in an additional 0.4% of neoplasms. Mutations were most commonly found in gastrointestinal samples with 12 of 119 (10%) colorectal and 10 of 100 (10%) gastric neoplasms, respectively, harboring changes. More than half of the mutated colorectal and gastric cancers displayed microsatellite instability (MSI) and the mutations in these tumors were out-of-frame insertions or deletions at mononucleotide repeats. Mutations were also identified in 2–8% of tumors of the pancreas, breast, brain (medulloblastomas), prostate, and lung, and none of these tumors displayed MSI. These findings suggest that the aberrant chromatin remodeling consequent to ARID1A inactivation contributes to a variety of different types of neoplasms. PMID:22009941

Jones, Sian; Li, Meng; Parsons, D Williams; Zhang, Xiaosong; Wesseling, Jelle; Kristel, Petra; Schmidt, Marjanka K; Markowitz, Sanford; Yan, Hai; Bigner, Darell; Hruban, Ralph H; Eshleman, James R; Iacobuzio-Donahue, Christine A; Goggins, Michael; Maitra, Anirban; Malek, Sami N; Powell, Steve; Vogelstein, Bert; Kinzler, Kenneth W; Velculescu, Victor E; Papadopoulos, Nickolas

2012-01-01

339

Recurrent mutations of NOTCH genes in follicular lymphoma identify a distinctive subset of tumours.  

PubMed

Follicular lymphoma (FL) is one of the most common malignant lymphomas. The t(14;18)(q32;q21) translocation is found in about 80% of cases and plays an important role in lymphomagenesis. However, the molecular mechanisms involved in the development and transformation of this lymphoma are not fully understood. Gain-of-function mutations of NOTCH1 or NOTCH2 have recently been reported in several B cell lymphoid neoplasms but the role of these mutations in FL is not known. In this study we investigated the mutational status of these genes in 112 FLs. NOTCH1 and NOTCH2 mutations were identified in five and two cases, respectively (total 7/112, 6.3%). All mutations predicted for truncated protein in the PEST domain and were identical to those identified in other B cell lymphoid neoplasms. NOTCH-mutated FL cases were characterized by lower frequency of t(14;18) (14% versus 69%, p = 0.01), higher incidence of splenic involvement (71% versus 25%, p = 0.02) and female predominance (100% versus 55%, p = 0.04). A diffuse large B cell lymphoma (DLBCL) component was more frequently identified in NOTCH-mutated FL than in wild-type cases (57% versus 18%, p = 0.03). These results indicate that NOTCH mutations are uncommon in FL but may occur in a subset of cases with distinctive, characteristic, clinicopathological features. Copyright Š 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID:25141821

Karube, Kennosuke; Martínez, Daniel; Royo, Cristina; Navarro, Alba; Pinyol, Magda; Cazorla, Maite; Castillo, Paola; Valera, Alexandra; Carrió, Anna; Costa, Dolors; Colomer, Dolors; Rosenwald, Andreas; Ott, German; Esteban, Daniel; Giné, Eva; López-Guillermo, Armando; Campo, Elias

2014-11-01

340

Mutations in the SPG7 gene cause chronic progressive external ophthalmoplegia through disordered mitochondrial DNA maintenance.  

PubMed

Despite being a canonical presenting feature of mitochondrial disease, the genetic basis of progressive external ophthalmoplegia remains unknown in a large proportion of patients. Here we show that mutations in SPG7 are a novel cause of progressive external ophthalmoplegia associated with multiple mitochondrial DNA deletions. After excluding known causes, whole exome sequencing, targeted Sanger sequencing and multiplex ligation-dependent probe amplification analysis were used to study 68 adult patients with progressive external ophthalmoplegia either with or without multiple mitochondrial DNA deletions in skeletal muscle. Nine patients (eight probands) were found to carry compound heterozygous SPG7 mutations, including three novel mutations: two missense mutations c.2221G>A; p.(Glu741Lys), c.2224G>A; p.(Asp742Asn), a truncating mutation c.861dupT; p.Asn288*, and seven previously reported mutations. We identified a further six patients with single heterozygous mutations in SPG7, including two further novel mutations: c.184-3C>T (predicted to remove a splice site before exon 2) and c.1067C>T; p.(Thr356Met). The clinical phenotype typically developed in mid-adult life with either progressive external ophthalmoplegia/ptosis and spastic ataxia, or a progressive ataxic disorder. Dysphagia and proximal myopathy were common, but urinary symptoms were rare, despite the spasticity. Functional studies included transcript analysis, proteomics, mitochondrial network analysis, single fibre mitochondrial DNA analysis and deep re-sequencing of mitochondrial DNA. SPG7 mutations caused increased mitochondrial biogenesis in patient muscle, and mitochondrial fusion in patient fibroblasts associated with the clonal expansion of mitochondrial DNA mutations. In conclusion, the SPG7 gene should be screened in patients in whom a disorder of mitochondrial DNA maintenance is suspected when spastic ataxia is prominent. The complex neurological phenotype is likely a result of the clonal expansion of secondary mitochondrial DNA mutations modulating the phenotype, driven by compensatory mitochondrial biogenesis. PMID:24727571

Pfeffer, Gerald; Gorman, Gráinne S; Griffin, Helen; Kurzawa-Akanbi, Marzena; Blakely, Emma L; Wilson, Ian; Sitarz, Kamil; Moore, David; Murphy, Julie L; Alston, Charlotte L; Pyle, Angela; Coxhead, Jon; Payne, Brendan; Gorrie, George H; Longman, Cheryl; Hadjivassiliou, Marios; McConville, John; Dick, David; Imam, Ibrahim; Hilton, David; Norwood, Fiona; Baker, Mark R; Jaiser, Stephan R; Yu-Wai-Man, Patrick; Farrell, Michael; McCarthy, Allan; Lynch, Timothy; McFarland, Robert; Schaefer, Andrew M; Turnbull, Douglass M; Horvath, Rita; Taylor, Robert W; Chinnery, Patrick F

2014-05-01

341

Plasmodium falciparum: Gene Mutations and Amplification of Dihydrofolate Reductase Genes in Parasites Grown in Vitro in Presence of Pyrimethamine  

Microsoft Academic Search

Thaithong, S., Ranford-Cartwright, L. C., Siripoon, N., Harnyuttanakorn, P., Kanchanakhan, N. S., Seugorn, A., Rungsihirunrat, K., Cravo, P. V. L., and Beale, G. H. 2001. Plasmodium falciparum: Gene mutations and amplification of dihydrofolate reductase genes in parasites grown in vitro in presence of pyrimethamine. Experimental Parasitology98, 59–70. Samples of three pyrimethamine-sensitive clones of Plasmodium falciparum were grown for periods of

S. Thaithong; L. C. Ranford-Cartwright; N. Siripoon; P. Harnyuttanakorn; N. S. Kanchanakhan; A. Seugorn; K. Rungsihirunrat; P. V. L. Cravo; G. H. Beale

2001-01-01

342

Mutations in RAD6, a yeast gene encoding a ubiquitin-conjugating enzyme, stimulate retrotransposition.  

PubMed Central

The Saccharomyces cerevisiae DNA repair gene RAD6 encodes a ubiquitin-conjugating enzyme which polyubiquitinates histones in vitro. Here we show that mutations in rad6 increase the frequency of transposition of the retrotransposon Ty into the CAN1 and URA3 loci. Using isogenic RAD6 and rad6 strains, we measured a more than 100-fold increase in the spontaneous rate of retrotransposition due to rad6, although there was no increase in the Ty message level. This is the first time that a mutation in a host gene has been shown to result in an increased rate of retrotransposition. Images PMID:2154679

Picologlou, S; Brown, N; Liebman, S W

1990-01-01

343

AGPAT2 gene mutation in a child with Berardinelli-Seip congenital lipodystrophy syndrome.  

