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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

Surface gene mutations of hepatitis B virus among high-risk patients with occult hepatitis B virus infection.  

PubMed

Surface gene mutants of hepatitis B virus (HBV) have been reported in a variety of patient groups. Because of limited data regarding these mutations in patients with occult HBV infections; we aimed to determine these mutations among high-risk patients with occult HBV infection. The presence of HBV-DNA was determined in patients with isolated anti-HBc by real-time polymerase chain reaction (PCR). Then, surface gene region was amplified by nested PCR and mutations were analyzed after sequencing. The mutations that resulted in nonfunctional hepatitis B surface antigen (HBsAg) were insertion of single nucleotide in 2 cases, which causes frameshift and single-nucleotide replacement, and premature stop codons at Leu15 and Gly10 in the other 2 cases. Amino acid substitution at amino acid position 207(S207N) was found in the other isolates. Our study suggested that "a" region mutations did not play a major role in HBsAg detection, and other genetic and nongenetic factors may be responsible for failure to detect HBsAg by routine laboratory tests. PMID:19903586

Hamkar, Rasool; Aghakhani, Arezoo; Soufian, Safyeh; Banifazl, Mohammad; Ghavami, Nastaran; Nadri, Mahsa; Sofian, Masoomeh; Ahmadi, Farrokhlagha; Razeghi, Effat; Eslamifar, Ali; Ramezani, Amitis

2010-03-01

3

PRRT2 gene mutations  

PubMed Central

ABSTRACT Objective: The proline-rich transmembrane protein (PRRT2) gene was recently identified using exome sequencing as the cause of autosomal dominant paroxysmal kinesigenic dyskinesia (PKD) with or without infantile convulsions (IC) (PKD/IC syndrome). Episodic neurologic disorders, such as epilepsy, migraine, and paroxysmal movement disorders, often coexist and are thought to have a shared channel-related etiology. To investigate further the frequency, spectrum, and phenotype of PRRT2 mutations, we analyzed this gene in 3 large series of episodic neurologic disorders with PKD/IC, episodic ataxia (EA), and hemiplegic migraine (HM). Methods: The PRRT2 gene was sequenced in 58 family probands/sporadic individuals with PKD/IC, 182 with EA, 128 with HM, and 475 UK and 96 Asian controls. Results: PRRT2 genetic mutations were identified in 28 out of 58 individuals with PKD/IC (48%), 1/182 individuals with EA, and 1/128 individuals with HM. A number of loss-of-function and coding missense mutations were identified; the most common mutation found was the p.R217Pfs*8 insertion. Males were more frequently affected than females (ratio 52:32). There was a high proportion of PRRT2 mutations found in families and sporadic cases with PKD associated with migraine or HM (10 out of 28). One family had EA with HM and another large family had typical HM alone. Conclusions: This work expands the phenotype of mutations in the PRRT2 gene to include the frequent occurrence of migraine and HM with PKD/IC, and the association of mutations with EA and HM and with familial HM alone. We have also extended the PRRT2 mutation type and frequency in PKD and other episodic neurologic disorders.

Gardiner, Alice R.; Bhatia, Kailash P.; Stamelou, Maria; Dale, Russell C.; Kurian, Manju A.; Schneider, Susanne A.; Wali, G.M.; Counihan, Tim; Schapira, Anthony H.; Spacey, Sian D.; Valente, Enza-Maria; Silveira-Moriyama, Laura; Teive, Helio A.G.; Raskin, Salmo; Sander, Josemir W.; Lees, Andrew; Warner, Tom; Kullmann, Dimitri M.; Wood, Nicholas W.; Hanna, Michael

2012-01-01

4

Mutations on the DNA Binding Surface of TBP Discriminate between Yeast TATA and TATA-Less Gene Transcription.  

PubMed

Most RNA polymerase (Pol) II promoters lack a TATA element, yet nearly all Pol II transcription requires TATA binding protein (TBP). While the TBP-TATA interaction is critical for transcription at TATA-containing promoters, it has been unclear whether TBP sequence-specific DNA contacts are required for transcription at TATA-less genes. Transcription factor IID (TFIID), the TBP-containing coactivator that functions at most TATA-less genes, recognizes short sequence-specific promoter elements in metazoans, but analogous promoter elements have not been identified in Saccharomyces cerevisiae. We generated a set of mutations in the yeast TBP DNA binding surface and found that most support growth of yeast. Both in vivo and in vitro, many of these mutations are specifically defective for transcription of two TATA-containing genes with only minor defects in transcription of two TATA-less, TFIID-dependent genes. TBP binds several TATA-less promoters with apparent high affinity, but our results suggest that this binding is not important for transcription activity. Our results are consistent with the model that sequence-specific TBP-DNA contacts are not important at yeast TATA-less genes and suggest that other general transcription factors or coactivator subunits are responsible for recognition of TATA-less promoters. Our results also explain why yeast TBP derivatives defective for TATA binding appear defective in activated transcription. PMID:24865972

Kamenova, Ivanka; Warfield, Linda; Hahn, Steven

2014-08-01

5

Mutations in Arabidopsis thaliana genes involved in the tryptophan biosynthesis pathway affect root waving on tilted agar surfaces  

NASA Technical Reports Server (NTRS)

Arabidopsis thaliana roots grow in a wavy pattern upon a slanted surface. A novel mutation in the anthranilate synthase alpha 1 (ASA1) gene, named trp5-2wvc1, and mutations in the tryptophan synthase alpha and beta 1 genes (trp3-1 and trp2-1, respectively) confer a compressed root wave phenotype on tilted agar surfaces. When trp5-2wvc1 seedlings are grown on media supplemented with anthranilate metabolites, their roots wave like wild type. Genetic and pharmacological experiments argue that the compressed root wave phenotypes of trp5-2wvc1, trp2-1 and trp3-1 seedlings are not due to reduced IAA biosynthetic potential, but rather to a deficiency in L-tryptophan (L-Trp), or in a L-Trp derivative. Although the roots of 7-day-old seedlings possess higher concentrations of free L-Trp than the shoot as a whole, trp5-2wvc1 mutants show no detectable alteration in L-Trp levels in either tissue type, suggesting that a very localized shortage of L-Trp, or of a L-Trp-derived compound, is responsible for the observed phenotype.

Rutherford, R.; Gallois, P.; Masson, P. H.

1998-01-01

6

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

7

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

PubMed

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

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

2013-07-01

8

A Novel Missense Mutation in the Thyroid Peroxidase Gene, R175Q, Resulting in Insufficient Cell Surface Enzyme in Two Siblings  

PubMed Central

Thyroid peroxidase (TPO) abnormality is one of the causes of congenital hypothyroidism. Two missense mutations were found as a compound heterozygous mutation in two siblings with congenital goitrous hypothyroidism. One of these mutations, G614A (R175Q), was a novel mutation. Characterization of the novel mutation and a cotransfection experiment with two mutated TPO mRNAs were carried out. G614A-mRNA introduced into CHO-K1 cells expressed TPO protein with the same molecular weight as that of wild-type mRNA. The R175Q-TPO was thought to possess enzyme activity. In terms of localization, a very small amount of mutated TPO was expressed on the plasma membrane of CHO-K1 cells. This plasma membrane expression of R175Q-TPO was insufficient to perform thyroid hormone synthesis, but was markedly different from R665W-TPO. When G614A- and C2083T-mRNAs were cotransfected, cell surface TPO-positive cells were only 13.1% in contrast to 54.4% for wild-type mRNA. The low positivity and intensity of cell surface TPO suggested that in the patients’ thyroids thyroid hormone synthesis was hardly performed. The congenital hypothyroidism of the patients was thought to be a result of the mutations of the TPO gene (G614A/C2083T).

Kotani, Tomio; Umeki, Kazumi; Kawano, Jun-ichi; Suganuma, Tatsuo; Yamamoto, Ikuo; Aratake, Yatsuki; Ichiba, Yozo; Furujo, Mahoko

2004-01-01

9

Overlapping Gene Mutations of Hepatitis B Virus in a Chronic Hepatitis B Patient with Hepatitis B Surface Antigen Loss during Lamivudine Therapy  

PubMed Central

Disappearance of hepatitis B surface antigens (HBsAg) in chronic hepatitis B usually indicates clearance of hepatitis B virus (HBV) infection. However, false HBsAg negativity with mutations in pre-S2 and 'a' determinant has been reported. It is also known that YMDD mutations decrease the production of HBV and escape detection of serum HBsAg. Here, we report overlapping gene mutations in a patient with HBsAg loss during the lamivudine therapy. After 36 months of lamivudine therapy in a 44-yr-old Korean chronic hepatitis B patient, serum HBsAg turned negative while HBV DNA remained positive by a DNA probe method. Nucleotide sequence of serum HBV DNA was compared with the HBV genotype C subtype adr registered in NCBI AF 286594. Deletion of nucleotides 23 to 55 (amino acids 12 to 22) was identified in the pre-S2 region. Sequencing of the 'a' determinant revealed amino acid substitutions as I126S, T131N, M133T, and S136Y. Methionine of rtM204 in the P gene was substituted for isoleucine indicating YIDD mutation (rtM204I). We identified a HBV mutant composed of pre-S2 deletions and 'a' determinant substitutions with YMDD mutation. Our result suggests that false HBsAg negativity can be induced by combination of overlapping gene mutations during the lamivudine therapy.

Lee, Sun-Young; Choi, Moon Seok; Lee, Dongho; Lee, Joon Hyoek; Koh, Kwang Cheol; Paik, Seung Woon

2005-01-01

10

The Human Gene Mutation Database  

NSDL National Science Digital Library

The Human Gene Mutation Database from the Institute of Medical Genetics at Cardiff provides practical information for researchers, physicians, and genetic counselors. The database is currently undergoing some reorganization, but information can be searched by "disease, gene name, or gene symbol." Search results are well organized and easy to navigate, linking directly to results from external Web databases without requiring that the user perform additional searches. Frequent users may also appreciate the listing of genes recently added to the database.

2008-09-09

11

The Human Gene Mutation Database  

NSDL National Science Digital Library

The Human Gene Mutation Database from the Institute of Medical Genetics at Cardiff provides practical information for researchers, physicians, and genetic counselors. The database is currently undergoing some reorganization, but information can be searched by "disease, gene name, or gene symbol." Search results are well organized and easy to navigate, linking directly to results from external Web databases without requiring that the user perform additional searches. Frequent users may also appreciate the listing of genes recently added to the database.

1997-01-01

12

Novel Mutation Identified in the PAH Gene  

Microsoft Academic Search

The investigation of a DNA-amplified fragment of a phenylketonuria (PKU) patient by sequencing reveals a novel mutation in the PAH gene. This mutation represents the deletion of a single base (guanine) localized at the intron 11\\/exon 12 junction. This newly described mutation may be a frameshift or a splicing mutation. The identified mutation expresses phenotypically as the severe form of

E. V. Charikova

1996-01-01

13

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

PubMed Central

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

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

1994-01-01

14

The androgen receptor gene mutations database.  

PubMed Central

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

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

1994-01-01

15

Hepatitis B virus genotype E surface antigen detection with different immunoassays and diagnostic impact of mutations in the preS/S gene.  

PubMed

The major neutralizing epitope, the "a" determinant of the hepatitis B virus (HBV) genotype E surface antigen (HBsAg) is most divergent from that of genotype A, which is used for preparing monoclonal antibodies used in commercially available HBV reagents. To evaluate the performance of the latest generation of HBsAg detection assays with respect to genotype E HBsAg. Three commercial assays were evaluated using sera from 200 Nigerian patients compared to the preS/S sequence of DNA positive samples. Out of 200 samples, 61 and 103 gave concordant positive and negative results between the three HBsAg assays. Of 36 samples with discordant results, 35 were confirmed negative by neutralisation. One of the three assays showed significantly high rate of false positives (29 of 35). DNA positive samples with no detectable HBsAg or reduced HBsAg detection signals (<75% of mean signal obtained with HBsAg positive samples) revealed several mutations (V14A, F46S, N48T, L49R, I49T, D51G, A53V, P54L, Q82P, F83C, L127P, A184V, T189I, S204N, V224A), mostly outside the a-determinant. Several of these mutations are found as wild type nucleotides normally in genotype A and only exceptionally in genotype E. All three assays showed comparable sensitivities for genotype E HBsAg detection (98.4-100%) but differed considerably in specificity (84-99%). Failure to detect HBsAg antigen and differences in signal intensity were mainly associated with mutations in the preS/S gene outside the "a" determinant. PMID:17503077

Olinger, Christophe M; Weber, Bernard; Otegbayo, Jesse A; Ammerlaan, Wim; van der Taelem-Brulé, Natascha; Muller, Claude P

2007-12-01

16

Mutagenesis: mutating a gene while reading it.  

PubMed

Is it possible to mutate DNA during transcription? A new study shows that UV-damaged DNA is deaminated during transcription, which is a probable mechanism underlying CC tandem mutations found in the p53 gene in skin cancers. PMID:20129038

Helleday, Thomas

2010-01-26

17

Gene Mutations in Children with Chronic Pancreatitis  

Microsoft Academic Search

In the last few years, several genes have been identified as being associated with hereditary and idiopathic chronic pancreatitis (CP), i.e. PRSS1, CFTR and SPINK1. In this study, we investigated 164 unrelated children and adolescents with CP for mutations in disease-associated genes by direct DNA sequencing, SSCP, RFLP and melting curve analysis. In 15 patients, we detected a PRSS1 mutation

Heiko Witt

2001-01-01

18

Fibrinogen gene mutations accounting for congenital afibrinogenemia.  