PubMed

Berardinelli-Seip congenital lipodystrophy (BSCL) syndrome is an autosomal recessive disorder, caused by mutation in the AGPAT2 gene, which could lead to insulin resistance and variety of complications. Herein, a 7-year old girl is presented with generalized loss of subcutaneous fat, prominent pectoral and thigh muscles and an early telarche. Laboratory studies revealed an elevated level of serum triglyceride. Ultrasonograph demonstrated enhanced size of ovary containing multiple mature follicles. Considering the clinical phenotype, AGPAT2 gene was sequenced which showed homozygote c.514G>A mutation. Therefore, the diagnosis of BSCL was confirmed in this patient. PMID:23337016

Rostami, Parastoo; Nakhaeimoghadam, Maryam; Bijani, Faezeh-Moghimpour; Sotoudeh, Arya; Rabbani, Ali; Hilbert, Pascale; Rezaei, Nima

2013-02-01

344

Human Genetic Disorders Caused by Mutations in Genes Encoding Biosynthetic Enzymes for Sulfated Glycosaminoglycans*  

PubMed Central

A number of genetic disorders are caused by mutations in the genes encoding glycosyltransferases and sulfotransferases, enzymes responsible for the synthesis of sulfated glycosaminoglycan (GAG) side chains of proteoglycans, including chondroitin sulfate, dermatan sulfate, and heparan sulfate. The phenotypes of these genetic disorders reflect disturbances in crucial biological functions of GAGs in human. Recent studies have revealed that mutations in genes encoding chondroitin sulfate and dermatan sulfate biosynthetic enzymes cause various disorders of connective tissues. This minireview focuses on growing glycobiological studies of recently described genetic diseases caused by disturbances in biosynthetic enzymes for sulfated GAGs. PMID:23457301

Mizumoto, Shuji; Ikegawa, Shiro; Sugahara, Kazuyuki

2013-01-01

345

Molecular analysis of contiguous exons of the phenylalanine hydroxylase gene: identification of a new PKU mutation.  

PubMed Central

A modified application of the chemical cleavage of mismatch (CCM) method has been used to screen three contiguous exons (exons 9, 10, and 11) of the phenylalanine hydroxylase gene in 17 Italian PKU patients. A new nonsense heterozygous C-->G transversion within exon 11 (S359X) was identified in a single patient. Only one of the four mutations previously reported in this DNA region in Caucasians was found. This lesion, IVS X-546, was detected in five of the 34 PKU alleles examined. Our results underline the versatility of the CCM method for scanning a gene for multiple mutations. Images PMID:8097261

Dianzani, I; Camaschella, C; Saglio, G; Ferrero, G B; Ramus, S; Ponzone, A; Cotton, R G

1993-01-01

346

A novel glycine decarboxylase gene mutation in an Indian family with nonketotic hyperglycinemia.  

PubMed

Nonketotic hyperglycinemia is an inborn error of glycine metabolism. It manifests mostly as an acute encephalopathy in the neonatal period, although later, atypical presentations have also been reported. Mutations in 3 different genes have been implicated in nonketotic hyperglycinemia. Here we report a novel mutation, c.2296G>T (p.Gly766Cys), in exon 19 of the glycine decarboxylase (GLDC) gene (Refseq accession number NM_000170.2) in a consanguineous Indian couple with a history of 4 neonatal deaths. PMID:23349517

Love, Jennifer M; Prosser, Debra; Love, Donald R; Chintakindi, Krishna Prakash; Dalal, Ashwin B; Aggarwal, Shagun

2014-01-01

347

BRCA1 Gene Mutations in Breast Cancer Patients from Kerman Province, Iran  

PubMed Central

Background Breast cancer is the most common malignancy in Iranian women. Mutations in BRCA1 gene is one of the important genetic predisposing factors in breast cancer. This gene is a tumor suppressor that plays an important role in regulating the functions of RAD51 protein for strand invasion in homologous recombination repair. Methods The BRCA1 gene has amplified in the DNA isolated from breast cancer patients' leukocytes, using Polymerase Chain Reaction technique. The PCR products have sequenced using an automated DNA sequencer and subsequently obtained data have aligned with the human BRCA1 DNA sequences available online. Results In this study, we have considered nine different mutations on 60 examined chromosomes from 30 patients, living in Kerman province. A deletion of one adenine (c.1017delA) and insertion of one cytosine (c.969InsC) have found as the most frequent (20%) mutation in this survey. A substitution of thymine for adenine (c.999T>A) has detected as the second common BRCA1 gene defect (6.7%). The other mutations have identified as single nucleotide replacement including: c.792A>C, c.825G>C, c.822T>A, c.1068A>G, c.969A>T and c.966T>C. Conclusion The identified BRCA1 mutations were in accordance with the previous reports. To our knowledge, four mutations: (c.969InsC, c.792A>C, c.825G>C, c.822T>A) which have identified in this study, have not been previously reported in the literature. A larger cohort study would help identifying all relevant BRCA1 mutations in this population.

Saleh-gohari, Nasrollah; Mohammadi-Anaie, Marzye; Kalantari-Khandani, Behjat

2012-01-01

348

Numerous BAF complex genes are mutated in Coffin-Siris syndrome.  

PubMed

Coffin-Siris syndrome (CSS; OMIM#135900) is a rare congenital anomaly syndrome characterized by intellectual disability, coarse face, hypertrichosis, and absence/hypoplasia of the fifth digits' nails. As the majority of patients are sporadic, an autosomal dominant inheritance model has been postulated. Recently, whole exome sequencing (WES) emerged as a comprehensive analytical method for rare variants. We applied WES on five CSS patients and found two de novo mutations in SMARCB1. SMARCB1 was completely sequenced in 23 CSS patients and the mutations were found in two more patients. As SMARCB1 encodes a subunit of the BAF complex functioning as a chromatin remodeling factor, mutations in 15 other subunit genes may cause CSS and thus were analyzed in 23 CSS patients. We identified heterozygous mutations in either of six genes (SMARCA4, SMARCB1, SMARCA2, SMARCE1, ARID1A, and ARID1B) in 20 out of 23 CSS patients. The patient with a SMARCA2 mutation was re-evaluated and identified as having Nicolaides-Baraitser syndrome (OMIM#601358), which is similar to but different from CSS. Additionally, 49 more CSS patients were analyzed as a second cohort. Together with the first cohort, 37 out of 71 (22 plus 49) patients were found to have a mutation in either one of five BAF complex genes. Furthermore, two CSS patients were reported to have a PHF6 abnormality, which can also cause Borjeson-Forssman-Lehmann syndrome (OMIM#301900), an X-linked intellectual disability syndrome with epilepsy and endocrine abnormalities. The current list of mutated genes in CSS is far from being complete and analysis of more patients is required. PMID:25081545

Miyake, Noriko; Tsurusaki, Yoshinori; Matsumoto, Naomichi

2014-09-01

349

Mutation analysis of tuberous sclerosis families using the chromosome 16 (TSC2) tuberin gene  

SciTech Connect

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder which affects numerous body systems, especially brain and kidneys. The estimated prevalence of TSC is 1 per 10,000 population and the disease occurs in all racial groups. TSC exhibits both incomplete penetrance and variable expression and it is estimated that approximately 50% of affected individuals are the result of new mutations. TSC is a heterogeneous disorder with at least two disease loci which linkage studies have mapped to chromosomes 9q34 (TSC1) and 16p13.3 (TSC2). The chromosome 16 TSC gene, a 5.5 kb transcript which has been named tuberin, has recently been isolated and the characterization of the gene and mutational analysis of chromosome 16 families are presently underway. Using cDNA clones which cover approximately 90%, including the 3{prime} end, of the tuberin gene, we have screened Southern blots of 44 confirmed familial and sporadic TSC cases using the restriction enzymes Bam HI, Hind III and Taq I. To date, we have detected no confirmed deletions in any of these cases. We are in the process of screening using Pvu II blots. In addition, our laboratory is beginning to screen the TSC cases for mutations using SSCP in conjunction with RT-PCR of lymphoblast RNA and PCR of lymphoblast DNA using primers prepared from the gene sequence. We have recently ascertained an additional 20 sproadic TSC cases which will be subjected to analysis and these results together with our mutation findings will be presented. Our results would indicate that the number of mutations detectable using Southern blotting is small, especially in the larger chromosome 16 TSC families as opposed to sporadic mutations, and that more detailed technical analysis will be necessary to determine the full range of mutations in the large majority of TSC cases.

Gilbert, J.; Wolpert, C.; Kumar, A. [Duke Univ. Medical Center, Durham, NC (United States)] [and others

1994-09-01

350

Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma.  