PubMed

This article reviews recent progress made in understanding the molecular basis of congenital afibrinogenemia, an autosomal recessive coagulation disorder characterized by the complete absence of detectable fibrinogen. We have identified the first causative mutations for this disorder in a non-consanguineous Swiss family; these were homozygous deletions of approximately 11 kb of the fibrinogen alpha chain (FGA) gene. Haplotype data implied that the deletions occurred on distinct ancestral chromosomes, suggesting that this region may be susceptible to deletion by a common mechanism. All the deletions were identical to the base pair, and probably resulted from non-homologous (illegitimate) recombination. In a subsequent study of 13 unrelated patients with congenital afibrinogenemia we analyzed the FGA gene in order to identify the causative mutations, and to determine the prevalence of the 11-kb FGA deletion. Although this deletion was found in an additional unrelated patient, the most common mutation was at the donor splice site of FGA intron 4 (IVS4 + 1 G > T). Three frameshift mutations, two nonsense mutations, and one other splice site mutation were also characterized. Other studies identified one further FGA nonsense mutation, two FGB missense mutations, and one FGG nonsense mutation, all in homozygosity in a single patient. In conclusion, the majority of patients have truncating mutations in the FGA gene although, intuitively, all three fibrinogen genes could be predicted to be equally implicated. These results will facilitate molecular diagnosis of the disorder, permit prenatal diagnosis for families who so desire, and pave the way for new therapeutic approaches such as gene therapy. PMID:11460507

Neerman-Arbez, M

2001-01-01

19

Gene deletion speeds mutation rate.  

PubMed

The APOBEC proteins fight off viruses by editing their genomes. A deletion that removes one of the proteins produces large numbers of mutations in the human genome, potentially leading to cancer. PMID:25002600

2014-07-01

20

Paraoxonase Gene Mutations in Amyotrophic Lateral Sclerosis  

PubMed Central

Three clustered, homologous paraoxonase genes (PON1, PON2 and PON3) have roles in preventing lipid oxidation and detoxifying organophosphates. Recent reports describe a genetic association between the PON genes and sporadic amyotrophic lateral sclerosis (ALS). We now report that in genomic DNA from individuals with familial and sporadic ALS we have identified at least seven PON gene mutations that are predicted to alter PON function.

Ticozzi, Nicola; LeClerc, Ashley Lyn; Keagle, Pamela; Glass, Jonathan D.; Wills, Anne-Marie; van Blitterswijk, Marka; Bosco, Daryl A.; Rodriguez-Leyva, Ildefonso; Gellera, Cinzia; Ratti, Antonia; Taroni, Franco; McKenna-Yasek, Diane M.; Sapp, Peter C.; Silani, Vincenzo; Furlong, Clement E.; Brown, Robert H.; Landers, John E.

2010-01-01

21

[Mutations in genes for sarcomeric proteins].  

PubMed

Idiopathic cardiomyopathy(ICM) is by definition of unknown etiology. There are four clinical types of ICM; hypertrophic cardiomyopathy(HCM) characterized by ventricular hypertrophy associated with reduced compliance of the heart and accompanied by myofibrillar disarray, dilated cardiomyopathy(DCM) characterized by dilated ventricles associated with systolic dysfunction, restricted cardiomyopathy (RCM) and arrhythmogenic right ventricular cardiomyopathy(ARVC). Recent molecular genetic analyses have now revealed disease-associated mutations in ICM, especially in familial HCM and familial DCM. Mutations in 9 different disease genes (MYH7, TNNT2, TPM1, MYBPC3, MYL3, MYL2, TNNI3, CACT and TTN) cause HCM, while mutations in 3 different genes(CACT, DES and DMD) cause DCM in adults. In this review, I will summarize our current data on sarcomere mutations found in Japanese ICM, especially in HCM and DCM. PMID:10885298

Kimura, A

2000-01-01

22

A novel mutation of the fibrillin gene causing Ectopia lentis  

Microsoft Academic Search

Ectopia lentis (EL), a dominantly inherited connective tissue disorder, has been genetically linked to the fibrillin gene on chromosome 15 (FBN1) in earlier studies. Here, the authors report the first EL mutation in the FBN1 gene confirming that EL is caused by mutations of this gene. So far, several mutations in the FBN1 gene have been reported in patients with

L. Loennqvist; K. Kainulainen; L. Puhakka; L. Peltonen; A. Child

1994-01-01

23

From Gene Mutation to Protein Characterization  

ERIC Educational Resources Information Center

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

Moffet, David A.

2009-01-01

24

LEOPARD Syndrome: Clinical Features and Gene Mutations  

PubMed Central

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

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

2012-01-01

25

Mutation scanning of peach floral genes  

PubMed Central

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

2011-01-01

26

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

27

Gene promoter hypermethylation in ductal lavage fluid from healthy BRCA gene mutation carriers and mutation-negative controls  

Microsoft Academic Search

INTRODUCTION: Female germline BRCA gene mutation carriers are at increased risk for developing breast cancer. The purpose of our study was to establish whether healthy BRCA mutation carriers demonstrate an increased frequency of aberrant gene promoter hypermethylation in ductal lavage (DL) fluid, compared with predictive genetic test negative controls, that might serve as a surrogate marker of BRCA1\\/2 mutation status

Imogen Locke; Zsofia Kote-Jarai; Mary Jo Fackler; Elizabeth Bancroft; Peter Osin; Ashutosh Nerurkar; Louise Izatt; Gabriella Pichert; Gerald PH Gui; Rosalind A Eeles

2007-01-01

28

Elastin gene mutations in transgenic mice.  

PubMed

We have constructed several rat tropoelastin minigene recombinants encoding the complete sequence of rat tropoelastin, two isoforms of rat tropoelastin and a truncated tropoelastin lacking the domains encoded by exons 19-31 of the rat gene. Coding and non-coding domains in all these recombinants were placed under the transcriptional control of 3 kb of the promoter domain of the rat tropoelastin gene. These minigenes were used to prepare a total of 28 separate founder lines of transgenic mice. A species-specific reverse-transcriptase polymerase chain reaction (RT-PCR) assay was established to demonstrate the synthesis of rat and mouse tropoelastin mRNA in several tissues obtained from both neonatal and adult transgenic mice. Thermolytic digestion of insoluble elastin isolated from several neonatal mouse tissues revealed the presence of rat tropoelastin peptides in progeny from all those founder mice in which detectable levels of rat tropoelastin mRNA were noted. Phenotypic and histopathological assessment of transgenic and non-transgenic animals revealed the development of two diverse elastic tissue disorders. The progeny of two separate founder lines overexpressing the rat tropoelastin isoform lacking exon 33, developed an emphysematous phenotype in early adulthood. In contrast, transgenic mice, in which expression of the truncated rat tropoelastin minigene lacking exons 19-31 had been observed, died of a ruptured ascending aortic aneurysm. Tropoelastin gene mutations, therefore, will result in heritable disorders of elastic tissue. Moreover, different mutations in the tropoelastin gene will be responsible for very different abnormalities in elastic tissue function. PMID:8575255

Sechler, J L; Sandberg, L B; Roos, P J; Snyder, I; Amenta, P S; Riley, D J; Boyd, C D

1995-01-01

29

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

PubMed Central

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

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

2007-01-01

30

Spectrum of mutations in the gene encoding the adrenoleukodystrophy protein.  

PubMed Central

X-linked adrenoleukodystrophy (ALD) has been associated with mutations in a gene encoding an ATP-binding transporter, which is located in the peroxisomal membrane. Deficiency of the gene leads to impaired peroxisomal beta-oxidation. Systematic analysis of the open reading frame of the ALD gene, using reverse transcriptase-PCR, followed by direct sequencing, revealed mutations in all 28 unrelated kindreds analyzed. No entire gene deletions or drastic promoter mutations were detected. In only one kindred did the mutation involve multiple exons. The other mutations were small alterations leading to missense (13 of 28) or nonsense mutations, a single amino acid deletion, frameshifts, or splice acceptor-site defects. Mutations affecting a single amino acid were concentrated in the region between the third and fourth putative transmembrane domains and in the ATP-binding domain. Mutations were detected in all investigated ALD kindreds, suggesting that this gene is the only gene responsible for X-linked ALD. This overview of mutations is useful in the determination of structurally and functionally important regions and provides an efficient screening strategy for identification of mutations in the ALD gene.

Ligtenberg, M J; Kemp, S; Sarde, C O; van Geel, B M; Kleijer, W J; Barth, P G; Mandel, J L; van Oost, B A; Bolhuis, P A

1995-01-01

31

Stiff child syndrome with mutation of DYT1 gene.  

PubMed

The authors report a Chinese boy with a DYT1 gene mutation having muscle stiffness, severe painful muscle spasm, myoclonus, and dystonia compatible with stiff child syndrome. Autoantibodies to glutamic acid decarboxylase (anti-GAD) were absent. His asymptomatic mother had a DYT1 mutation. His asymptomatic sister has diabetes mellitus and antibodies to glutamic acid decarboxylase but no DYT1 mutation. PMID:16275837

Wong, Virginia C N; Lam, Ching-Wan; Fung, Cheuk Wing

2005-11-01

32

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

33

Mixture distribution analysis of phenotypic markers reflecting HFE gene mutations  

Microsoft Academic Search

The goal of this study was to determine whether statistical modeling of popula- tion data for a phenotypic marker could reflect a major locus gene defect. Identify- ing mutations in the HFE gene makes it possible to assess the association be- tween transferrin saturation (TS) sub- populations and HFE mutations. Data were analyzed from 27 895 white patients who attended

Christine E. McLaren; Kuo-Tung Li; Chad P. Garner; Ernest Beutler; Victor R. Gordeuk

2003-01-01

34

Mutations in the hemochromatosis gene (HFE) and stroke  

Microsoft Academic Search

BACKGROUND AND PURPOSE: Increased serum iron is found to be a risk factor for stroke. Carriers of HFE C282Y and H63D mutations have elevated serum iron levels and may have an increased risk for stroke. We studied the association between HFE gene mutations, carotid atherosclerosis, and stroke. METHODS: We compared the frequency of the HFE C282Y and H63D gene mutations

O. T. Njajou; M. Hollander; P. J. Koudstaal; A. Hofman; Duijn van C. M; J. C. M. Witteman; M. M. B. Breteler

2002-01-01

35

Mutations in the Hemochromatosis Gene (HFE) and Stroke  

Microsoft Academic Search

Background and Purpose—Increased serum iron is found to be a risk factor for stroke. Carriers of HFE C282Y and H63D mutations have elevated serum iron levels and may have an increased risk for stroke. We studied the association between HFE gene mutations, carotid atherosclerosis, and stroke. Methods—We compared the frequency of the HFE C282Y and H63D gene mutations in 202

Omer T. Njajou; Monika Hollander; Peter J. Koudstaal; Albert Hofman; Jacqueline C. M. Witteman; Monique M. B. Breteler; Cornelia M. van Duijn

36

Mutation screening of X-chromosomal neuroligin genes: no mutations in 196 autism probands.  

PubMed

Autism, a childhood neuropsychiatric disorder with a strong genetic component, is currently the focus of considerable attention within the field of human genetics as well many other medical-related disciplines. A recent study has implicated two X-chromosomal neuroligin genes, NLGN3 and NLGN4, as having an etiological role in autism, having identified a frameshift mutation in one gene and a substitution mutation in the other, segregating in multiplex autism spectrum families (Jamain et al. [2003: Nat Genet 34:27-29]). The function of neuroligin as a trigger for synapse formation would suggest that such mutations would likely result in some form of pathological manifestation. Our own study, screening a larger sample of 196 autism probands, failed to identify any mutations that would affect the coding regions of these genes. Our findings suggest that mutations in these two genes are infrequent in autism. PMID:15274046

Vincent, John B; Kolozsvari, Debbie; Roberts, Wendy S; Bolton, Patrick F; Gurling, Hugh M D; Scherer, Stephen W

2004-08-15

37

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.

Jiang, Yong-hui; Ehlers, Michael D.

2013-01-01

38

Screening for mutations in candidate genes for hypospadias.  

PubMed

Hypospadias. a condition with a frontally placed urethral orifice on the penis, is the most common malformation in males. During fetal development several components are necessary for normal male genital development. Testosterone and dihydrotestosterone act via the androgen receptor but a defective receptor function results in different degrees of genital malformations. Testosterone-5alpha-reductase converts testosterone to dihydrotestosterone, which is crucial for normal differentiation, and a total lack of this enzyme results, in syndromes with hypospadias. The Wilms' tumour 1 (WT1) gene is expressed in the fetal gonad and genital malformations can occur due to WT1 gene mutations. These genes are therefore strong candidate genes for hypospadias. We have analysed 35 boys with hypopadias and one girl diagnosed as with complete androgen insensitivity syndrome, using exon by exon polymerase chain reaction (PCR) amplification of the AR, WTI and 5alpha-reductase genes and screened for point mutations and performed subsequent DNA sequencing. No mutations in any of these genes were found in the 26 patients with isolated hypospadias. Two patients with severe hypospadias with cryptorchidism were found to carry mutations in the androgen receptor gene. Also the girl with clinically diagnosed complete androgen insensitivity was found to be homozygous for a splice mutation in the 5alpha-reductase gene. In summary, mutations in the WT1, AR and 5alpha-reductase genes are not common causes of isolated hypospadias. PMID:10092153

Nordenskjöld, A; Friedman, E; Tapper-Persson, M; Söderhäll, C; Leviav, A; Svensson, J; Anvret, M

1999-01-01

39

Androgen receptor gene mutation, rearrangement, polymorphism  

PubMed Central

Genetic aberrations of the androgen receptor (AR) caused by mutations, rearrangements, and polymorphisms result in a mutant receptor that has varied functions compared to wild type AR. To date, over 1,000 mutations have been reported in the AR with most of these being associated with androgen insensitivity syndrome (AIS). While mutations of AR associated with prostate cancer occur less often in early stage localized disease, mutations in castration-resistant prostate cancer (CRPC) patients treated with anti-androgens occur more frequently with 10–30% of these patients having some form of mutation in the AR. Resistance to anti-androgen therapy usually results from gain-of-function mutations in the LBD such as is seen with bicalutamide and more recently with enzalutamide (MDV3100). Thus, it is crucial to investigate these new AR mutations arising from drug resistance to anti-androgens and other small molecule pharmacological agents.

Eisermann, Kurtis; Wang, Dan; Jing, Yifeng; Pascal, Laura E.; Wang, Zhou

2014-01-01

40

Crystallin gene mutations in Indian families with inherited pediatric cataract  

PubMed Central

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

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

2008-01-01

41

Common Familial Mediterranean Fever gene mutations in a Turkish cohort.  

PubMed

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

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

2011-11-01

42

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

43

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.

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

44

Mutation screening of the ARX gene in patients with autism.  