PubMed

Glioblastoma multiforme (GBM) is a lethal brain tumour in adults and children. However, DNA copy number and gene expression signatures indicate differences between adult and paediatric cases. To explore the genetic events underlying this distinction, we sequenced the exomes of 48 paediatric GBM samples. Somatic mutations in the H3.3-ATRX-DAXX chromatin remodelling pathway were identified in 44% of tumours (21/48). Recurrent mutations in H3F3A, which encodes the replication-independent histone 3 variant H3.3, were observed in 31% of tumours, and led to amino acid substitutions at two critical positions within the histone tail (K27M, G34R/G34V) involved in key regulatory post-translational modifications. Mutations in ATRX (?-thalassaemia/mental retardation syndrome X-linked) and DAXX (death-domain associated protein), encoding two subunits of a chromatin remodelling complex required for H3.3 incorporation at pericentric heterochromatin and telomeres, were identified in 31% of samples overall, and in 100% of tumours harbouring a G34R or G34V H3.3 mutation. Somatic TP53 mutations were identified in 54% of all cases, and in 86% of samples with H3F3A and/or ATRX mutations. Screening of a large cohort of gliomas of various grades and histologies (n = 784) showed H3F3A mutations to be specific to GBM and highly prevalent in children and young adults. Furthermore, the presence of H3F3A/ATRX-DAXX/TP53 mutations was strongly associated with alternative lengthening of telomeres and specific gene expression profiles. This is, to our knowledge, the first report to highlight recurrent mutations in a regulatory histone in humans, and our data suggest that defects of the chromatin architecture underlie paediatric and young adult GBM pathogenesis. PMID:22286061

Schwartzentruber, Jeremy; Korshunov, Andrey; Liu, Xiao-Yang; Jones, David T W; Pfaff, Elke; Jacob, Karine; Sturm, Dominik; Fontebasso, Adam M; Quang, Dong-Anh Khuong; Tönjes, Martje; Hovestadt, Volker; Albrecht, Steffen; Kool, Marcel; Nantel, Andre; Konermann, Carolin; Lindroth, Anders; Jäger, Natalie; Rausch, Tobias; Ryzhova, Marina; Korbel, Jan O; Hielscher, Thomas; Hauser, Peter; Garami, Miklos; Klekner, Almos; Bognar, Laszlo; Ebinger, Martin; Schuhmann, Martin U; Scheurlen, Wolfram; Pekrun, Arnulf; Frühwald, Michael C; Roggendorf, Wolfgang; Kramm, Christoph; Dürken, Matthias; Atkinson, Jeffrey; Lepage, Pierre; Montpetit, Alexandre; Zakrzewska, Magdalena; Zakrzewski, Krzystof; Liberski, Pawel P; Dong, Zhifeng; Siegel, Peter; Kulozik, Andreas E; Zapatka, Marc; Guha, Abhijit; Malkin, David; Felsberg, Jörg; Reifenberger, Guido; von Deimling, Andreas; Ichimura, Koichi; Collins, V Peter; Witt, Hendrik; Milde, Till; Witt, Olaf; Zhang, Cindy; Castelo-Branco, Pedro; Lichter, Peter; Faury, Damien; Tabori, Uri; Plass, Christoph; Majewski, Jacek; Pfister, Stefan M; Jabado, Nada

2012-02-01

351

Mutations in Iron-Sulfur Cluster Scaffold Genes NFU1 and BOLA3 Cause a Fatal Deficiency of Multiple  

E-print Network

ARTICLE Mutations in Iron-Sulfur Cluster Scaffold Genes NFU1 and BOLA3 Cause a Fatal Deficiency of targeting to the mitochondria (deter- mined with Mitoprot7 ). Two mitochondrial genes involved in iron-sulfur

Shoubridge, Eric

352

CRISPR-mediated direct mutation of cancer genes in the mouse liver.  

PubMed

The study of cancer genes in mouse models has traditionally relied on genetically-engineered strains made via transgenesis or gene targeting in embryonic stem cells. Here we describe a new method of cancer model generation using the CRISPR/Cas (clustered regularly interspaced short palindromic repeats/CRISPR-associated proteins) system in vivo in wild-type mice. We used hydrodynamic injection to deliver a CRISPR plasmid DNA expressing Cas9 and single guide RNAs (sgRNAs) to the liver that directly target the tumour suppressor genes Pten (ref. 5) and p53 (also known as TP53 and Trp53) (ref. 6), alone and in combination. CRISPR-mediated Pten mutation led to elevated Akt phosphorylation and lipid accumulation in hepatocytes, phenocopying the effects of deletion of the gene using Cre-LoxP technology. Simultaneous targeting of Pten and p53 induced liver tumours that mimicked those caused by Cre-loxP-mediated deletion of Pten and p53. DNA sequencing of liver and tumour tissue revealed insertion or deletion mutations of the tumour suppressor genes, including bi-allelic mutations of both Pten and p53 in tumours. Furthermore, co-injection of Cas9 plasmids harbouring sgRNAs targeting the ?-catenin gene and a single-stranded DNA oligonucleotide donor carrying activating point mutations led to the generation of hepatocytes with nuclear localization of ?-catenin. This study demonstrates the feasibility of direct mutation of tumour suppressor genes and oncogenes in the liver using the CRISPR/Cas system, which presents a new avenue for rapid development of liver cancer models and functional genomics. PMID:25119044

Xue, Wen; Chen, Sidi; Yin, Hao; Tammela, Tuomas; Papagiannakopoulos, Thales; Joshi, Nikhil S; Cai, Wenxin; Yang, Gillian; Bronson, Roderick; Crowley, Denise G; Zhang, Feng; Anderson, Daniel G; Sharp, Phillip A; Jacks, Tyler

2014-10-16

353

Genechip-detecting mutations in exon 8 in cTnI gene associated with FHCM  

NASA Astrophysics Data System (ADS)

As the rate of gene discovery accelerates, more efficient methods are needed to analyze genes in human tissues. Genechip, a kind of new device, is composed of DNA probes immobilized on a solid substrate. With the advantage of the high throughput information, genechip has become one of the best solutions to detect and analyse the mutations in genes. Hypertrophic cardiomyopathy (HCM), the most common cause of the sudden death in the young, is one of the diseases damaging people health most badly. It is an autosomal dominant disease. More than 55% of the HCM patients are genetic. The mutations of exon 8 in the Cardiac troponin I (cTnI) gene are closely associated with Family Hypertrophic Cardiomyopathy (FHCM). Our purpose is to perform the assay of the mutations in exon 8 in cTnI gene based on the genechip theory and technology. Special probes were designed to fabricate the genechip to detect the mutations in cTnI gene simultaneously. We designed two oligonucleotide sequences 5"-end labeled with fluorescein, one simulating wild-type and the other simulating mutant. We mixed oligonucleotide I and II together to simulate heterozygote. After optimizing the hybridization protocols, the fabricated genechip can detect the mutations in exon 8 in cTnI gene with relative high sensitivity and specificity. When applying the fabricated genechip to detect the target DNA sequence, we found that the fully complementary probe gave a fluorescent signal almost 50% stronger than that of the one base mismatched one, which is in accordance with the result from theoretic estimate. It is believed that an applicable special genechip can be developed for investigating and diagnosing FHCM after further improvement.

Zhang, Yuanying; He, Nongyue; Guo, Huishi; Yang, Di; Wan, Wenhui; Bian, Zhiping; Zhang, Jinan

2005-01-01

354

A novel small deletion mutation in RUNX2 gene in one Chinese family with cleidocranial dysplasia.  

PubMed

Cleidocranial dysplasia (CCD) is a skeletal dysplasia with autosomal-dominant inheritance. The runt related transcription factor 2 (RUNX2) gene is the only gene in which mutations are known to cause CCD. We report identification of a novel small deletions mutation in the RUNX2 gene in a Chinese family with CCD. A 29-year-old female was diagnosed as proband of CCD based on the clinical findings, which show delayed closure of the fontanels, hypoplastic or aplastic clavicles and dental anomalies. Similar dental and skeletal symptoms were also observed in the other three affected individuals. We prepared genomic DNA from all four affected individuals, unaffected individual from her family members, as well as 100 unrelated healthy controls. PCR was conducted using the above genomic DNA as template and the RUNX2 gene-specific primers. The PCR product was subjected to direct sequencing and the sequence was compared to that of RUNX2 gene within the NCBI database. We detected a small deletion CCTA from nucleotide 635 to nucleotide 638 in exon 3 of RUNX2 gene of the proband. This will lead to the introduction of a translational stop codon at codon 220, resulting in a truncated RUNX2 protein, and therefore within the runt domain of the RUNX2 protein. We detected the same mutation in the the other three affected individuals, and did not detect any mutation in the unaffected family members or the 100 unrelated healthy controls, demonstrating that this is a novel missense mutation in RUNX2 gene and therefore, contributes to the molecular diagnosis of CCD. PMID:24966961

Chen, Ting; Hou, Jin; Hu, Ling-Ling; Gao, Jie; Wu, Bu-Ling

2014-01-01

355

Genetics of craniosynostosis: genes, syndromes, mutations and genotype-phenotype correlations.  

PubMed

Craniosynostosis is a very heterogeneous group of disorders, in the etiology of which genetics play an important role. Chromosomal alterations are important causative mechanisms of the syndromic forms of craniosynostosis accounting for at least 10% of the cases. Mutations in 7 genes are unequivocally associated with mendelian forms of syndromic craniosynostosis: FGFR1, FGFR2, FGFR3, TWIST1, EFNB1, MSX2 and RAB23. Mutations in 4 other genes, FBN1, POR, TGFBR1 and TGFBR2, are also associated with craniosynostosis, but not causing the major clinical feature of the phenotype or with an apparently low penetrance. The identification of these genes represented a great advance in the dissection of the genetics of craniosynostosis in the last 15 years, and today they explain the etiology of about 30% of the syndromic cases. The paucity in the identification of genes associated with this defect has partly been due to the rarity of familial cases. In contrast, very little is known about the molecular and cellular factors leading to nonsyndromic forms of craniosynostosis. Revealing the molecular pathology of craniosynostosis is also of great value for diagnosis, prognosis and genetic counseling. This chapter will review (1) the chromosomal regions associated with syndromic forms of the malformation, (2) the genes in which a large number of mutations have been reported by independent studies (FGFR1, FGFR2, FGFR3, TWIST1 and EFNB1) and (3) the molecular mechanisms and genotype-phenotype correlations of such mutations. PMID:18391498

Passos-Bueno, Maria Rita; Serti Eacute, Andr Eacute A L; Jehee, Fernanda S; Fanganiello, Roberto; Yeh, Erika

2008-01-01

356

A Homozygous Missense Mutation in the Ciliary Gene TTC21B Causes Familial FSGS.  

PubMed

Several genes, mainly involved in podocyte cytoskeleton regulation, have been implicated in familial forms of primary FSGS. We identified a homozygous missense mutation (p.P209L) in the TTC21B gene in seven families with FSGS. Mutations in this ciliary gene were previously reported to cause nephronophthisis, a chronic tubulointerstitial nephropathy. Notably, tubular basement membrane thickening reminiscent of that observed in nephronophthisis was present in patients with FSGS and the p.P209L mutation. We demonstrated that the TTC21B gene product IFT139, an intraflagellar transport-A component, mainly localizes at the base of the primary cilium in developing podocytes from human fetal tissue and in undifferentiated cultured podocytes. In contrast, in nonciliated adult podocytes and differentiated cultured cells, IFT139 relocalized along the extended microtubule network. We further showed that knockdown of IFT139 in podocytes leads to primary cilia defects, abnormal cell migration, and cytoskeleton alterations, which can be partially rescued by p.P209L overexpression, indicating its hypomorphic effect. Our results demonstrate the involvement of a ciliary gene in a glomerular disorder and point to a critical function of IFT139 in podocytes. Altogether, these data suggest that this homozygous TTC21B p.P209L mutation leads to a novel hereditary kidney disorder with both glomerular and tubulointerstitial damages. PMID:24876116

Cong, Evelyne Huynh; Bizet, Albane A; Boyer, Olivia; Woerner, Stéphanie; Gribouval, Olivier; Filhol, Emilie; Arrondel, Christelle; Thomas, Sophie; Silbermann, Flora; Canaud, Guillaume; Hachicha, Jamil; Ben Dhia, Nasr; Peraldi, Marie-Noëlle; Harzallah, Kais; Iftene, Daouia; Daniel, Laurent; Willems, Marjolaine; Noel, Laure-Hélčne; Bole-Feysot, Christine; Nitschké, Patrick; Gubler, Marie-Claire; Mollet, Géraldine; Saunier, Sophie; Antignac, Corinne

2014-11-01

357

Mutations in Fanconi anemia genes and the risk of esophageal cancer.  

PubMed

The incidence of esophageal squamous cell carcinoma (ESCC) is very high in northeastern Iran. Previously, we reported a strong familial component of ESCC among Turkmens, who constitute approximately one-half of the population of this region. We hypothesized that the genes which cause Fanconi anemia might be candidate genes for ESCC. We sequenced the entire coding regions of 12 Fanconi anemia genes in the germline DNA of 190 Turkmen cases of ESCC. We identified three heterozygous insertion/deletion mutations: one in FANCD2 (p.Val1233del), one in FANCE (p.Val311SerfsX2), and one in FANCL (p.Thr367AsnfsX13). All three patients had a strong family history of ESCC. In addition, four patients (out of 746 tested) were homozygous for the FANCA p.Ser858Arg mutation, compared to none of 1,373 matched controls (OR = 16.7, 95% CI = 6.2-44.2, P = 0.01). The p. Lys3326X mutation in BRCA2 (also known as Fanconi anemia gene FANCD1) was present in 27 of 746 ESCC cases and in 16 of 1,373 controls (OR = 3.38, 95% CI = 1.97-6.91, P = 0.0002). In summary, both heterozygous and homozygous mutations in several Fanconi anemia-predisposing genes are associated with an increased risk of ESCC in Iran. PMID:21279724

Akbari, Mohammad R; Malekzadeh, Reza; Lepage, Pierre; Roquis, David; Sadjadi, Ali R; Aghcheli, Karim; Yazdanbod, Abbas; Shakeri, Ramin; Bashiri, Jafar; Sotoudeh, Masoud; Pourshams, Akram; Ghadirian, Parviz; Narod, Steven A

2011-05-01

358

Mutation analysis of the polycystic kidney disease 1 (PKD1) gene  

SciTech Connect

The gene which is mutated in most cases of autosomal dominant polycystic kidney disease (ADPKD), PKD1, has recently been identified on chromosome 16. Three quarters of this gene lies in a region of genomic DNA that is duplicated elsewhere on chromosome 16. Consequently, the search for mutations has proved difficult and our efforts so far have concentrated on screening the single copy 3{prime} region of the gene. We have employed the methods of field inversion gel electrophoresis, conventional Southern blotting, RT-PCR and heteroduplex analysis. From the examination of DNA of approximately 300 PKD1 patients, two deletions have been identified. One is a 5.5 kb genomic deletion, which is transmitted with the disease and results in a 3 kb deletion of the PKD1 transcript. The other is a de novo genomic deletion of 2 kb which removes {approximately}500 bp of the transcript. In addition, analysis of lymphoblast RNA by RT-PCR from 50 patients has revealed one splicing mutation resulting in the removal of a 135 bp exon. Further analysis of the single copy region of this gene is underway and strategies to screen the duplicated area of the gene for mutations are being explored.

Peral, B.; Ward, C.J.; Thomas, S. [John Radcliffe Hospital, Oxford (United Kingdom)] [and others

1994-09-01

359

A novel Twinkle (PEO1) gene mutation in a Chinese family with adPEO  

PubMed Central

Purpose Autosomal dominant progressive external ophthalmoplegia (adPEO) is a genetically heterogeneous, adult-onset disease. Thus far, disease loci have been identified on four different nuclear genes. The purpose of this study is to identify the gene responsible for causing adPEO in a Chinese family. Methods Clinical data and genomic DNA of a Chinese adPEO family were collected following informed consent. Gene scan by two-point linkage analysis was performed for four genes, and mutation screening was conducted in the Twinkle (PEO1) gene by direct sequencing. Results A maximum two-point LOD score of 2.8 at ?=0.00 was obtained with marker D10S192 in close proximity to PEO1. A novel missense mutation (c.1423G>A, p.475A>T) was identified. Conclusions This study widens the mutation spectrum of PEO1 and is the first to report the PEO1 mutation in the Chinese population. PMID:18989381

Liu, Zhirong; Du, Ailian; Zhang, Baorong; Zhao, Guohua

2008-01-01

360

Targeted disruption of Ataxia-telangiectasia mutated gene in miniature pigs by somatic cell nuclear transfer.  