PubMed

Mutations in the Aristaless related homeobox (ARX) gene are associated with a broad spectrum of disorders, including nonsyndromic X-linked mental retardation, sometimes associated with epilepsy, as well as syndromic forms with brain abnormalities and abnormal genitalia. Furthermore, ARX mutations have been described in a few patients with autism or autistic features. In this study, we screened the ARX gene in 226 male patients with autism spectrum disorders and mental retardation; 42 of the patients had epilepsy. The mutation analysis was performed by direct sequencing of all exons and flanking regions. No ARX mutations were identified in any of the patients tested. These findings indicate that mutations in the ARX gene are very rare in autism. PMID:17044103

Chaste, Pauline; Nygren, Gudrun; Anckarsäter, Henrik; Råstam, Maria; Coleman, Mary; Leboyer, Marion; Gillberg, Christopher; Betancur, Catalina

2007-03-01

45

Two novel PAH gene mutations detected in Italian phenylketonuric patients  

Microsoft Academic Search

We report the identification by denaturing gradient gel electrophoresis and sequence analysis of two new phenylalanine hydroxylase\\u000a (PAH) gene mutations (IVS4nt-2 and N207S) in single chromosomes of two unrelated Italian phenylketonuric (PKU) patients. Interestingly,\\u000a mutation Y204C, found on the second mutant allele of family F1, has been previously detected in Chinese patients. Haplotype\\u000a analysis showed that the latter mutation is

Alessandra Argiolas; Paolo Bosco; Francesco Calì; Nadia Ceratto; Guido Anello; Enrica Riva; Giacomo Biasucci; Carla Carducci; Valentino Romano

1997-01-01

46

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, ...

47

A Japanese family with nonautoimmune hyperthyroidism caused by a novel heterozygous thyrotropin receptor gene mutation.  

PubMed

Background:Hyperthyroidism caused by activating mutations of the thyrotropin receptor gene (TSHR) is rare in the pediatric population.Methods:We found a Japanese family with hyperthyroidism without autoantibody. DNA sequence analysis of TSHR was undertaken in this family. The functional consequences for the Gs-adenylyl cyclase and Gq/11-phospholipase C signaling pathways and cell surface expression of receptors were determined in vitro using transiently transfected human embryonic kidney 293 cells.Results:We identified a heterozygous mutation (M453R) in exon 10 of TSHR. In this family, this mutation was found in all individuals who exhibited hyperthyroidism. The results showed that this mutation resulted in constitutive activation of the Gs-adenylyl cyclase system. However, this mutation also caused a reduction in the activation capacity of the Gq/11-phospholipase C pathway, compared with the wild type.Conclusion:We demonstrate that the M453R mutation is the cause of nonautoimmune hyperthyroidism. PMID:24608569

Nakamura, Akie; Morikawa, Shuntaro; Aoyagi, Hayato; Ishizu, Katsura; Tajima, Toshihiro

2014-06-01

48

SANDO: two novel mutations in POLG1 gene.  

PubMed

Sensory ataxia with neuropathy, dysarthria and ophthalmoparesis represent the clinical triad of SANDO, a specific mitochondrial phenotype first reported in 1997 in association with multiple mitochondrial DNA deletions and mutations in POLG1 or more rarely in the C10orf2 (twinkle-helicase) gene. We report a 44-year-old man with SANDO who harboured two novel mutations (P648R/R807C) in the POLG1 gene. PMID:16919951

Gago, Miguel Fernandes; Rosas, M J; Guimarães, Joana; Ferreira, Mariana; Vilarinho, Laura; Castro, Lígia; Carpenter, Stirling

2006-08-01

49

Microarray-based mutation detection in the dystrophin gene.  

PubMed

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

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

2008-09-01

50

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

PubMed Central

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

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

2010-01-01

51

Spectrum of perforin gene mutations in familial hemophagocytic lymphohistiocytosis.  

PubMed

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, approximately 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 approximately 10%, whereas the major part of the FHL cases are caused by mutations in not-yet-identified genes. PMID:11179007

Göransdotter Ericson, K; Fadeel, B; Nilsson-Ardnor, S; Söderhäll, C; Samuelsson, A; Janka, G; Schneider, M; Gürgey, A; Yalman, N; Révész, T; Egeler, R; Jahnukainen, K; Storm-Mathiesen, I; Haraldsson, A; Poole, J; de Saint Basile, G; Nordenskjöld, M; Henter, J

2001-03-01

52

Different pattern of gene mutations in Iranian patients with severe congenital neutropenia (including 2 new mutations).  

PubMed

Severe congenital neutropenia (SCN) is a rare primary immunodeficiency disease. Different genes are found to be associated with SCN, including ELA2, HAX1, WAS, GFI1, G-CSFR and G6PC3. The aim of this study was to find different gene mutations responsible for SCN in Iranian patients. Twenty-seven patients with SCN referred to Immunology, Asthma and Allergy Research Institute during a five year priod 5 years (May 2007 and May 2012), were included in this study. Neutropenia related exons and flanking regions of ELA2, HAX1, WAS, GFI1, G-CSFR and G6PC3 were amplified by PCR and the sequences were analyzed. The results showed different mutations including 4 ELANE mutations, 11 HAX1 mutations and 2 G6PC3 mutations. None of the patients had GFI1 mutation and also one mutation was found in G-CSFR in a patient with ELANE mutation. Ten patients had unknown genetic diagnosis which was compatible with other studies. According to these results, most of the patients showed HAX1 mutations and this finding which significantly differed from other reports, might be related to differences in Iranian ethnicity and also in high rate of consanguineous marriages in Iran. PMID:23454784

Alizadeh, Zahra; Fazlollahi, Mohammad Reza; Houshmand, Massoud; Maddah, Marzieh; Chavoshzadeh, Zahra; Hamidieh, Amir Ali; Shamsian, Bibi Shahin; Eshghi, Payman; Bolandghamat Pour, Samaneh; Sadaaie Jahromi, Hoda; Mansouri, Mahboobeh; Movahedi, Masoud; Nayebpour, Mohsen; Pourpak, Zahra; Moin, Mostafa

2013-03-01

53

Microarray-based mutation detection in the dystrophin gene  

PubMed Central

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

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

2008-01-01

54

Neurocognitive Profiles in Duchenne Muscular Dystrophy and Gene Mutation Site  

PubMed Central

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

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

2011-01-01

55

A novel mutation of the fibrillin gene causing Ectopia lentis  

SciTech Connect

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

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

1994-02-01

56

Somatic cell gene mutations in humans: biomarkers for genotoxicity.  

PubMed Central

Somatic cell gene mutations arising in vivo in humans provide biomarkers for genotoxicity. Four assays, each measuring changes in a different "recorder" gene, are available for detecting mutations of the hemoglobin (Hb) and glycophorin A (gpa) genes in red blood cells and the hypoxanthine-guanine phosphoribosyltransferase (hprt) and HLA genes in T-lymphocytes. Mean adult background mutant frequencies have been established; i.e., approximately 4 x 10(-8) (Hb), 5-10 x 10(-6) (hprt), 10-20 x 10(-6) (gpa) and 30 x 10(-6) (HLA). All the assays have now been used in studies of individuals exposed to physical and/or chemical genotoxic agents, and all have shown elevated values following exposures; examples are presented. In addition to quantitation, the lymphocyte assays allow molecular analyses of in vivo mutations, the definition of background and induced mutational spectra, and the search for unique changes for characterizing specific mutagens. The HPRT system currently has the largest database in this regard. Approximately 15% of adult background hprt mutations are due to gross structural alterations (primarily deletions) having random breakpoints; 85% result from "point" changes detected only by sequencing. In contrast, a specific intragenic deletion due to DNA cleavage at specific sites characterizes fetal hprt mutations, implicating a developmental mistake in their genesis. (This kind of developmental mistake in other genes is frequently observed in lymphoid malignancies.) Mutational spectra are just beginning to be defined for induced hprt mutations, e.g., ionizing radiation produces large deletions.(ABSTRACT TRUNCATED AT 250 WORDS)

Albertini, R J; Nicklas, J A; O'Neill, J P

1993-01-01

57

Prioritization of neurodevelopmental disease genes by discovery of new mutations.  

PubMed

Advances in genome sequencing technologies have begun to revolutionize neurogenetics, allowing the full spectrum of genetic variation to be better understood in relation to disease. Exome sequencing of hundreds to thousands of samples from patients with autism spectrum disorder, intellectual disability, epilepsy and schizophrenia provides strong evidence of the importance of de novo and gene-disruptive events. There are now several hundred new candidate genes and targeted resequencing technologies that allow screening of dozens of genes in tens of thousands of individuals with high specificity and sensitivity. The decision of which genes to pursue depends on many factors, including recurrence, previous evidence of overlap with pathogenic copy number variants, the position of the mutation in the protein, the mutational burden among healthy individuals and membership of the candidate gene in disease-implicated protein networks. We discuss these emerging criteria for gene prioritization and the potential impact on the field of neuroscience. PMID:24866042

Hoischen, Alexander; Krumm, Niklas; Eichler, Evan E

2014-06-01

58

p53 gene mutations in asbestos associated cancers.  

PubMed

The accumulation of mutant p53 protein in cancer cells was observed by immunohistochemistry analysis. DNA was extracted from paraffin-embedded tissue. Exons 5, 7 and 8 were amplified and studied by PCR-SSCP and sequencing analysis. Ten cases of asbestos associated cancer tissue were studied, of which five cases had adenocarcinoma, and the other five had mesothelioma, squamous carcinoma, small cell lung cancer, adenosquamous carcinoma and malignant lymphoma respectively. Employing monoclonal antibody PAb1801, five cases were found to be mutant p53 protein positive. Seven cases were found to have mutations by PCR-SSCP. A total of 7 cases (8 mutations) were found to be positive and 4 cases were found to be positive by both of these analyses. Of the 8 mutations found by SSCP analysis, 4(50%, 4/8) were clustered in exon 8. A high mutation frequency was noticed in adenocarcinoma (80%, 4/5). Sequencing analysis on two specimens revealed two hotspot mutations. In codon 234, TAC for tyrosin was mutated to AAC for asparagine by a T to A transversion of the first letter. In codon 273, CGT for arginine was mutated to AGT for serine by a C to A transversion of the first letter. In conclusion, the mutation of p53 gene is common in asbestos associated cancers. However, the mutational spectrum of asbestos associated cancers might be different from that of non-asbestos associated cancers. PMID:9861481

Liu, B C; Fu, D C; Miao, Q; Wang, H H; You, B R

1998-09-01

59

The impact of mutation and gene conversion on the local diversification of antigen genes in African trypanosomes.  

PubMed

Patterns of genetic diversity in parasite antigen gene families hold important information about their potential to generate antigenic variation within and between hosts. The evolution of such gene families is typically driven by gene duplication, followed by point mutation and gene conversion. There is great interest in estimating the rates of these processes from molecular sequences for understanding the evolution of the pathogen and its significance for infection processes. In this study, a series of models are constructed to investigate hypotheses about the nucleotide diversity patterns between closely related gene sequences from the antigen gene archive of the African trypanosome, the protozoan parasite causative of human sleeping sickness in Equatorial Africa. We use a hidden Markov model approach to identify two scales of diversification: clustering of sequence mismatches, a putative indicator of gene conversion events with other lower-identity donor genes in the archive, and at a sparser scale, isolated mismatches, likely arising from independent point mutations. In addition to quantifying the respective probabilities of occurrence of these two processes, our approach yields estimates for the gene conversion tract length distribution and the average diversity contributed locally by conversion events. Model fitting is conducted using a Bayesian framework. We find that diversifying gene conversion events with lower-identity partners occur at least five times less frequently than point mutations on variant surface glycoprotein (VSG) pairs, and the average imported conversion tract is between 14 and 25 nucleotides long. However, because of the high diversity introduced by gene conversion, the two processes have almost equal impact on the per-nucleotide rate of sequence diversification between VSG subfamily members. We are able to disentangle the most likely locations of point mutations and conversions on each aligned gene pair. PMID:22735079

Gjini, Erida; Haydon, Daniel T; Barry, J David; Cobbold, Christina A

2012-11-01

60

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

PubMed

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

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

2013-11-01

61

Plectin Gene Mutations Can Cause Epidermolysis Bullosa with Pyloric Atresia  

Microsoft Academic Search

Epidermolysis bullosa with pyloric atresia (EB-PA), manifesting with neonatal blistering and gastric anomalies, is known to be caused by mutations in the hemidesmosomal genes ITGA6 and ITGB4, which encode the ?6 and ?4 integrin polypeptides, respectively. As part of our molecular diagnostics program, we have now encountered four families with EB-PA in which no mutations could be identified in these

Ellen Pfendner; Jouni Uitto

2005-01-01

62

Gene expression profile study in CFTR mutated bronchial cell lines  

Microsoft Academic Search

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

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

2006-01-01

63

Mutation Analysis of the HFE Gene in Brazilian Populations  

Microsoft Academic Search

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

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

1999-01-01

64

Mutations of the HFE Gene in Patients With Hepatocellular Carcinoma  

Microsoft Academic Search

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

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

2003-01-01

65

Mutation Analysis of the HFE Gene in Brazilian Populations  

Microsoft Academic Search

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

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

1999-01-01

66

Gene mutations and molecularly targeted therapies in acute myeloid leukemia  

PubMed Central

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

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

2013-01-01

67

Oncological implications of RET gene mutations in Hirschsprung's disease  

PubMed Central

Background—Germline mutations of the RET proto-oncogene identical to those found in the tumour predisposition syndrome multiple endocrine neoplasia type 2A (MEN2A), were detected in 2.5-5% of sporadic and familial cases of Hirschsprung's disease. Some patients with Hirschsprung's disease may therefore be exposed to a highly increased risk of tumours. ?Aims—To define clinical use of RET gene testing in Hirschsprung's disease and related patient management from an oncological point of view. ?Methods—Sixty patients with Hirschsprung's disease were screened for RET mutations. In three, MEN2A type RET mutations were detected. Case reports for these three patients are presented. ?Results and conclusions—Only 22 families or sporadic patients with Hirschsprung's disease and MEN2A type RET mutations have been reported. Therefore, it is difficult to predict tumour risk for patients with familial or sporadic Hirschsprung's disease, and their relatives, who carry these mutations. For these mutation carriers, periodic screening for tumours as in MEN2A is advised, but prophylactic thyroidectomy is offered hesitantly. RET gene testing in familial or sporadic Hirschsprung's disease is not recommended at present outside a complete clinical research setting. In combined MEN2A/Hirschsprung's disease families RET gene testing, tumour screening, and prophylactic thyroidectomy are indicated as in MEN2A. ?? Keywords: DNA analysis; Hirschsprung's disease; multiple endocrine neoplasia type 2A; RET

Sijmons, R; Hofstra, R; Wijburg, F; Links, T; Zwierstra, R; Vermey, A; Aronson, D; Tan-Sindhunata, G; Brouwers-Smalbraa..., G; Maas, S; Buys, C

1998-01-01

68

Optimization of Gene Expression through Divergent Mutational Paths  

PubMed Central

SUMMARY Adaptation under similar selective pressure often leads to comparable phenotypes. A longstanding question is whether such phenotypic repeatability entails similar (parallelism) or different genotypic changes (convergence). To better understand this, we characterized mutations that optimized expression of a plasmid-borne metabolic pathway during laboratory evolution of a bacterium. Expressing these pathway genes was essential for growth but came with substantial costs. Starting from overexpression, replicate populations founded by this bacterium all evolved to reduce expression. Despite this phenotypic repetitiveness, the underlying mutational spectrum was highly diverse. Analysis of these plasmid mutations identified three distinct means to modulate gene expression: (1) reducing the gene copy number, (2) lowering transcript stability, and (3) integration of the pathway-bearing plasmid into the host genome. Our study revealed diverse molecular changes beneath convergence to a simple phenotype. This complex genotype-phenotype mapping presents a challenge to inferring genetic evolution based solely on phenotypic changes.