PubMed

Ataxia telangiectasia (A-T) is a recessive autosomal disorder associated with pleiotropic phenotypes, including progressive cerebellar degeneration, gonad atrophy, and growth retardation. Even though A-T is known to be caused by the mutations in the Ataxia telangiectasia mutated (ATM) gene, the correlation between abnormal cellular physiology caused by ATM mutations and the multiple symptoms of A-T disease has not been clearly determined. None of the existing ATM mouse models properly reflects the extent to which neurological degeneration occurs in human. In an attempt to provide a large animal model for A-T, we produced gene-targeted pigs with mutations in the ATM gene by somatic cell nuclear transfer. The disrupted allele in the ATM gene of cloned piglets was confirmed via PCR and Southern blot analysis. The ATM gene-targeted pigs generated in the present study may provide an alternative to the current mouse model for the study of mechanisms underlying A-T disorder and for the development of new therapies. PMID:25193705

Kim, Young June; Ahn, Kwang Sung; Kim, Minjeong; Kim, Min Ju; Park, Sang-Min; Ryu, Junghyun; Ahn, Jin Seop; Heo, Soon Young; Kang, Jee Hyun; Choi, You Jung; Choi, Seong-Jun; Shim, Hosup

2014-10-01

361

A mutation in arylsulfatase B gene causes mucopolysuccharidosis VI in rats  

SciTech Connect

Mucopolysuccharidosis (MPS) type VI comprises a group of autosomal recessive disorders caused by the deficiency of arylsulfatase B (ARSB) and subsequent lysosomal storage of glucosaminoglycans. We have identified a mutant rat strain that has remarkable similarites to human MPS VI. Recently, we have localized the autosomal recessive gene for the mutant phenotype on rat chromosome 2 by linkage analysis. The rat chromosome 2 is syntenic with the human and mouse chromosomes on which ARSB genes were assigned. Thus the mutant rats were expected to have a mutation in the ARSB gene. A normal rat liver cDNA library was screened using the cat ARSB cDNA as a probe, and clones which cover almost all of the complete ARSB open reading frame were isolated. The nucleotide sequence and amino acid sequence of the rat ARSB sequence showed 80% and 85% similarities with the human ARSB gene, respectively. The ARSB gene was assigned to rat chromosome 2 by using a rat-mouse hybrid cell panel, confirming the linkage analysis. Based on the nucleotide sequence of the normal rat ARSB gene, RT-PCR using liver RNA of the mutant rat was carried out to isolate the cDNA of the mutant rat ARSB gene. By sequencing several independent clones, the cDNA of the mutant rat was found to have a one base insertion at nucleotide 507, resulting in a frameshift mutation in the coding region of the rat ARSB gene, which introduces a stop codon in position 258 of the putative ARSB polypeptide. All affected MPS VI rats were homozygous for the mutant allele, while all phenotypically normal rats were heterozygous or homozygous for the wild type allele, indicating a perfect correspondence between the MPS VI phenotype and the genotype of the mutation. We conclude that the mutation in the ARSB gene is responsible for MPS VI in the rat, and that the mutant rat is an excellent model for study of human MPS VI pathogenesis and treatment.

Kunieda, T.; Ikadai, H.; Desnick, R.J. [Mt. Sinai School of Medicine, New York, NY (United States)] [and others

1994-09-01

362

Germ-line mutations in mismatch repair genes associated with prostate cancer.  

PubMed

Genetic predisposition to prostate cancer includes multiple common variants with a low penetrance (single nucleotide polymorphisms) and rare variants with higher penetrance. The mismatch repair (MMR) genes MLH1, MSH2, MSH6, and PMS2 are associated with Lynch syndrome where colon and endometrial cancers are the predominant phenotypes. The purpose of our study was to investigate whether germ-line mutations in these genes may be associated with prostate cancer. One hundred and six male carriers or obligate carriers of MMR mutations were identified. Nine had contracted prostate cancer. Immunohistochemical analysis was done on tumor tissue from eight of the nine tumors. Observed incidence, cumulative risk at 60 and 70 years of age, age of onset, and Gleason score were compared with expected as assessed from population-based series. Absence of gene product from the mutated MMR gene was found in seven of eight tumors. Expected number of prostate cancers was 1.52 compared with 9 observed (P < 0.01). Mean age of onset of prostate cancer was 60.4 years compared with 66.6 expected (P = 0.006); the number of men with a Gleason score between 8 and 10 was significantly higher than expected (P < 0.00001). Kaplan-Meier analysis suggested that cumulative risk by 70 years in MMR mutation carriers may be 30% (SE, 0.088) compared with 8.0% in the general population. This is similar to the high risk associated with BRCA2 mutations. To our knowledge, this study is the first to indicate that the MMR genes may be among the rare genetic variants that confer a high risk of prostate cancer when mutated. PMID:19723918

Grindedal, Eli Marie; Mřller, Pĺl; Eeles, Ros; Stormorken, Astrid Tenden; Bowitz-Lothe, Inger Marie; Landrř, Stefan Magnus; Clark, Neal; Kvĺle, Rune; Shanley, Susan; Maehle, Lovise

2009-09-01

363

Mutational and expressional analysis of SMC2 gene in gastric and colorectal cancers with microsatellite instability.  

PubMed

Structural maintenance of chromosomes 2 (SMC2) gene encodes condensin complexes that are required for proper chromosome segregation and maintenance of chromosomal stability. Although cells with defective chromosome segregation become aneuploid and are prone to harbor chromosome instability, pathologic implications of SMC2 gene alterations are largely unknown. In a public database, we found that SMC2 gene had mononucleotide repeats that could be mutated in cancers with microsatellite instability (MSI). In this study, we analyzed these repeats in 32 gastric cancers (GC) with high MSI (MSI-H), 59 GC with low MSI (MSI-L)/stable MSI (MSS), 43 colorectal cancers (CRC) with MSI-H and 60 CRC with MSI-L/MSS by single-strand conformation polymorphism (SSCP) and DNA sequencing. We also analyzed SMC2 protein expression in GC and CRC tissues using immunohistochemistry. We found SMC2 frameshift mutations in two GC and two CRC that would result in truncation of SMC2. The mutations were detected exclusively in MSI-H cancers, but not in MSI-L/MSS cancers. Loss of SMC2 expression was observed in 22% of GC and 25% of CRC. Of note, all of the cancers with SMC2 frameshift mutations displayed loss of SMC2 expression. Also, both GC and CRC with MSI-H had significantly higher incidences in SMC2 frameshift mutations and loss of SMC2 expression than those with MSI-L/MSS. Our data indicate that SMC2 gene is altered by both frameshift mutation and loss of expression in GC and CRC with MSI-H, and suggest that SMC2 gene alterations might be involved in pathogenesis of these cancers. PMID:24483990

Je, Eun Mi; Yoo, Nam Jin; Lee, Sug Hyung

2014-06-01

364

Nonsense mutation-associated Becker muscular dystrophy: interplay between exon definition and splicing regulatory elements within the DMD gene.  