Chou, Hsin-Hung; Marx, Christopher J.

2012-01-01

69

Frequent mutations in chromatin-remodelling genes in pulmonary carcinoids.  

PubMed

Pulmonary carcinoids are rare neuroendocrine tumours of the lung. The molecular alterations underlying the pathogenesis of these tumours 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-remodelling 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 lung tumours, TP53 and RB1 mutations are rare events, suggesting that pulmonary carcinoids are not early progenitor lesions of the highly aggressive lung neuroendocrine tumours but arise through independent cellular mechanisms. These data also suggest that inactivation of chromatin-remodelling genes is sufficient to drive transformation in pulmonary carcinoids. PMID:24670920

Fernandez-Cuesta, Lynnette; Peifer, Martin; Lu, Xin; Sun, Ruping; Ozreti?, Luka; Seidel, Danila; Zander, Thomas; Leenders, Frauke; George, Julie; Müller, Christian; Dahmen, Ilona; Pinther, Berit; Bosco, Graziella; Konrad, Kathryn; Altmüller, Janine; Nürnberg, Peter; Achter, Viktor; Lang, Ulrich; Schneider, Peter M; Bogus, Magdalena; Soltermann, Alex; Brustugun, Odd Terje; Helland, Åslaug; Solberg, Steinar; Lund-Iversen, Marius; Ansén, Sascha; Stoelben, Erich; Wright, Gavin M; Russell, Prudence; Wainer, Zoe; Solomon, Benjamin; Field, John K; Hyde, Russell; Davies, Michael P A; Heukamp, Lukas C; Petersen, Iver; Perner, Sven; Lovly, Christine M; Cappuzzo, Federico; Travis, William D; Wolf, Jürgen; Vingron, Martin; Brambilla, Elisabeth; Haas, Stefan A; Buettner, Reinhard; Thomas, Roman K

2014-01-01

70

Nonsense mutations in the dihydrofolate reductase gene affect RNA processing.  

PubMed Central

Steady-state dihydrofolate reductase (dhfr) mRNA levels were decreased as a result of nonsense mutations in the dhfr gene. Thirteen DHFR-deficient mutants were isolated after treatment of Chinese hamster ovary cells with UV irradiation. The positions of most point mutations were localized by RNA heteroduplex mapping, the mutated regions were isolated by cloning or by enzymatic amplification, and base changes were determined by DNA sequencing. Two of the mutants suffered large deletions that spanned the entire dhfr gene. The remaining 11 mutations consisted of nine single-base substitutions, one double-base substitution, and one single-base insertion. All of the single-base substitutions took place at the 3' position of a pyrimidine dinucleotide, supporting the idea that UV mutagenesis proceeds through the formation of pyrimidine dimers in mammalian cells. Of the 11 point mutations, 10 resulted in nonsense codons, either directly or by a frameshift, suggesting that the selection method favored a null phenotype. An examination of steady-state RNA levels in cells carrying these mutations and a comparison with similar data from other dhfr mutants (A. M. Carothers, R. W. Steigerwalt, G. Urlaub, L. A. Chasin, and D. Grunberger, J. Mol. Biol., in press) showed that translation termination mutations in any of the internal exons of the gene gave rise to a low-RNA phenotype, whereas missense mutations in these exons or terminations in exon 6 (the final exon) did not affect dhfr mRNA levels. Nuclear run-on experiments showed that transcription of the mutant genes was normal. The stability of mature dhfr mRNA also was not affected, since (i) decay rates were the same in wild-type and mutant cells after inhibition of RNA synthesis with actinomycin D and (ii) intronless minigene versions of cloned wild-type and nonsense mutant genes were expressed equally after stable transfection. We conclude that RNA processing has been affected by these nonsense mutations and present a model in which both splicing and nuclear transport of an RNA molecule are coupled to its translation. Curiously, the low-RNA mutant phenotype was not exhibited after transfer of the mutant genes, suggesting that the transcripts of transfected genes may be processed differently than are those of their endogenous counterparts. Images

Urlaub, G; Mitchell, P J; Ciudad, C J; Chasin, L A

1989-01-01

71

Altered Chromosomal Positioning, Compaction, and Gene Expression with a Lamin A/C Gene Mutation  

PubMed Central

Background Lamins A and C, encoded by the LMNA gene, are filamentous proteins that form the core scaffold of the nuclear lamina. Dominant LMNA gene mutations cause multiple human diseases including cardiac and skeletal myopathies. The nuclear lamina is thought to regulate gene expression by its direct interaction with chromatin. LMNA gene mutations may mediate disease by disrupting normal gene expression. Methods/Findings To investigate the hypothesis that mutant lamin A/C changes the lamina's ability to interact with chromatin, we studied gene misexpression resulting from the cardiomyopathic LMNA E161K mutation and correlated this with changes in chromosome positioning. We identified clusters of misexpressed genes and examined the nuclear positioning of two such genomic clusters, each harboring genes relevant to striated muscle disease including LMO7 and MBNL2. Both gene clusters were found to be more centrally positioned in LMNA-mutant nuclei. Additionally, these loci were less compacted. In LMNA mutant heart and fibroblasts, we found that chromosome 13 had a disproportionately high fraction of misexpressed genes. Using three-dimensional fluorescence in situ hybridization we found that the entire territory of chromosome 13 was displaced towards the center of the nucleus in LMNA mutant fibroblasts. Additional cardiomyopathic LMNA gene mutations were also shown to have abnormal positioning of chromosome 13, although in the opposite direction. Conclusions These data support a model in which LMNA mutations perturb the intranuclear positioning and compaction of chromosomal domains and provide a mechanism by which gene expression may be altered.

Abuisneineh, Fida; Fahrenbach, John P.; Zhang, Yuan; MacLeod, Heather; Dellefave, Lisa; Pytel, Peter; Selig, Sara; Labno, Christine M.; Reddy, Karen; Singh, Harinder; McNally, Elizabeth

2010-01-01

72

Encephalocraniocutaneous lipomatosis with a mutation in the NF1 gene.  

PubMed Central

Encephalocraniocutaneous lipomatosis (ECCL) is a congenital hamartomatous disorder characterised by unilateral skin lesions, lipomas, and ipsilateral ophthamological and cerebral malformations. The disorder is thought to represent a localised form of Proteus syndrome. In this report, a child is described with ECCL and a de novo nonsense mutation in exon 29 (S1745X) of the neurofibromatosis type 1 (NF1) gene. Although it is possible that both ECCL and NF1 occur coincidentally in this patient, we favour the hypothesis that in exceptional cases a mutation in the NF1 gene might give rise to severe congenital malformations such as ECCL. Possible pathogenetic mechanisms for these malformations are discussed. Images

Legius, E; Wu, R; Eyssen, M; Marynen, P; Fryns, J P; Cassiman, J J

1995-01-01

73

Mutational spectrum of the steroid 21-hydroxylase gene in Austria: identification of a novel missense mutation.  

PubMed

This study attempted an analysis of the mutational spectrum of 21-hydroxylase deficiency in 79 unrelated Austrian patients with classical and nonclassical forms of congenital adrenal hyperplasia and their respective 112 family members. Apparent large gene deletions/conversions were present in 31% of the 158 unrelated congenital adrenal hyperplasia alleles, whereas the most frequent point mutations were intron 2 splice (22.8%), I172N (15.8%), V281L (12%), and P30L (7.6%), in line with the frequencies reported for other countries. In 5 of the 12 congenital adrenal hyperplasia alleles carrying a P30L mutation the aberration is based on a single base substitution, whereas the remaining 7 represent part of a CYP21B conversion (1 allele) or CYP21B/21A hybrid gene (6 alleles), the latter characterized by a junction site before intron 2 as indicated by Southern blot, PCR, and sequence analyses. Previously described mutations were not present in 1.2% of unrelated congenital adrenal hyperplasia alleles, including one female patient presenting with severe genital virilization. Sequence analysis of the complete functional 21-hydroxylase gene revealed an as yet undescribed mutation in exon 10-Arg(426)His, which has not yet been described to represent a common pseudogene sequence. In vitro expression experiments showed the Arg(426)His mutant to exhibit only low enzyme activity toward the natural substrate 17-hydroxyprogesterone corresponding to the degree of disease manifestation in the patient in whom it was found. PMID:11600539

Baumgartner-Parzer, S M; Schulze, E; Waldhäusl, W; Pauschenwein, S; Rondot, S; Nowotny, P; Meyer, K; Frisch, H; Waldhauser, F; Vierhapper, H

2001-10-01

74

Mutations in the dopa decarboxylase gene affect learning in Drosophila.  

PubMed Central

Fruit flies synthesize several monoamine neurotransmitters. Dopa decarboxylase (Ddc) mutations affect synthesis of two of these, dopamine and serotonin. Both transmitters are implicated in vertebrate and invertebrate learning. Therefore, we bred flies of various Ddc genotypes and tested their learning ability in positively and negatively reinforced learning tasks. Mutations in the Ddc gene diminished learning acquisition approximately in proportion to their effect on enzymatic activity. Courtship and mating sequences of the mutants appeared normal, except for one aspect of male courtship that had previously been shown to be experience dependent. In contrast, the effect on behavior patterns that do not involve learning--phototaxis, geotaxis, olfactory acuity, responsiveness to sucrose--was relatively slight under these conditions. Moderate Ddc mutations affected the acquisition of learned responses while leaving memory retention unaltered. This is in contrast to the mutations dunce , rutabaga , and amnesiac , which primarily affect short-term memory.

Tempel, B L; Livingstone, M S; Quinn, W G

1984-01-01

75

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.

76

Cyclin D1 gene (CCND1) mutations in endometrial cancer.  

PubMed

Cyclin D1 is frequently overexpressed in human neoplasias by gene rearrangement and amplification, but no mutations in the CCND1 gene have so far been reported. However, in vitro mutagenesis of CCND1 has shown that substitutions affecting threonine 286 residue produced cyclin D1 nuclear accumulation, by interfering with protein degradation and induced neoplastic transformation in murine fibroblasts. To test whether similar genetic changes may occur in vivo, we analysed a series of 60 endometrioid endometrial carcinomas (EECs) for cyclin D1 expression and gene amplification by immunohistochemistry and FISH, respectively. Two of 17 carcinomas showing cyclin D1 expression in more than 5% of neoplastic cells, but without gene amplification, were found to harbor single-base substitutions in CCND1 that changed proline 287 into threonine and serine, respectively. Both cases expressed cyclin D1 in more than 50% of neoplastic cells. Additionally, seven tumors with cyclin D1 overexpression of an independent series of 59 EECs were also analysed, and a 12-bp in-frame deletion that eliminated amino acids 289-292 was detected in one case with cylin D1 expression in more than 50% of neoplastic cells. In contrast, no mutations of the CCND1 gene were detected in a set of breast carcinomas with cyclin D1 overexpression without gene amplification. In summary, our data indicate that mutations of CCND1, which probably render the protein insensitive to degradation, represent a previously unreported mechanism of cyclin D1 overexpression in human tumors in vivo. PMID:12955092

Moreno-Bueno, Gema; Rodríguez-Perales, Sandra; Sánchez-Estévez, Carolina; Hardisson, David; Sarrió, David; Prat, Jaime; Cigudosa, Juan C; Matias-Guiu, Xavier; Palacios, José

2003-09-01

77

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.

78

Induced mutations in the Green and Gene Revolutions  

Microsoft Academic Search

As in genomic research in animals, chemical and physical mutagenesis has become widely used in plants to close the gap between the available mutant resources and the full range of phenotypes that are essential to exploit the function of all genes of investigated species. Among various approaches, mutational analysis of plant traits appears to be one of the simplest routes

MIROSLAW MALUSZYNSKI; IWONA SZAREJKO

2005-01-01

79

Telomere stability genes are not mutated in osteosarcoma cell lines  

Microsoft Academic Search

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

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

2005-01-01

80

Detecting gene mutations in Japanese Alzheimer's patients by semiconductor sequencing.  