PubMed

Nonsense mutations are usually predicted to function as null alleles due to premature termination of protein translation. However, nonsense mutations in the DMD gene, encoding the dystrophin protein, have been associated with both the severe Duchenne Muscular Dystrophy (DMD) and milder Becker Muscular Dystrophy (BMD) phenotypes. In a large survey, we identified 243 unique nonsense mutations in the DMD gene, and for 210 of these we could establish definitive phenotypes. We analyzed the reading frame predicted by exons flanking those in which nonsense mutations were found, and present evidence that nonsense mutations resulting in BMD likely do so by inducing exon skipping, confirming that exonic point mutations affecting exon definition have played a significant role in determining phenotype. We present a new model based on the combination of exon definition and intronic splicing regulatory elements for the selective association of BMD nonsense mutations with a subset of DMD exons prone to mutation-induced exon skipping. PMID:21972111

Flanigan, Kevin M; Dunn, Diane M; von Niederhausern, Andrew; Soltanzadeh, Payam; Howard, Michael T; Sampson, Jacinda B; Swoboda, Kathryn J; Bromberg, Mark B; Mendell, Jerry R; Taylor, Laura E; Anderson, Christine B; Pestronk, Alan; Florence, Julaine M; Connolly, Anne M; Mathews, Katherine D; Wong, Brenda; Finkel, Richard S; Bonnemann, Carsten G; Day, John W; McDonald, Craig; Weiss, Robert B

2011-03-01

365

Nonsense mutation-associated Becker muscular dystrophy: interplay between exon definition and splicing regulatory elements within the DMD gene  

PubMed Central

Nonsense mutations are usually predicted to function as null alleles due to premature termination of protein translation. However, nonsense mutations in the DMD gene, encoding the dystrophin protein, have been associated with both the severe Duchenne Muscular Dystrophy (DMD) and milder Becker Muscular Dystrophy (BMD) phenotypes. In a large survey, we identified 243 unique nonsense mutations in the DMD gene, and for 210 of these we could establish definitive phenotypes. We analyzed the reading frame predicted by exons flanking those in which nonsense mutations were found, and present evidence that nonsense mutations resulting in BMD likely do so by inducing exon skipping, confirming that exonic point mutations affecting exon definition have played a significant role in determining phenotype. We present a new model based on the combination of exon definition and intronic splicing regulatory elements for the selective association of BMD nonsense mutations with a subset of DMD exons prone to mutation-induced exon skipping. PMID:21972111

Flanigan, Kevin M.; Dunn, Diane M.; von Niederhausern, Andrew; Soltanzadeh, Payam; Howard, Michael T.; Sampson, Jacinda B.; Swoboda, Kathryn J.; Bromberg, Mark B.; Mendell, Jerry R.; Taylor, Laura; Anderson, Christine B.; Pestronk, Alan; Florence, Julaine; Connolly, Anne M.; Mathews, Katherine D.; Wong, Brenda; Finkel, Richard S.; Bonnemann, Carsten G.; Day, John W.; McDonald, Craig; Weiss, Robert B.

2013-01-01

366

Deficiency of Factor XIII Gene in Chinese: 3 Novel Mutations  

Microsoft Academic Search

A defect in the factor XIII gene can result in lifelong bleeding tendency. In 3 Chinese families, hereditary coagulation factor\\u000a XIII deficiency was diagnosed on the basis of the clinical syndrome and solubility of fibrin clot in 5 mol\\/L urea. We sequenced\\u000a all of the FXIIIA gene exons and the flanking region and found 3 novel defects in the factor

Baohua Duan; Xuefeng Wang; Haiyan Chu; Yiqun Hu; Xiaping Huang; Bin Qu; Hongli Wang; Zhenyi Wang

2003-01-01

367

Mutation analysis of the MSMB gene in familial prostate cancer  

Microsoft Academic Search

Background:MSMB, a gene coding for ?-microseminoprotein, has been identified as a candidate susceptibility gene for prostate cancer (PrCa) in two genome-wide association studies (GWAS). SNP rs10993994 is 2 bp upstream of the transcription initiation site of MSMB and was identified as an associated PrCa risk variant. The MSMB protein is underexpressed in PrCa and it was previously proposed to be

Z Kote-Jarai; D Leongamornlert; M Tymrakiewicz; H Field; M Guy; A A Al Olama; J Morrison; L O'Brien; R Wilkinson; A Hall; E Sawyer; K Muir; F Hamdy; J Donovan; D Neal; D Easton; R Eeles

2010-01-01

368

Multigenerational Brazilian family with malignant hyperthermia and a novel mutation in the RYR1 gene.  

PubMed

Malignant hyperthermia (MH) is a pharmacogenetic disease triggered in susceptible individuals by the administration of volatile halogenated anesthetics and/or succinylcholine, leading to the development of a hypermetabolic crisis, which is caused by abnormal release of Ca2+ from the sarcoplasmic reticulum, through the Ca2+ release channel ryanodine receptor 1 (RyR1). Mutations in the RYR1 gene are associated with MH in the majority of susceptible families. Genetic screening of a 5-generation Brazilian family with a history of MH-related deaths and a previous MH diagnosis by the caffeine halothane contracture test (CHCT) in some individuals was performed using restriction and sequencing analysis. A novel missense mutation, Gly4935Ser, was found in an important functional and conserved locus of this gene, the transmembrane region of RyR1. In this family, 2 MH-susceptible individuals previously diagnosed with CHCT carry this novel mutation and another 24 not previously diagnosed members also carry it. However, this same mutation was not found in another MH-susceptible individual whose CHCT was positive to the test with caffeine but not to the test with halothane. None of the 5 MH normal individuals of the family, previously diagnosed by CHCT, carry this mutation, nor do 100 controls from control Brazilian and USA populations. The Gly4932Ser variant is a candidate mutation for MH, based on its co-segregation with disease phenotype, absence among controls and its location within the protein. PMID:19918671

Matos, A R; Sambuughin, N; Rumjanek, F D; Amoedo, N D; Cunha, L B P; Zapata-Sudo, G; Sudo, R T

2009-12-01

369

Mutations in mutT genes of Mycobacterium tuberculosis isolates of Beijing genotype.  

PubMed

Missense alterations in genes mutT4 and mutT2, which encode DNA repair enzymes, were sequenced from 30 clinical isolates of Mycobacterium tuberculosis of Beijing genotype, mostly from patients with primary tuberculosis, to evaluate their contribution to anti-mycobacterial drug resistance. The mutation Arg to Gly at codon position 48 (CGG to GGG) of mutT4 was found in 21 isolates; of these, 16 isolates also harboured the mutation Gly to Arg at position 58 (GGA to CGA) of mutT2. No statistically significant association was found between mutT4 and mutT2 mutations, and drug resistance. Furthermore, no mutations in mutT4 or mutT2 were found in any of 24 isolates resistant to multiple drugs, nor in 28 anti-mycobacterial drug-susceptible isolates of different genotypes. These data confirm that the polymorphism of mutT genes is characteristic and unique to the Beijing phylogenetic lineage. The mutator phenotype does not appear to increase prevalence of drug resistance, but further studies are required to investigate the mutation rates of Beijing isolates in response to drug exposure. PMID:16585648

Lari, Nicoletta; Rindi, Laura; Bonanni, Daniela; Tortoli, Enrico; Garzelli, Carlo

2006-05-01

370

Germ-line mutations in the neurofibromatosis 2 gene: Correlations with disease severity and retinal abnormalities  

SciTech Connect

Neurofibromatosis 2 (NF2) features bilateral vestibular schwannomas, other benign neural tumors, and cataracts. Patients in some families develop many tumors at an early age and have rapid clinical progression, whereas in other families, patients may not have symptoms until much later and vestibular schwannomas may be the only tumors. The NF2 gene has been cloned from chromosome 22q; most identified germ-line mutations result in a truncated protein and severe NF2. To look for additional mutations and clinical correlations, we used SSCP analysis to screen DNA from 32 unrelated patients. We identified 20 different mutations in 21 patients (66%): 10 nonsense mutations, 2 frameshifts, 7 splice-site mutations, and 1 large in-frame deletion. Clinical information on 47 patients from the 21 families included ages at onset and at diagnosis, numbers of meningiomas, spinal and skin tumors, and presence of cataracts and retinal abnormalities. We compared clinical findings in patients with nonsense or frameshift mutations to those with splice-site mutations. When each patient was considered as an independent random event, the two groups differed (P {le} .05) for nearly every variable. Patients with nonsense or frameshift mutations were younger at onset and at diagnosis and had a higher frequency and mean number of tumors, supporting the correlation between nonsense and frameshift mutations and severe NF2. When each family was considered as an independent random event, statistically significant differences between the two groups were observed only for mean ages at onset and at diagnosis. A larger data set is needed to resolve these discrepancies. We observed retinal hamartomas and/or epiretinal membranes in nine patients from five families with four different nonsense mutations. This finding, which may represent a new genotype-phenotype correlation, merits further study. 58 refs., 2 tabs.

Parry, D.M. [National Cancer Inst., Bethesda, WA (United States); Kaiser-Kupfer, M. [National Eye Inst., Bethesda, MD (United States); Eldridge, R. [Public Health Service, Bethesda, MD (United States)] [and others

1996-09-01

371

RFLP haplotyping and mutation analysis of the phenylalanine hydroxylase gene in Dutch phenylketonuria families.  