PubMed

Alzheimer's disease (AD) is the most common form of dementia. To date, several genes have been identified as the cause of AD, including PSEN1, PSEN2, and APP. The association between APOE and late-onset AD has also been reported. We here used a bench top next-generation sequencer, which uses an integrated semiconductor device, detects hydrogen ions, and operates at a high-speed using nonoptical technology. We examined 45 Japanese AD patients with positive family histories, and 29 sporadic patients with early onset (<60-year-old). Causative mutations were detected in 5 patients in the familial group (11%). Three patients had a known heterozygous missense mutation in the PSEN1 gene (p.H163R). Two patients from 1 family had a novel heterozygous missense mutation in the PSEN1 gene (p.F386L). In the early onset group, 1 patient carrying homozygous APOE?4 had a novel heterozygous missense mutation in the PSEN2 gene (p.T421M). Approximately 43% patients were APOE?4 positive in our study. This new sequencing technology is useful for detecting genetic variations in familial AD. PMID:24559647

Yagi, Ryoichi; Miyamoto, Ryosuke; Morino, Hiroyuki; Izumi, Yuishin; Kuramochi, Masahito; Kurashige, Takashi; Maruyama, Hirofumi; Mizuno, Noriyoshi; Kurihara, Hidemi; Kawakami, Hideshi

2014-07-01

81

Inactivating mutations of caspase-8 gene in colorectal carcinomas  

Microsoft Academic Search

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

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

2003-01-01

82

Inactivating mutations of CASPASE7 gene in human cancers  

Microsoft Academic Search

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

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

2003-01-01

83

Mutations in RNA Binding Protein Gene Cause Familial Dilated Cardiomyopathy  

PubMed Central

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

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

2009-01-01

84

Mutagenesis in cloned yeast genes. Mutation frequencies in a yeast gene in plasmid and chromosome  

Microsoft Academic Search

Yeast cells were transformed with o-methyl-hydroxylamine-treated plasmid DNA. A collection of mutants possessing a mutated allele of the ADE2 gene in the plasmid was selected. The mutations were subjected to interallelic complementation and suppression-induced interallelic complementation tests. Some of the mutations were imparted to the chromosome via the conversion mechanism. Three pairs of strains, each of which carried an identical

L. M. Gracheva; G. V. Kasinova; V. G. Korolev; I. V. Fedorova

1989-01-01

85

[Three PHEX gene mutations in Chinese subjects with hypophosphatemic rickets and literature review].  

PubMed

The clinical data of three Chinese children who had been definitely diagnosed with X-link dominate hypophosphatemic rickets (XLH) by gene mutation analysis of phosphate-regulating gene with homologies to endopeptidases on the X chromosome (PHEX) were retrospectively studied and the relevant literature was reviewed. PHEX gene mutations were detected in all 3 XLH children; a nonsense mutation (c.58C>T) in one case and splicing mutations (c.1645+1G>A, c.436+1G>A) in the other two cases. Among these mutations, c.436+1G>A was novel. As of January 2014, a total of 329 PHEX gene mutations were reported, primarily within three mutation hot spots, throughout the world. Missense mutations accounted for the highest proportion (24%) among all mutations. There is literature showing geographic differences in the total number of XLH subjects and PHEX mutation types across the world. In the current literature, 89 cases of XLH with 28 types of PHEX mutations have been reported in the population of mainland China. Exon 22 is the most frequent mutation site (18%) and missense mutations are the most common type of mutations (61%). It is concluded that exon 22 is the mutation hot spot and missense mutation is the most common type of mutation in the PHEX gene in Chinese XLH patients and that c.436+1G>A detected in this study is a novel PHEX gene mutation in Chinese with XLH. PMID:24857004

Liu, Shuang; Wei, Min; Xiao, Juan; Wang, Chang-Yan; Qiu, Zheng-Qing

2014-05-01

86

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.

2013-01-01

87

RB1 gene mutations in Iranian patients with retinoblastoma: report of four novel mutations.  

PubMed

Mutations in the RB1 gene lead to retinoblastoma, which is the most common intraocular tumor in children under the age of 6. In the present survey, the mutations of 18 unrelated Iranian retinoblastoma patients were characterized. Mutation analysis of the RB1 gene was performed in patients by sequencing all coding regions and by multiplex ligation probe-dependent amplification analysis. Clinical signs and symptoms of the retinoblastoma patients were similar to those of previously described patients with retinoblastoma. Eight known mutations and four novel mutations (c.832_833insT, c.1943delC, c.1206C>T, and c.2029delG) were determined. In silico analysis of the c.1206C>T variant showed that exon 12 contained an SC-35 consensus sequence, and this variation disrupted the splicing enhancer element and caused skipping of exon 12. Molecular genetic testing of retinoblastoma patients greatly affects the genetic counseling of the families involved, as well as the management of the disease in patients and at-risk relatives. PMID:21763628

Ahani, Ali; Behnam, Babak; Khorshid, Hamid Reza Khorram; Akbari, Mohammad Taghi

2011-06-01

88

Association of Ataxia Telangiectasia Mutated (ATM) gene mutation/deletion with Rhabdomyosarcoma  

PubMed Central

Background Rhabdomyosarcoma is a common malignancy in children. There are two major types of rhabdomyosarcomas, the embryonal and the alveolar, differing in cytogenetic and morphologic features. The alveolar type of rhabdomyosarcoma is frequently associated with chromosome translocation t(2, 13) and poor clinical prognosis. Pathogenesis of rhabdomyosarcoma remains obscure, and especially it occurs in the location where skeletal muscle is absent. We report here that there is a high frequency of association of rhabdomyosarcoma with ataxia telangiectasia mutated (ATM) gene mutation/deletion. Result Totally 17 cases of rhabdomyosarcoma specimens were studied by immunohistochemical or immunofluorescent staining with ATM antibody and revealed that 7 of the 17 cases were negative for ATM expression (41%). Further analyses of rhabdomyosarcoma cell lines with RT-PCR revealed that in Rh30 cells, an alveolar rhabdomyosarcoma cell line, there are three separate deletions/mutations of the ATM mRNA. Western blotting analysis of the Rh30 cellular extract with anti-ATM antibody showed that there is an aberrant form of ATM protein within the Rh30 cells that are smaller than normal control. Conclusion These results suggest a link of ATM gene deletion/mutation with rhabdomyosarcoma, and since ATM kinase is a crucial regulatory protein in DNA damage repair signaling pathway, and ATM deletion/mutation may contribute to pathogenesis of rhabdomyosarcoma.

Zhang, Peilin; Bhakta, Kunjan S; Puri, Pier Lorenzo; Newbury, Robert O; Feramisco, James R; Wang, Jean Y

2003-01-01

89

Mutations of the tyrosinase gene produce autosomal recessive ocular albinism  

SciTech Connect

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

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

1994-09-01

90

Mutational Analysis of the Wilms' Tumor (WTI) Gene.  

PubMed

Mutations of the Wilms' tumor (WT1) gene have been shown to underlie a proportion of cases of Wilms' tumor, an embryonal kidney cancer occurring mainly in childhood. The WTl gene comprtses ten exons spanning approx 50 kb of genomrc DNA. The messenger RNA is approx 3 kb in length and encodes a zinc finger protein. The four zinc fingers, which he at the C-terminal end of the protein, are encoded by separate exons 7-10. The 5' end of the gene is extremely GC-rich, with areas approaching a 70% GC content. This makes this region difficult to amplify in polymerase chain reactions. PMID:21380703

King-Underwood, L; Pritchard-Jones, K

1996-01-01

91

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

92

Novel mutation in VCP gene causes atypical amyotrophic lateral sclerosis  

PubMed Central

Objective: To identify the genetic variant that causes autosomal dominantly inherited motor neuron disease in a 4-generation Israeli-Arab family using genetic linkage and whole exome sequencing. Methods: Genetic linkage analysis was performed in this family using Illumina single nucleotide polymorphism chips. Whole exome sequencing was then undertaken on DNA samples from 2 affected family members using an Illumina 2000 HiSeq platform in pursuit of potentially pathogenic genetic variants that comigrate with the disease in this pedigree. Variants meeting these criteria were then screened in all affected individuals. Results: A novel mutation (p.R191G) in the valosin-containing protein (VCP) gene was identified in the index family. Direct sequencing of the VCP gene in a panel of DNA from 274 unrelated individuals with familial amyotrophic lateral sclerosis (FALS) revealed 5 additional mutations. Among them, 2 were previously identified in pedigrees with a constellation of inclusion body myopathy with Paget disease of the bone and frontotemporal dementia (IBMPFD) and in FALS, and 2 other mutations (p.R159C and p.R155C) in IBMPFD alone. We did not detect VCP gene mutations in DNA from 178 cases of sporadic amyotrophic lateral sclerosis. Conclusions: We report a novel VCP mutation identified in an amyotrophic lateral sclerosis family (p.R191G) with atypical clinical features. In our experience, VCP mutations arise in approximately 1.5% of FALS cases. Our study supports the view that motor neuron disease is part of the clinical spectrum of VCP-associated disease.

Gonzalez-Perez, Paloma; Cirulli, Elizabeth T.; Drory, Vivian E.; Dabby, Ron; Nisipeanu, Puiu; Carasso, Ralph L.; Sadeh, Menachem; Fox, Andrew; Festoff, Barry W.; Sapp, Peter C.; McKenna-Yasek, Diane; Goldstein, David B.

2012-01-01

93

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

94

Novel Germline Mutations in the SDHB and SDHD Genes in Japanese Pheochromocytomas  

Microsoft Academic Search

The SDHA, SDHB, SDHC, and SDHD genes code for subunits of succinate dehydrogenase (SDH), which forms part of the mitochondrial respiratory chain. Germline mutations in the genes encoding SDHB and SDHD have been reported in familial paragangliomas\\/pheochromocytomas and in apparently sporadic pheochromocytomas. SDHB and SDHD mutations are widely distributed along the genes with no apparent hot spots. SDHB mutations are

Kazumasa Isobe; Shigeru Minowada; Ichiro Tatsuno; Kazumi Suzukawa; Sumiko Nissato; Toru Nanmoku; Hisato Hara; Toru Yashiro; Yasushi Kawakami; Kazuhiro Takekoshi

2007-01-01

95

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

Code of Federal Regulations, 2010 CFR

...true TSCA in vitro mammalian cell gene mutation test. 799.9530 Section 799.9530...9530 TSCA in vitro mammalian cell gene mutation test. (a) Scope. This section...The in vitro mammalian cell gene mutation test can be used to detect...

2010-07-01

96

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

Code of Federal Regulations, 2010 CFR

...false TSCA in vitro mammalian cell gene mutation test. 799.9530 Section 799.9530...9530 TSCA in vitro mammalian cell gene mutation test. (a) Scope. This section...The in vitro mammalian cell gene mutation test can be used to detect...

2009-07-01

97

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.

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

98

Sister chromatid exchange, DNA repair, and single-gene mutation  

SciTech Connect

Sister chromatid exchange (SCE) has been studied in cultured mammalian cells with regard to the nature of the inducing lesion, mutation induction, and factors that modify the observed frequency following mutagen exposure, SCEs can be induced by a wide spectrum of DNA lesions and, for nine agents examined, the frequency of induced SCE is linearly related to induced single-gene mutation. Further, a deficiency in DNA repair may alter the expression of both SCE and mutation in a qualitatively similar manner. The frequency of SCE induced by mitomycin-C is suppressed in heterochromatic relative to euchromatin and, in nondividing lymphocytes, the lesions leading to the formation of SCEs may persist for several months.

Carrano, A.V.; Thompson, L.H.

1982-01-01

99

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

100

Mutations in the protamine 1 gene associated with male infertility.  

PubMed

In elongating spermatids, human sperm chromatin undergoes a complex compaction in which the transition proteins are extensively replaced by the protamine proteins. Several human studies demonstrate that expression of the protamine proteins is altered in some men with male infertility. For this study, we screened the PRM1 (protamine 1) gene for mutations in a large cohort of 281 men seeking infertility treatment. We identified the c.102G>T transversion that results in an p.Arg34Ser amino acid change in two men. One of these patients presented with oligozoospermia associated with increased sperm DNA fragmentation. The second individual was normospermic but together with his partner sought treatment for idiopathic couple infertility. We also identified a novel missense mutation (c.119G>A, p.Cys40Tyr) in a man with oligoasthenozoospermia. These mutations were not observed in control populations. Interestingly, we also detected variants both 5' and 3' to the PRM1 open-reading frame specifically in infertile individuals. Four individuals with unexplained severe oligozoospermia were heterozygote for a c.-107G>C change that is located at -15 bp from the transcription initiation site of the gene. This mutation may influence PRM1 expression. In addition, a c.*51G>C variant was detected in the 3'UTR of PRM1 specifically in a man with severe oligoasthenozoospermia. PMID:17494104

Ravel, C; Chantot-Bastaraud, S; El Houate, B; Berthaut, I; Verstraete, L; De Larouziere, V; Lourenço, D; Dumaine, A; Antoine, J M; Mandelbaum, J; Siffroi, J P; McElreavey, K

2007-07-01

101

Familial Dysautonomia Is Caused by Mutations of the IKAP Gene  

PubMed Central

The defective gene DYS, which is responsible for familial dysautonomia (FD) and has been mapped to a 0.5-cM region on chromosome 9q31, has eluded identification. We identified and characterized the RNAs encoded by this region of chromosome 9 in cell lines derived from individuals homozygous for the major FD haplotype, and we observed that the RNA encoding the I?B kinase complex–associated protein (IKAP) lacks exon 20 and, as a result of a frameshift, encodes a truncated protein. Sequence analysis reveals a T?C transition in the donor splice site of intron 20. In individuals bearing a minor FD haplotype, a missense mutation in exon 19 disrupts a consensus serine/threonine kinase phosphorylation site. This mutation results in defective phosphorylation of IKAP. These mutations were observed to be present in a random sample of Ashkenazi Jewish individuals, at approximately the predicted carrier frequency of FD. These findings demonstrate that mutations in the gene encoding IKAP are responsible for FD.

Anderson, Sylvia L.; Coli, Rocco; Daly, Ira W.; Kichula, Elizabeth A.; Rork, Matthew J.; Volpi, Sabrina A.; Ekstein, Josef; Rubin, Berish Y.

2001-01-01

102

Heterogeneous AVPR2 gene mutations in congenital nephrogenic diabetes insipidus.  

PubMed Central

Mutations in the AVPR2 gene encoding the receptor for arginine vasopressin in the kidney (V2 ADHR) have been reported in patients with congenital nephrogenic diabetes insipidus, a predominantly X-linked disorder of water homeostasis. We have used restriction-enzyme analysis and direct DNA sequencing of genomic PCR product to evaluate the AVPR2 gene in 11 unrelated affected males. Each patient has a different DNA sequence variation, and only one matches a previously reported mutation. Cosegregation of the variations with nephrogenic diabetes insipidus was demonstrated for two families, and a de novo mutation was documented in two additional cases. Carrier detection was accomplished in one family. All the variations predict frameshifts, truncations, or nonconservative amino acid substitutions in evolutionarily conserved positions in the V2 ADHR and related receptors. Of interest, a 28-bp deletion is found in one patient, while another, unrelated patient has a tandem duplication of the same 28-bp segment, suggesting that both resulted from the same unusual unequal crossing-over mechanism facilitated by 9-mer direct sequence repeats. Since the V2 ADHR is a member of the seven-transmembrane-domain, G-protein-coupled receptor superfamily, the loss-of-function mutations from this study and others provide important clues to the structure-function relationship of this and related receptors. Images Figure 1 Figure 2 Figure 3

Wildin, R. S.; Antush, M. J.; Bennett, R. L.; Schoof, J. M.; Scott, C. R.