PubMed

Restriction fragment length polymorphism haplotyping of mutated and normal phenylalanine hydroxylase (PAH) alleles in 49 Dutch phenylketonuria (PKU) families was performed. All mutant PAH chromosomes identified by haplotyping (n = 98) were screened for eight of the most predominant mutations. Compound heterozygosity was proven in 40 kindreds. Homozygosity was found for the IVS/2nt1 mutation in 5 families, and for the R158Q and IVS10nt546 mutations in one family each. All patients from these families suffer from severe PKU, providing additional proof that these mutations are deleterious for the PAH gene. Genotypical heterogeneity was evident for mutant haplotype 1 (n = 27) carrying the mutations R261Q (n = 12), E280K (n = 4, P281L (n = 1) and unknown (n = 10), and likewise for mutant haplotype 4 (n = 30) carrying the mutations R158Q (n = 13), Y414C (n = 1) and unknown (n = 16). Mutant haplotype 3 (n = 20), in tight association with mutation IVS12nt1, appeared to be in strong linkage disequilibrium (LDE) with its normal counterpart allele (n = 4). Mutant haplotype 6 (n = 4), in tight association with the IVS10nt546 mutation, showed moderate LDE with its counterpart allele (n = 1). The distribution of the mutant PAH haplotypes 1, 3 and 4 among the Dutch PKU population resembles that in other Northern and Western European countries, but it is striking that mutant haplotype 2 and its associated mutation R408W is nearly absent in The Netherlands, in strong contrast to its neighbouring countries. PMID:7903270

Meijer, H; Jongbloed, R J; Hekking, M; Spaapen, L J; Geraedts, J P

1993-12-01

372

Mutations in tubulin genes are frequent causes of various foetal malformations of cortical development including microlissencephaly  

PubMed Central

Complex cortical malformations associated with mutations in tubulin genes are commonly referred to as “Tubulinopathies”. To further characterize the mutation frequency and phenotypes associated with tubulin mutations, we studied a cohort of 60 foetal cases. Twenty-six tubulin mutations were identified, of which TUBA1A mutations were the most prevalent (19 cases), followed by TUBB2B (6 cases) and TUBB3 (one case). Three subtypes clearly emerged. The most frequent (n?=?13) was microlissencephaly with corpus callosum agenesis, severely hypoplastic brainstem and cerebellum. The cortical plate was either absent (6/13), with a 2–3 layered pattern (5/13) or less frequently thickened (2/13), often associated with neuroglial overmigration (4/13). All cases had voluminous germinal zones and ganglionic eminences. The second subtype was lissencephaly (n?=?7), either classical (4/7) or associated with cerebellar hypoplasia (3/7) with corpus callosum agenesis (6/7). All foetuses with lissencephaly and cerebellar hypoplasia carried distinct TUBA1A mutations, while those with classical lissencephaly harbored recurrent mutations in TUBA1A (3 cases) or TUBB2B (1 case). The third group was polymicrogyria-like cortical dysplasia (n?=?6), consisting of asymmetric multifocal or generalized polymicrogyria with inconstant corpus callosum agenesis (4/6) and hypoplastic brainstem and cerebellum (3/6). Polymicrogyria was either unlayered or 4-layered with neuronal heterotopias (5/6) and occasional focal neuroglial overmigration (2/6). Three had TUBA1A mutations and 3 TUBB2B mutations. Foetal TUBA1A tubulinopathies most often consist in microlissencephaly or classical lissencephaly with corpus callosum agenesis, but polymicrogyria may also occur. Conversely, TUBB2B mutations are responsible for either polymicrogyria (4/6) or microlissencephaly (2/6). PMID:25059107

2014-01-01

373

A novel mutation in the ADA gene causing severe combined immunodeficiency in an Arab patient: a case report  

PubMed Central

Introduction About 20% of the cases of human severe combined immunodeficiency are the result of the child being homozygous for defective genes encoding the enzyme adenosine deaminase. To our knowledge, the mutation pattern in Arab patients with severe combined immunodeficiency has never been reported previously. Case presentation A 14-month-old Arab boy had clinical features typical of severe combined immunodeficiency. His clinical picture and flow cytometric analysis raised the diagnosis of adenosine deaminase deficiency and prompted us to screen the adenosine deaminase gene for mutation(s). We detected a novel mutation in exon 9 of the adenosine deaminase gene (p.Arg282>Gln), which we believe is the cause of the severe combined immunodeficiency phenotype observed in our patient. Conclusion This is the first report of adenosine deaminase mutation in an Arab patient with severe combined immunodeficiency due to a novel pathogenic mutation in the adenosine deaminase gene. PMID:19830125

2009-01-01

374

Spontaneous recurrent mutations and a complex rearrangement in the MECP2 gene in the light of current models of mutagenesis.  

PubMed

Mutations in the methyl-CpG-binding protein 2 (MECP2) gene are associated with Rett syndrome (RTT). The MECP2 gene has some unique characteristics: (1) it is mainly affected by de novo mutations, due to recurrent independent mutational events in a defined "hot spot" regions or positions; (2) complex mutational events along a single allele are frequently found in this gene; (3) most mutations arise on paternal X chromosome. The recurrent point mutations involve mainly CpG dinucleotides, where C>T transitions are explained by methylation-mediated deamination. The complex mutational events might be explained by the genomic architecture of the region involving the MECP2 gene. The finding that most spontaneous mutations arise on paternal X-chromosome supports the higher contribution of replication-mediated mechanism of mutagenesis. We present 9 types of mutations in the MECP2 gene, detected in a group of 22 Bulgarian and 6 Romanian classical RTT patients. Thirteen patients were clarified on molecular level (46.4%). The point mutations in our sample account for 61.5%. One intraexonic deletion was detected in the present study (7.7%). One novel insertion c.321_322insGAAG, p.(Lys107_Leu108insGluAlafs2*) was found (7.7%). Large deletions and complex mutations account for 23%. A novel complex mutational event c.[584_624del41insTT; 638delTinsCA] was detected in a Romanian patient. We discuss different types of the MECP2 mutations detected in our sample in the light of the possible mechanisms of mutagenesis. Complex gene rearrangements involving a combination of deletions and insertions have always been most difficult to detect, to specify precisely and hence to explain in terms of their underlying mutational mechanisms. PMID:22525432

Todorov, Tihomir; Todorova, Albena; Motoescu, Cristina; Dimova, Petia; Iancu, Daniela; Craiu, Dana; Stoian, Daniela; Barbarii, Ligia; Bojinova, Veneta; Mitev, Vanyo

2012-06-01

375

Boundaries of somatic mutation in rearranged immunoglobulin genes: 5' boundary is near the promoter, and 3' boundary is approximately 1 kb from V(D)J gene  

PubMed Central

To investigate why somatic mutations are spatially restricted to a region around the rearranged V(D)J immunoglobulin gene, we compared the distribution of mutations flanking murine V gene segments that had rearranged next to either proximal or distal J gene segments. 124 nucleotide substitutions, nine deletions, and two insertions were identified in 32,481 bp of DNA flanking the coding regions from 17 heavy and kappa light chain genes. Most of the mutations occurred within a 2-kb region centered around the V(D)J gene, regardless of which J gene segment was used, suggesting that the structural information for mutation is located in sequences around and within the V(D)J gene, and not in sequences downstream of the J gene segments. The majority of mutations were found within 300 bp of DNA flanking the 5' side of the V(D)J gene and 850 bp flanking the 3' side at a frequency of 0.8%, which was similar to the frequency in the coding region. The frequency of flanking mutations decreased as a function of distance from the gene. There was no evidence for hot spots in that every mutation was unique and occurred at a different position. No mutations were found upstream of the promoter region, suggesting that the promoter delimits a 5' boundary, which provides strong evidence that transcription is necessary to generate mutation. The 3' boundary was approximately 1 kb from the V(D)J gene and was not associated with a DNA sequence motif. Occasional mutations were located in the nuclear matrix association and enhancer regions. The pattern of substitutions suggests that there is discrimination between the two DNA strands during mutation, in that the four bases were mutated with different frequencies on each strand. The high frequency of mutations in the 3' flanking region and the uniqueness of each mutation argues against templated gene conversion as a mechanism for generating somatic diversity in murine V(D)J genes. Rather, the data support a model for random point mutations where the mechanism is linked to the transcriptional state of the gene. PMID:2258702

1990-01-01

376

The G389R mutation in the MAPT gene presenting as sporadic corticobasal syndrome.  