1994-01-01

103

A new spontaneous mouse mutation in the Kcne1 gene.  

PubMed

A new mouse mutant, punk rocker (allele symbol Kcne1(pkr)), arose spontaneously on a C57BL/10J inbred strain background and is characterized by a distinctive head-tossing, circling, and ataxic phenotype. It is also profoundly and bilaterally deaf. The mutation resides in the Kcne1 gene on Chromosome (Chr) 16 and has been identified as a single base change within the coding region of the third exon. The C to T nucleotide substitution causes an arginine to be altered to a termination codon at amino acid position 67, and predictably this will result in a significantly truncated protein product. The Kcne1(pkr) mutant represents the first spontaneous mouse model for the human disorder, Jervell and Lange-Nielsen syndrome, associated with mutations in the homologous KCNE1 gene on human Chr 21. PMID:11003695

Letts, V A; Valenzuela, A; Dunbar, C; Zheng, Q Y; Johnson, K R; Frankel, W N

2000-10-01

104

A new spontaneous mouse mutation in the Kcne1 gene  

PubMed Central

A new mouse mutant, punk rocker (allele symbol Kcne1pkr), arose spontaneously on a C57BL/10J inbred strain background and is characterized by a distinctive head-tossing, circling, and ataxic phenotype. It is also profoundly and bilaterally deaf. The mutation resides in the Kcne1 gene on Chromosome (Chr) 16 and has been identified as a single base change within the coding region of the third exon. The C to T nucleotide substitution causes an arginine to be altered to a termination codon at amino acid position 67, and predictably this will result in a significantly truncated protein product. The Kcne1pkr mutant represents the first spontaneous mouse model for the human disorder, Jervell and Lange-Nielsen syndrome, associated with mutations in the homologous KCNE1 gene on human Chr 21.

Letts, V.A.; Valenzuela, A.; Dunbar, C.; Zheng, Q.Y.; Johnson, K.R.; Frankel, W.N.

2010-01-01

105

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

Microsoft Academic Search

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

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

2008-01-01

106

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

107

Fifty-four novel mutations in the NF1 gene and integrated analyses of the mutations that modulate splicing.  

PubMed

Neurofibromatosis type 1 (NF1) is a common autosomal dominant genetic disorder caused by mutations in the NF1 gene. One of the hallmarks of NF1 is the high mutation rate in this gene. In this study, we present 127 different NF1 mutations and 54 novel mutations detected at both the genomic DNA and mRNA level using a retrospective case series review. We found that 25.2% of these different mutations induced aberrant splicing. Of note, 40.6% of these splicing errors were caused by exonic variants. In addition, one mutation produced mosaicism in the post-transcriptional profile. However, studies investigating these splicing aberrations are limited. In order to better understand the pathogenicity of NF1 and to provide a more accurate interpretation in molecular diagnostic testing, combined computational analyses were employed to elucidate the underlying mechanisms of the variants modulating NF1 gene splicing. PMID:24789688

Xu, Weihong; Yang, Xiao; Hu, Xiaoxia; Li, Shibo

2014-07-01

108

Fifty-four novel mutations in the NF1 gene and integrated analyses of the mutations that modulate splicing  

PubMed Central

Neurofibromatosis type 1 (NF1) is a common autosomal dominant genetic disorder caused by mutations in the NF1 gene. One of the hallmarks of NF1 is the high mutation rate in this gene. In this study, we present 127 different NF1 mutations and 54 novel mutations detected at both the genomic DNA and mRNA level using a retrospective case series review. We found that 25.2% of these different mutations induced aberrant splicing. Of note, 40.6% of these splicing errors were caused by exonic variants. In addition, one mutation produced mosaicism in the post-transcriptional profile. However, studies investigating these splicing aberrations are limited. In order to better understand the pathogenicity of NF1 and to provide a more accurate interpretation in molecular diagnostic testing, combined computational analyses were employed to elucidate the underlying mechanisms of the variants modulating NF1 gene splicing.

XU, WEIHONG; YANG, XIAO; HU, XIAOXIA; LI, SHIBO

2014-01-01

109

Cloning of a gene mutation for parkinson's disease  

US Patent & Trademark Office Database

Parkinson's disease (PD) is a common neurodegenrative disorder with a lifetime incidence of approximately 2 percent. It was recently reported that a PD susceptibility gene is located on the long arm of human chromosome four. The present invention reports the subsequent identification of a mutation in the alpha synuclein gene, which codes for a presynaptic protein thought to be involved in neuronal plasticity. The finding of a specific molecular alteration which is causative for PD will permit the detailed understanding of the pathophysiology of the disorder, which will lead to potential therapetuic interventions, as well as a means for diagnosing individuals having an increased risk of developing the disease.

2006-02-21

110

Validation of high-resolution DNA melting analysis for mutation scanning of the CDKL5 gene: identification of novel mutations.  

PubMed

Mutations in the cyclin-dependent kinase-like 5 gene (CDKL5) have been predominantly described in epileptic encephalopathies of female, including infantile spasms with Rett-like features. Up to now, detection of mutations in this gene was made by laborious, expensive and/or time consuming methods. Here, we decided to validate high-resolution melting analysis (HRMA) for mutation scanning of the CDKL5 gene. Firstly, using a large DNA bank consisting to 34 samples carrying different mutations and polymorphisms, we validated our analytical conditions to analyse the different exons and flanking intronic sequences of the CDKL5 gene by HRMA. Secondly, we screened CDKL5 by both HRMA and denaturing high performance liquid chromatography (dHPLC) in a cohort of 135 patients with early-onset seizures. Our results showed that point mutations and small insertions and deletions can be reliably detected by HRMA. Compared to dHPLC, HRMA profiles are more discriminated, thereby decreasing unnecessary sequencing. In this study, we identified eleven novel sequence variations including four pathogenic mutations (2.96% prevalence). HRMA appears cost-effective, easy to set up, highly sensitive, non-toxic and rapid for mutation screening, ideally suited for large genes with heterogeneous mutations located along the whole coding sequence, such as the CDKL5 gene. PMID:23064044

Raymond, Laure; Diebold, Bertrand; Leroux, Céline; Maurey, Hélène; Drouin-Garraud, Valérie; Delahaye, Andre; Dulac, Olivier; Metreau, Julia; Melikishvili, Gia; Toutain, Annick; Rivier, François; Bahi-Buisson, Nadia; Bienvenu, Thierry

2013-01-01

111

Genotypic prediction of resistant mutation in HIV-1 pol gene towards the antiretroviral drugs.  

PubMed

Mutation in HIV-1 pol gene confers the resistance to antiretroviral drugs. Three nucleotide sequences of HIV-1 pol gene products were selected and HIV BLAST was performed. Amino acid positions of 30 sequences were compared with HXB2 reference strain. Two sequences of protease show the major mutation with mutations sites of I54V and V82A and 8 sequences shown other mutations. One sequence of integrase with minor mutation of E157Q and 9 sequences with other mutations were inferred. This study is useful in making more accurate prediction of results with better combination Highly Active Antiretroviral Therapy (HAART) and important mutations. PMID:21441094

Kumar, Amit; Jadhav, Chandrakant

2011-01-01

112

Identifying highly mutated IGHD genes in the junctions of rearranged human immunoglobulin heavy chain genes  

Microsoft Academic Search

The reliable identification of IGHD genes within human immunoglobulin heavy chains is challenging with up to one third of rearrangements having no identifiable IGHD gene. The short, mutated IGHD genes are generally assumed to be indistinguishable from the N-REGIONS of non-template encoded nucleotides that surround them. In this study we have characterised N-REGIONS, demonstrating the importance of nucleotide composition biases

Katherine J. L. Jackson; Bruno A. Gaëta; Andrew M. Collins

2007-01-01

113

SEX: DIFFERENCES IN MUTATION, RECOMBINATION, SELECTION, GENE FLOW, AND GENETIC DRIFT  

Microsoft Academic Search

In many instances, there are large sex differences in mutation rates, recombination rates, selection, rates of gene flow, and genetic drift. Mutation rates are often higher in males, a difference that has been estimated both directly and indirectly. The higher male mutation rate appears related to the larger number of cell divisions in male lineages but mutation rates also appear

Philip W. Hedrick

2007-01-01

114

Characterisation of germline mutations in the neurofibromatosis type 1 (NF1) gene  

Microsoft Academic Search

Neurofibromatosis type 1 is one of the most common inherited disorders with an incidence of 1 in 3000. The search for NF1 mutations has been hampered by the overall size of the gene, the large number of exons, and the high mutation rate. To date, fewer than 90 mutations have been reported to the NF1 mutation analysis consortium and the

M Upadhyaya; J Maynard; M Osborn; S M Huson; M Ponder; B A Ponder; P S Harper

1995-01-01

115

Gene expression, chromosome position and lamin A/C mutations.  

PubMed

The nuclear lamina is increasingly being appreciated for its epigenetic role in regulating gene expression. The nuclear lamina underlies the inner nuclear membrane and, in post mitotic cells, is composed of a latticework primarily formed by the intermediate filament protein, lamin A/C. Although not well defined, lamin-associated domains have been described, and these domains are determined by DNA sequence and chromatin conformation. Lamin-associated domains are positioned to mediate the interaction with the nuclear membrane, where they contribute to transcriptional regulation. Although lamin-associated domains are primarily considered to be repressive in nature, those nearer to nuclear pores may actually promote transcription. Mutations in LMNA, the gene encoding lamins A and C, are a relatively common cause of inherited cardiomyopathy. As substantial data supports a role for the lamina in its interaction with chromatin and gene regulation, we examined the role of a genetically disrupted lamina and the consequences thereof. A dominant LMNA mutation, E161K, that causes inherited cardiomyopathy was studied. Gene expression changes were profiled in a human cardiomyopathic E161K heart, and it was found that chromosome 13 had a high percentage of misexpressed genes. Chromosome 13 was also found to be less tightly associated with the nuclear membrane in E161K mutant cells, thereby linking abnormal gene expression and intranuclear position. These and other studies support a role for the nuclear membrane as an active regulator of gene expression and provide additional support that disrupting this regulation is a mechanism of human disease. PMID:21818408

Puckelwartz, Megan J; Depreux, Frederic Fs; McNally, Elizabeth M

2011-01-01

116

Identification of factor VIII gene mutations in patients with severe haemophilia A in Venezuela: identification of seven novel mutations.  

PubMed

Haemophilia A is caused by mutations in the gene encoding coagulation factor VIII (FVIII). In severe Haemophilia A (sHA), two inversions are responsible for approximately 50% of the genetic alterations (intron 22 and intron 1 inversions). The other mutations are extremely diverse and each affected family generally has its own mutation. Our aim was to detect the genetic alterations present in the FVIII gene (F8) in 54 unrelated male patients with sHA in Venezuela. We initially detected the presence of the intron 22 inversion by performing inverse PCR, and the negative patients for this inversion were analysed for the intron 1 inversion by PCR. Patients negative for both inversions were analysed using Conformation Sensitive Gel Electrophoresis for mutations in all exons, promoter region and 3'-UTR. sHA causative mutations were identified in 49 patients. Intron-22 and -1 inversions were detected in 41% and 0% of patients respectively. Besides these two mutations, 25 different mutations were identified, including nine nonsense, four small deletions, two small insertions, four missense, three splicing mutations and three large deletions. Seven novel mutations were identified, including two nonsense mutations, two small deletions, one small insertion, one missense mutation and one splicing mutation. Thirty one percent of the patients with identified mutations developed inhibitors against exogenous FVIII. This is the first report of F8 mutations in patients with sHA in Venezuela; the data from this study suggests that the spectrum of gene defects found in these patients is as heterogeneous as reported previously for other populations. PMID:21371196

Albánez, S; Ruiz-Sáez, A; Boadas, A; de Bosch, N; Porco, A

2011-09-01

117

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

Code of Federal Regulations, 2010 CFR

...2010-07-01 true Detection of gene mutations in somatic cells in culture. 798...Toxicity § 798.5300 Detection of gene mutations in somatic cells in culture. (a...culture systems may be used to detect mutations induced by chemical...

2010-07-01

118

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

Code of Federal Regulations, 2010 CFR

...2009-07-01 false Detection of gene mutations in somatic cells in culture. 798...Toxicity § 798.5300 Detection of gene mutations in somatic cells in culture. (a...culture systems may be used to detect mutations induced by chemical...

2009-07-01

119

Familial Ohtahara syndrome due to a novel ARX gene mutation.  

PubMed

Recently, it has been reported that longer expansions of the polyalanine tract of the ARX gene could cause an early infantile encephalopathy with suppression burst pattern and that the length of this repeat region could be related to the severity of the electroclinical picture. We describe the history of two male individuals, born from monozygotic twin sisters, with Ohtahara syndrome (OS) that evolved into West syndrome phenotype and epileptic encephalopathy. In both children, we have found a previously unreported missense mutation in exon 5 of ARX gene (c.1604T>A) resulting in the substitution of a leucine with a glutamine in the aminoacid sequence. The two mothers and the maternal grandmother carry the same mutation which segregates with the disease phenotype in the family. This study confirms that ARX is involved in the pathogenesis of cryptogenic early onset epileptic encephalopathy, such as OS, and suggests that the severity of the electroclinical picture is likely to not exclusively correlate with the extent of expansions of the polyalanine tracts, but rather with the functional effect of different pathogenetic mutations. PMID:21108397

Giordano, L; Sartori, S; Russo, S; Accorsi, P; Galli, J; Tiberti, A; Bettella, E; Marchi, M; Vignoli, A; Darra, F; Murgia, A; Bernardina, B Dalla

2010-12-01

120

[Pachyonychia congenita. Keratin gene mutations with pleiotropic effect].  