PubMed

A few patients with mutations in the microtubule-associated protein tau gene (MAPT), affected by frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17T), may clinically present with a corticobasal syndrome (CBS). We report a case of apparently sporadic CBS bearing a mutation in the MAPT gene so far associated with frontotemporal dementia (FTD) phenotype. The patient is a 41-year-old man with progressive asymmetric signs of cortical and basal ganglia involvement consistent with CBS. Magnetic resonance imaging showed asymmetric cortical atrophy and unusual corticospinal tract hyperintensity in T2-weighted images. Genetic testing revealed a heterozygous G to C mutation at the first base of codon 389 of the MAPT gene, changing glycine to arginine (G389R), in the patient and his unaffected elderly father. In conclusion, the MAPT G389R mutation shows phenotypic variability resulting in both FTD and CBS. The mutation also demonstrates incomplete penetrance. Corticospinal tract degeneration is an exceptional finding. PMID:18307268

Rossi, Giacomina; Marelli, Cecilia; Farina, Laura; Laurŕ, Matilde; Maria Basile, Anna; Ciano, Claudia; Tagliavini, Fabrizio; Pareyson, Davide

2008-04-30

377

Identification of mutations in the NUCB2/nesfatin gene in children with severe obesity.  

PubMed

Nesfatin-1 is the N-terminal fragment of nucleobindin-2 (NUCB2) that was identified as a novel satiety molecule in rodents. The protein is reported to exert anorexigenic effects and appears to play an important role in hypothalamic pathways regulating energy homeostasis and food intake. In this study, we hypothesized that mutations in the nesfatin encoding gene NUCB2 might cause obesity in humans. Therefore, we screened the entire coding region of the NUCB2 gene for mutations in a population of 471 obese children and adolescents. Mutation analysis of NUCB2 identified a total of seven sequence variants of which four were previously reported as polymorphisms. The remaining three variants included ex9+6G>C, L125H and K178X and were found in 3 unrelated individuals in the obese population only (0.6%). Biochemical experiments including ELISA and western blot were performed on plasma samples of the obese patient carrying the nonsense mutation K178X. However, neither NUCB2/nesfatin-1 immunoreactive plasma levels of the patient, nor expression of full length NUCB2 differed significantly from matched obese control individuals. In conclusion, we have identified the first genetic variants in the NUCB2 gene in obese individuals, although further functional characterization will be essential to verify disease causality of the mutations. PMID:23141462

Zegers, Doreen; Beckers, Sigri; de Freitas, Fenna; Jennes, Karen; Van Camp, Jasmijn K; Mertens, Ilse L; Van Hoorenbeeck, Kim; Rooman, Raoul P; Desager, Kristine N; Massa, Guy; Van Gaal, Luc F; Van Hul, Wim

2012-12-01

378

Frequent Mutations of Chromatin Remodeling Gene ARID1A in Ovarian Clear Cell Carcinoma  

PubMed Central

Ovarian Clear Cell Carcinoma (OCCC) is an aggressive human cancer that is generally resistant to therapy. To explore the genetic origin of OCCC, we determined the exomic sequences of eight tumors after immunoaffinity purification of cancer cells. Through comparative analyses of normal cells from the same patients, we identified four genes that were mutated in at least two tumors. PIK3CA, which encodes a subunit of phosphatidylinositol-3 kinase, and KRAS, which encodes a well known oncoprotein, had previously been implicated in OCCC. The other two mutated genes were novel: PPP2R1A encodes a regulatory subunit of serine/threonine phosphatase 2 and ARID1A encodes AT-rich interactive domain-containing protein 1A, which participates in chromatin remodeling. The nature and pattern of the mutations suggest that PPP2R1A functions as an oncogene and ARID1A as a tumor suppressor gene. In a total of 42 OCCCs, 7% had mutations in PPP2R1A and 57% had mutations in ARID1A. These results suggest that aberrant chromatin remodeling contributes to the pathogenesis of OCCC. PMID:20826764

Jones, Sian; Wang, Tian-Li; Shih, Ie-Ming; Mao, Tsui-Lien; Nakayama, Kentaro; Roden, Richard; Glas, Ruth; Slamon, Dennis; Diaz, Luis A.; Vogelstein, Bert; Kinzler, Kenneth W.; Velculescu, Victor E.; Papadopoulos, Nickolas

2011-01-01

379

Frequent mutations of chromatin remodeling gene ARID1A in ovarian clear cell carcinoma.  

PubMed

Ovarian clear cell carcinoma (OCCC) is an aggressive human cancer that is generally resistant to therapy. To explore the genetic origin of OCCC, we determined the exomic sequences of eight tumors after immunoaffinity purification of cancer cells. Through comparative analyses of normal cells from the same patients, we identified four genes that were mutated in at least two tumors. PIK3CA, which encodes a subunit of phosphatidylinositol-3 kinase, and KRAS, which encodes a well-known oncoprotein, had previously been implicated in OCCC. The other two mutated genes were previously unknown to be involved in OCCC: PPP2R1A encodes a regulatory subunit of serine/threonine phosphatase 2, and ARID1A encodes adenine-thymine (AT)-rich interactive domain-containing protein 1A, which participates in chromatin remodeling. The nature and pattern of the mutations suggest that PPP2R1A functions as an oncogene and ARID1A as a tumor-suppressor gene. In a total of 42 OCCCs, 7% had mutations in PPP2R1A and 57% had mutations in ARID1A. These results suggest that aberrant chromatin remodeling contributes to the pathogenesis of OCCC. PMID:20826764

Jones, Siân; Wang, Tian-Li; Shih, Ie-Ming; Mao, Tsui-Lien; Nakayama, Kentaro; Roden, Richard; Glas, Ruth; Slamon, Dennis; Diaz, Luis A; Vogelstein, Bert; Kinzler, Kenneth W; Velculescu, Victor E; Papadopoulos, Nickolas

2010-10-01

380

Mutations of the CEP290 gene encoding a centrosomal protein cause Meckel-Gruber syndrome.  

PubMed

Meckel-Gruber syndrome (MKS) is an autosomal recessive, lethal multisystemic disorder characterized by meningooccipital encephalocele, cystic kidney dysplasia, hepatobiliary ductal plate malformation, and postaxial polydactyly. Recently, genes for MKS1 and MKS3 were identified, putting MKS on the list of ciliary disorders (ciliopathies). By positional cloning in a distantly related multiplex family, we mapped a novel locus for MKS to a 3-Mb interval on 12q21. Sequencing of the CEP290 gene located in the minimal critical region showed a homozygous 1-bp deletion supposed to lead to loss of function of the encoded centrosomal protein CEP290/nephrocystin-6. CEP290 is thought to be involved in chromosome segregation and localizes to cilia, centrosomes, and the nucleus. Subsequent analysis of another consanguineous multiplex family revealed homozygous haplotypes and the same frameshift mutation. Our findings add to the increasing body of evidence that ciliopathies can cause a broad spectrum of disease phenotypes, and pleiotropic effects of CEP290 mutations range from single organ involvement with isolated Leber congenital amaurosis to Joubert syndrome and lethal early embryonic multisystemic malformations in Meckel-Gruber syndrome. We compiled clinical and genetic data of all patients with CEP290 mutations described so far. No clear-cut genotype-phenotype correlations were apparent as almost all mutations are nonsense, frameshift, or splice-site changes and scattered throughout the gene irrespective of the patients' phenotypes. Conclusively, other factors than the type and location of CEP290 mutations may underlie phenotypic variability. PMID:17705300

Frank, Valeska; den Hollander, Anneke I; Brüchle, Nadina Ortiz; Zonneveld, Marijke N; Nürnberg, Gudrun; Becker, Christian; Du Bois, Gabriele; Kendziorra, Heide; Roosing, Susanne; Senderek, Jan; Nürnberg, Peter; Cremers, Frans P M; Zerres, Klaus; Bergmann, Carsten

2008-01-01

381

The DNA Polymerase Replication Error Spectrum in the Adenomatous Polyposis Coli Gene Contains Human Colon Tumor Mutational Hotspots1  

Microsoft Academic Search

We have found a significant concordance between the in vitro replica- tion errors of human DNA polymerase and in vivo point mutations of the adenomatous polyposis coli (APC) gene that leads to colon cancer. We determined the error spectrum of DNA polymerase in the human APC gene under PCR conditions and compared it with the set of mutations