PubMed

Pachyonychia congenita (PC) comprises a heterogeneous group of autosomal dominantly inherited conditions showing characteristic nail thickening and associated signs such as palmoplantar keratoderma, follicular keratoses, and mucosal leukokeratoses. Less frequently epidermal cysts, hairshaft abnormalities, natal teeth and laryngeal involvement may be seen. Phenotypically and genetically two major forms of PC are recognized, pachyonychia congenita Jadassohn-Lewandowsky/PC type I (Medelian inheritance in man-MIM-167200) and pachyonychia congenita Jackson-Lawler/PC type II (MIM 167210). Both conditions show nail deformities, focal palmoplantar keratoderma, and follicular hyperkeratoses. Diagnostically relevant are leukokeratoses of the oral mucosa in patients with PC type I. In contrast individuals affected with PC type II show premature dentition and multiple pilosebaceous cysts predominantly affecting the upper trunk. The latter closely resemble eruptive vellus hair cysts and steatocystoma multiplex. By mutational analysis keratin K6a and K16 gene mutations have been detected in patients with PC type I, and keratin K6b and K17 gene mutations have been shown to be the underlying genetic defect in patients with PC type II. PMID:10464680

Swensson, O

1999-07-01

121

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

122

Identification of mutated core cancer modules by integrating somatic mutation, copy number variation, and gene expression data  

PubMed Central

Motivation Understanding the molecular mechanisms underlying cancer is an important step for the effective diagnosis and treatment of cancer patients. With the huge volume of data from the large-scale cancer genomics projects, an open challenge is to distinguish driver mutations, pathways, and gene sets (or core modules) that contribute to cancer formation and progression from random passengers which accumulate in somatic cells but do not contribute to tumorigenesis. Due to mutational heterogeneity, current analyses are often restricted to known pathways and functional modules for enrichment of somatic mutations. Therefore, discovery of new pathways and functional modules is a pressing need. Results In this study, we propose a novel method to identify Mutated Core Modules in Cancer (iMCMC) without any prior information other than cancer genomic data from patients with tumors. This is a network-based approach in which three kinds of data are integrated: somatic mutations, copy number variations (CNVs), and gene expressions. Firstly, the first two datasets are merged to obtain a mutation matrix, based on which a weighted mutation network is constructed where the vertex weight corresponds to gene coverage and the edge weight corresponds to the mutual exclusivity between gene pairs. Similarly, a weighted expression network is generated from the expression matrix where the vertex and edge weights correspond to the influence of a gene mutation on other genes and the Pearson correlation of gene mutation-correlated expressions, respectively. Then an integrative network is obtained by further combining these two networks, and the most coherent subnetworks are identified by using an optimization model. Finally, we obtained the core modules for tumors by filtering with significance and exclusivity tests. We applied iMCMC to the Cancer Genome Atlas (TCGA) glioblastoma multiforme (GBM) and ovarian carcinoma data, and identified several mutated core modules, some of which are involved in known pathways. Most of the implicated genes are oncogenes or tumor suppressors previously reported to be related to carcinogenesis. As a comparison, we also performed iMCMC on two of the three kinds of data, i.e., the datasets combining somatic mutations with CNVs and secondly the datasets combining somatic mutations with gene expressions. The results indicate that gene expressions or CNVs indeed provide extra useful information to the original data for the identification of core modules in cancer. Conclusions This study demonstrates the utility of our iMCMC by integrating multiple data sources to identify mutated core modules in cancer. In addition to presenting a generally applicable methodology, our findings provide several candidate pathways or core modules recurrently perturbed in GBM or ovarian carcinoma for further studies.

2013-01-01

123

Gene mutation profiles and prognostic implications in Korean patients with T-lymphoblastic leukemia.  

PubMed

Genetic alterations implicated in the leukemogenesis of T cell acute lymphoblastic leukemia (T-ALL) have been identified in recent years. In this study, we investigated gene mutation profiles and prognostic implications in a series of Korean T-ALL patients. The study patients were 29 Korean patients with T-ALL; 13 adults (45 %) and 16 children (55 %; male-to-female ratio, 25:4). Clinical, hematologic, and cytogenetic findings were reviewed. We performed mutation analyses for NOTCH1, FBXW7, PHF6, and IL7R genes and survival analyses according to the mutational status. Gene mutations were identified in 66 % of the patients in our series (19/29). Eighteen patients (62 %) had NOTCH1/FBXW7 mutations. Sixteen patients (55 %) had NOTCH1 mutations including nine novel mutations, and eight patients (28 %) had known FBXW7 mutations. Eight patients (28 %; six males and two females) had PHF6 mutations including four novel mutations. Three patients (10 %) had IL7R mutations, which were all novel in-frame insertion or deletion-insertions. The gene mutation profile combined with cytogenetics and FISH study for the p16 gene detected genetic aberrations in 90 % of patients (26/29). There was no significant difference in the frequency of gene mutations between the pediatric and adult patients with T-ALL. Survival analyses suggested a favorable prognostic implication of NOTCH1 mutations in adult T-ALL. Gene mutation studies for NOTCH1, FBXW7, PHF6, and IL7R could detect genetic alterations in a majority of Korean T-ALL patients with novel mutations. We observed similar mutation profiles between adult and pediatric T-ALL, and a favorable prognostic implication of NOTCH1 mutations in adult T-ALL. PMID:23354995

Huh, Hee Jae; Lee, Soo Hyun; Yoo, Keon Hee; Sung, Ki Woong; Koo, Hong Hoe; Jang, Jun Ho; Kim, Kihyun; Kim, Seok Jin; Kim, Won Seog; Jung, Chul Won; Lee, Ki-O; Kim, Sun-Hee; Kim, Hee-Jin

2013-05-01

124

Optimal Control of Gene Mutation in DNA Replication  

PubMed Central

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

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

2012-01-01

125

Novel chloride channel gene mutations in two unrelated Chinese families with myotonia congenita.  

PubMed

Myotonia congenita (MC) is a genetic disease characterized by mutations in the muscle chloride channel gene (CLCN1). To date, approximately 130 different mutations on the CLCN1 gene have been identified. However, most of the studies have focused on Caucasians, and reports on CLCN1 mutations in Chinese population are rare. This study investigated the mutation of CLCN1 in two Chinese families with MC. Direct sequencing of the CLCN1 gene revealed a heterozygous mutation (892G>A, resulting in A298T) in one family and a compound heterozygous mutations (782A>G, resulting in Y261C; 1679T>C, resulting in M560T) in the other family, None of the 100 normal controls had these mutations. Our findings add more to the available information on the CLCN1 mutation spectrum, and provide a valuable reference for studying the mutation types and inheritance pattern of CLCN1 in the Chinese population. PMID:21045501

Gao, Feng; Ma, Fu Chan; Yuan, Zhe Feng; Yang, Cui Wei; Li, Hai Feng; Xia, Zhe Zhi; Shui, Quan Xiang; Jiang, Ke Wen

2010-01-01

126

Prognostic implications of gene mutations in acute myeloid leukemia with normal cytogenetics.  

PubMed

In recent years, a number of somatically acquired mutational changes have been identified in patients with acute myeloid leukemia (AML). Most of these genetic alterations occur in AML exhibiting a normal karyotype, representing the largest cytogenetic subgroup (40%-50%) of AML. These molecular findings not only provide novel insights into the pathogenesis of AML but also are of clinical importance. In this review we will discuss the most relevant gene alterations, including NPM1 gene mutations, internal tandem duplications (ITD) or tyrosine kinase domain (TKD) mutations of the FLT3 gene, CEBPA gene mutations, and partial tandem duplications (PTD) of the MLL gene, as well as mutations in the NRAS and WT1 genes. In part, these gene mutations have emerged as important prognostic markers and they now allow us to dissect cytogenetically normal (CN)-AML in distinct prognostic subgroups. Furthermore, these mutant molecules represent potential targets for molecular therapies. PMID:18692685

Gaidzik, Verena; Döhner, Konstanze

2008-08-01

127

BCS1L gene mutation causing GRACILE syndrome: case report.  

PubMed

Abstract 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, Ci?dem Seher; Tümer, Leyla; Ezgü, Fatih Suheyl; Küçükçongar, Aynur; Hasano?lu, Alev

2014-07-01

128

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

PubMed

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

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

2012-03-01

129

Mutation analysis of PAH gene and characterization of a recurrent deletion mutation in Korean patients with phenylketonuria  

Microsoft Academic Search

Phenylketonuria (PKU; MIM 261600) is an autosomal recessive metabolic disorder caused by a deficiency of phenylalanine hydroxylase (PAH; EC 1.14.16.1). Point mutations in the PAH gene are known to cause PKU in various ethnic groups, and large deletions or duplications account for up to 3% of the PAH mutations in some ethnic groups. However, a previous study could not identify

Yong-Wha Lee; Dong Hwan Lee; Nam-Doo Kim; Seung-Tae Lee; Jee Young Ahn; Tae-Youn Choi; You Kyoung Lee; Sun-Hee Kim; Jong-Won Kim; Chang-Seok Ki

2008-01-01

130

PIK3CA gene is frequently mutated in breast carcinomas and hepatocellular carcinomas  

Microsoft Academic Search

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

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

2005-01-01

131

A novel ATP8 gene mutation in an infant with tetralogy of Fallot.  

PubMed

We report the case of a novel mitochondrial DNA mutation in the MT-ATP8 gene in an infant with tetralogy of Fallot. Next-generation sequencing was applied to sequence whole mitochondrial DNA of the patient. A known Leber's hereditary optic neuropathy-associated mutation (G9804A), a heteroplasmic T7501C mutation (17%), and a novel C8481 T Pro > Leu missense mutation in the MT-ATP8 gene was identified. PMID:23735083

Tansel, Turkan; Paçal, Ferda; Ustek, Duran

2014-06-01

132

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

PubMed Central

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

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

2012-01-01

133

Mutation of the CgPDR16 gene attenuates azole tolerance and biofilm production in pathogenic Candida glabrata.  

PubMed

The PDR16 gene encodes the homologue of Sec14p, participating in protein secretion, regulation of lipid synthesis and turnover in vivo and acting as a phosphatidylinositol transfer protein in vitro. This gene is also involved in the regulation of multidrug resistance in Saccharomyces cerevisiae and pathogenic yeasts. Here we report the results of functional analysis of the CgPDR16 gene, whose mutation has been previously shown to enhance fluconazole sensitivity in Candida glabrata mutant cells. We have cloned the CgPDR16 gene, which was able to complement the pdr16? mutation in both C. glabrata and S. cerevisiae. Along with fluconazole, the pdr16? mutation resulted in increased susceptibility of mutant cells to several azole antifungals without changes in sensitivity to polyene antibiotics, cycloheximide, NQO, 5-fluorocytosine and oxidants inducing the intracellular formation of reactive oxygen species. The susceptibility of the pdr16? mutant strain to itraconazole and 5-fluorocytosine was enhanced by CTBT [7-chlorotetrazolo(5,1-c)benzo(1,2,4)triazine] inducing oxidative stress. The pdr16? mutation increased the accumulation of rhodamine 6G in mutant cells, decreased the level of itraconazole resistance caused by gain-of-function mutations in the CgPDR1 gene, and reduced cell surface hydrophobicity and biofilm production. These results point to the pleiotropic phenotype of the pdr16? mutant and support the role of the CgPDR16 gene in the control of drug susceptibility and virulence in the pathogenic C. glabrata. PMID:23939632

Culakova, Hana; Dzugasova, Vladimira; Perzelova, Jana; Gbelska, Yvetta; Subik, Julius

2013-10-01

134

Analysis of the p53 gene mutations in acute myelogenous leukemia: The p53 gene mutations associated with a deletion of chromosome 17  

Microsoft Academic Search

In order to determine the relevance of the p53 tumor suppressor gene mutations in acute myelogenous leukemia (AML), we analyzed the p53 gene in genomic DNA of 18 unselected cases of AML by polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) and direct sequencing. We detected three cases (16.7%) with the p53 gene mutations showing only the mutant alleles; the high incidence

M. Kurosawa; M. Okabe; Y. Kunieda; M. Asaka

1995-01-01

135

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

Microsoft Academic Search

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

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

2007-01-01

136

Genetic syndromes caused by mutations in epigenetic genes.  

PubMed

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

Berdasco, María; Esteller, Manel

2013-04-01

137

Mutation spectrum and splicing variants in the OPA1 gene.  

PubMed

Optic atrophy type 1 (OPA1, MIM 165500) is a dominantly inherited optic neuropathy that features low visual acuity leading in many cases to legal blindness. We have recently shown, with others, that mutations in the OPA1 gene encoding a dynamin-related mitochondrial protein, underlie the dominant form of optic atrophy. Here we report that OPA1 has eight mRNA isoforms as a result of the alternative splicing of exon 4 and two novel exons named 4b and 5b. In addition, we screened a cohort of 19 unrelated patients with dominant optic atrophy by direct sequencing of the 30 OPA1 exons (including exons 4b and 5b) and found mutations in 17 (89%) of them of which 8 were novel. A majority of these mutations were truncative (65%) and located in exons 8 to 28, but a number of them were amino acid changes predominantly found in the GTPase domain (exons 8 to 15). We hypothesize that at least two modifications of OPA1 may lead to dominant optic atrophy, that is alteration in GTPase activity and loss of the last seven C-terminal amino acids that putatively interact with other proteins. PMID:11810270

Delettre, C; Griffoin, J M; Kaplan, J; Dollfus, H; Lorenz, B; Faivre, L; Lenaers, G; Belenguer, P; Hamel, C P

2001-12-01

138

Prenatal cortical hyperostosis with COL1A1 gene mutation.  

PubMed

Infantile cortical hyperostosis (Caffey disease) is benign and self-limiting when it presents near or after birth but it is usually lethal when it presents earlier. We present the clinical, ultrasonic, radiographic, and pathologic findings in an instructive case of early onset prenatal cortical hyperostosis. The pregnancy of a 21-year-old woman was medically terminated at 30 weeks of gestation after a diagnosis of severe osteogenesis imperfecta. Prenatal ultrasounds showed short long bones. Postmortem radiographs showed hyperostosis in long bones, ribs and mandible. The affected skeleton showed marked bony sclerosis and ballooning of the diaphyses of the long bones with periosteal sclerosis. A complete autopsy showed characteristic histologic findings of infantile cortical hyperostosis in affected bones. A missense mutation (3040C --> T) in exon 41 the gene encoding the alpha 1 chain of type I collagen was found in fetus pulmonary tissue. Neither the severe form nor the mild form of prenatal cortical hyperostosis were thought to be related to collagen I mutations. Our study indicates that a heterozygous 3040C --> T mutation can also be found in lethal prenatal cortical hyperostosis. PMID:18553566

Kamoun-Goldrat, Agnès; Martinovic, Jelena; Saada, Julien; Sonigo-Cohen, Pascale; Razavi, Ferechte; Munnich, Arnold; Le Merrer, Martine

2008-07-15

139

[Mutations in 21-hydroxylase gene caused by gene conversion-like events].  

PubMed

Two steroid 21-hydroxylase genes (CYP21A and CYP21B) alternate in tandem with two genes for the fourth component of complement (C4A and C4B) on the short arm of chromosome 6 between the loci of HLA-B and HLA-DR. The CYP21B gene encodes an adrenal microsomal cytochrome P-450, which is specific for steroid 21-hydroxylation (P450c21). A defect of this protein would cause 21-hydroxylase deficiency, which is an autosomal recessive disease and is the most common cause of congenital adrenal hyperplasia (CAH). On the other hand, the CYP21A gene, which is homologous to the CYP21B gene up to 98% in the nucleotide sequences, is a pseudogene due to several mutations in the coding region. One of the mutations is a C----T change leading a termination codon, TAG, in the 8th exon. 1) I cloned a CYP21B gene from a patient homozygous for HLA-Bw75-DRw9 by descent. I found a C----T change in the 8th exon of the CYP21B gene. This mutation would prevent a synthesis of 21-hydroxylase and was thought to be a crucial change to cause CAH in this patient. Because there was no apparent gross change in the organization of the C4-CYP21 region and this mutation is usually found in the CYP21A pseudogene, it seemed that a gene conversion-like event transferred the mutation from the CYP21A gene to the CYP21B gene. 2) A population study on the organization of C4-CYP21 region revealed that a reciprocal change, i.e. a T----C change in the 8th exon of the CYP21A gene, was observed in two HLA haplotypes, HLA-B44-DRw13 and HLA-Bw46-DRw8 haplotypes in Japanese population. The reciprocal changes also may be considered as a result of gene conversion-like events. PMID:2328938

Urabe, K

1990-02-01

140

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

PubMed

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

Lee, Yung Seng

2012-12-01

141

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

142

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

Microsoft Academic Search

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

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

2009-01-01

143

Mutation analysis of the Fanconi Anemia Gene FACC  

SciTech Connect

Fanconi anemia (FA) is a genetically heterogeneous autosomal recessive disorder characterized by a unique hypersensitivity of cells to DNA cross-linking agents; a gene for complementation group C (FACC) has recently been cloned. The authors have amplified FACC exons with their flanking intron sequences from genomic DNA from 174 racially and ethnically diverse families in the International Fanconi Anemia Registry and have screened for mutations by using SSCP analysis. They have identified eight different variants in 32 families; three were detected in exon 1, one in exon 4, one in intron 4, two in exon 6, and one in exon 14. Two of the eight variants, in seven families, did not segregate with the disease allele in multiplex families, suggesting that these variants represented benign polymorphisms. Disease-associated mutations in FACC were detected in a total of 25 (14.4%) of 174 families screened. The most frequent mutations were IVS4 + 4 A [yields] T (intron 4; 12 families) and 322delG (exon 1; 9 families). Other, less common mutations include Q13X in exon 1, R185X and D195V in exon 6, and L554P in exon 14. The polymorphisms were S26F in exon 1 and G139E in exon 4. All patients in the study with 322delG, Q13X, R185X, and D195V are of northern or eastern European or southern Italian ancestry, and 18 of 19 have a mild form of the disease, while the 2 patients with L554P, both from the same family, have a severe phenotype. All 19 patients with IVS4 + 4 A [yields] T have Jewish ancestry and have a severe phenotype. 19 refs., 1 fig., 3 tabs.

Verlander, P.C.; Lin, J.D.; Udono, M.U.; Zhang, Q.; Auerbach, A.D. (Rockefeller Univ., New York, NY (United States)); Gibson, R.A.; Mathew, C.G. (Guy's Hospital, London (United Kingdom))

1994-04-01

144

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

PubMed Central

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

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

1997-01-01

145

Transcriptional and Translational Effects of Intronic CAPN3 Gene Mutations  

PubMed Central

Variants of unknown significance in the CAPN3 gene constitute a significant challenge for genetic counselling. Despite the frequency of intronic nucleotide changes in this gene (15–25% of all mutations), so far their pathogenicity has only been inferred by in-silico analysis, and occasionally, proven by RNA analysis. In this study, 5 different intronic variants (one novel) that bioinformatic tools predicted would affect RNA splicing, underwent comprehensive studies which were designed to prove they are disease-causing. Muscle mRNA from 15 calpainopathy patients was analyzed by RT-PCR and splicing-specific-PCR tests. We established the previously unrecognized pathogenicity of these mutations, which caused aberrant splicing, most frequently by the activation of cryptic splicing sites or, occasionally, by exon skipping. The absence or severe reduction of protein demonstrated their deleterious effect at translational level. We concluded that bioinformatic tools are valuable to suggest the potential effects of intronic variants; however, the experimental demonstration of the pathogenicity is not always easy to do even when using RNA analysis (low abundance, degradation mechanisms), and it might not be successful unless splicing-specific-PCR tests are used. A comprehensive approach is therefore recommended to identify and describe unclassified variants in order to offer essential data for basic and clinical geneticists. ©2010 Wiley-Liss, Inc.

Nascimbeni, Anna Chiara; Fanin, Marina; Tasca, Elisabetta; Angelini, Corrado

2010-01-01

146

Ten-Eleven Translocation-2 gene mutations: A potential new molecular marker in malignant gliomas (Review)  

PubMed Central

Alterations of the Ten-Eleven Translocation-2 (TET2) gene in myeloid malignancies and isocitrate dehydrogenase (IDH) gene mutations in gliomas and myeloid malignancies have recently been identified using molecular, comparative genomic hybridization and single nucleotide polymorphism array techniques. The mutations of the TET2 gene have been shown to be mutually exclusive with IDH1/2 mutations in acute myeloid leukemia (AML) and evidence has been found to provide a biochemical basis for the mutual exclusivity of IDH1/2 and TET2 gene mutations. Based on mounting evidence, we aimed to investigate whether TET2 mutations may be identified as novel mutations in malignant gliomas without IDH1/2 mutations, and indicate their possible significance in gliomas.

YU, LEI; QI, SONGTAO

2012-01-01

147

The landscape of cancer genes and mutational processes in breast cancer  

PubMed Central

All cancers carry somatic mutations in their genomes. A subset, known as driver mutations, confer clonal selective advantage on cancer cells and are causally implicated in oncogenesis1, and the remainder are passenger mutations. The driver mutations and mutational processes operative in breast cancer have not yet been comprehensively explored. Here we examine the genomes of 100 tumours for somatic copy number changes and mutations in the coding exons of protein-coding genes. The number of somatic mutations varied markedly between individual tumours. We found strong correlations between mutation number, age at which cancer was diagnosed and cancer histological grade, and observed multiple mutational signatures, including one present in about ten per cent of tumours characterized by numerous mutations of cytosine at TpC dinucleotides. Driver mutations were identified in several new cancer genes including AKT2, ARID1B, CASP8, CDKN1B, MAP3K1, MAP3K13, NCOR1, SMARCD1 and TBX3. Among the 100 tumours, we found driver mutations in at least 40 cancer genes and 73 different combinations of mutated cancer genes. The results highlight the substantial genetic diversity underlying this common disease.

Stephens, Philip J.; Tarpey, Patrick S.; Davies, Helen; Loo, Peter Van; Greenman, Chris; Wedge, David C.; Nik-Zainal, Serena; Martin, Sancha; Varela, Ignacio; Bignell, Graham R.; Yates, Lucy R.; Papaemmanuil, Elli; Beare, David; Butler, Adam; Cheverton, Angela; Gamble, John; Hinton, Jonathan; Jia, Mingming; Jayakumar, Alagu; Jones, David; Latimer, Calli; Lau, King Wai; McLaren, Stuart; McBride, David J.; Menzies, Andrew; Mudie, Laura; Raine, Keiran; Rad, Roland; Chapman, Michael Spencer; Teague, Jon; Easton, Douglas; Langer?d, Anita; OSBREAC; Lee, Ming Ta Michael; Shen, Chen-Yang; Tee, Benita Tan Kiat; Huimin, Bernice Wong; Broeks, Annegien; Vargas, Ana Cristina; Turashvili, Gulisa; Martens, John; Fatima, Aquila; Miron, Penelope; Chin, Suet-Feung; Thomas, Gilles; Boyault, Sandrine; Mariani, Odette; Lakhani, Sunil R.; van de Vijver, Marc; van 't Veer, Laura; Foekens, John; Desmedt, Christine; Sotiriou, Christos; Tutt, Andrew; Caldas, Carlos; Reis-Filho, Jorge S.; Aparicio, Samuel A. J. R.; Salomon, Anne Vincent; B?rresen-Dale, Anne-Lise; Richardson, Andrea L.; Campbell, Peter J.; Futreal, P. Andrew; Stratton, Michael R.

2012-01-01

148

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.

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

1990-01-01

149

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

PubMed Central

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

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

2013-01-01

150

Mutagenesis in cloned yeast genes. Mutation frequencies in a yeast gene in plasmid and chromosome  

SciTech Connect

Yeast cells were transformed with o-methyl-hydroxylamine-treated plasmid DNA. A collection of mutants possessing a mutated allele of the ADE2 gene in the plasmid was selected. The mutations were subjected to interallelic complementation and suppression-induced interallelic complementation tests. Some of the mutations were imparted to the chromosome via the conversion mechanism. Three pairs of strains, each of which carried an identical mutant allele in the plasmid and chromosome, were picked up. These alleles in the plasmid and chromosome were back-mutated by UV light and hydroxylaminopurine (HAP) and the results were compared. The plasmid alleles were shown to mutate less efficiently on exposure to UV light than to HAP. The HAP-induced mutation rate was 8-10 times higher in the plasmid than in the chromosome, which apparently reflected the plurality of plasmid copies in the cell. After UV irradiation the difference was only two- or threefold; the reason for this difference might be a different repair efficiency in chromosome and plasmid.

Gracheva, L.M.; Kasinova, G.V.; Korolev, V.G.; Fedorova, I.V.

1989-01-01

151

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

152

Software and database for the analysis of mutations in the human FBN1 gene  

Microsoft Academic Search

Fibrillin is the major component of extracellular microfibrils. Mutations in the fibrillin gene on chromo- some 15 (FBN1) were described at first in the heritable connective tissue disorder, Marfan syndrome (MFS). More recently, FBN1 has also been shown to harbor mutations related to a spectrum of conditions phe- notypically related to MFS and many mutations will have to be accumulated

Gwenaëlle Collod; Christophe Béroud; Thierry Soussi; Claudine Junien; Catherine Boileau

1996-01-01

153

A common mutation site in the ?-galactosidase gene originates in Puerto Rico  

Microsoft Academic Search

Several mutation sites have been found in the ?-galactosidase gene of patients with GMI gangliosidosis. In a previous report we found a common point mutation site in American patients with GMl gangliosidosis resulting in a 208Arg ? Cys amino acid substitution. From the patients' family history, we suggested that this mutation may have come to South and North America via

Nan-Chan Chin; Wei-Hua Qian; Alan L. Shanske; Susan Sklower Brooks; Rose-Mary Boustany

1996-01-01

154

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

155

Clinical Manifestations in Paroxysmal Kinesigenic Dyskinesia Patients with Proline-Rich Transmembrane Protein 2 Gene Mutation  

PubMed Central

Background and Purpose Given the diverse phenotypes including combined non-dyskinetic symptoms in patients harboring mutations of the gene encoding proline-rich transmembrane protein 2 (PRRT2), the clinical significance of these mutations in paroxysmal kinesigenic dyskinesia (PKD) is questionable. In this study, we investigated the clinical characteristics of PKD patients with PRRT2 mutations. Methods Familial and sporadic PKD patients were enrolled and PRRT2 gene sequencing was performed. Demographic and clinical data were compared between PKD patients with and without a PRRT2 mutation. Results Among the enrolled PKD patients (8 patients from 5 PKD families and 19 sporadic patients), PRRT2 mutations were detected in 3 PKD families (60%) and 2 sporadic cases (10.5%). All familial patients with a PRRT2 gene mutation had the c.649dupC mutation, which is the most commonly reported mutation. Two uncommon mutations (c.649delC and c.629dupC) were detected only in the sporadic cases. PKD patients with PRRT2 mutation were younger at symptom onset and had more non-dyskinetic symptoms than those without PRRT2 mutation. However, the characteristics of dyskinetic movement did not differ between the two groups. Conclusions This is the first study of PRRT2 mutations in Korea. The presence of a PRRT2 mutation was more strongly related to familial PKD, and was clinically related with earlier age of onset and common non-dyskinetic symptoms in PKD patients.

Youn, Jinyoung; Kim, Ji Sun; Lee, Munhyang; Lee, Jeehun; Roh, Hakjae

2014-01-01

156

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.

Bohlega, Saeed

2011-01-01

157

A Novel Alpha-thalassemia Nonsense Mutation in HBA2: C.382 A > T globin Gene.  

PubMed

In this study, a new alpha globin gene mutation on the ?2-globin gene is reported. This mutation resulted in a Lys > stop codon substitution at position 127 which was detected in four individuals (three males and one female). DNA sequencing revealed this mutation in unrelated persons in Khuzestan province, Southwestern Iran of Lor ethnicity. This mutation caused no severe hematological abnormalities in the carriers. From the nature of substituted residues in ?2-globin, it is widely expected that this mutation leads to unstable and truncated protein and should be detected in couples at risk for ?-thalassemia. PMID:24979558

Hamid, Mohammad; Bokharaei Merci, Hanieh; Galehdari, Hamid; Saberi, Ali Hossein; Kaikhaei, Bijan; Mohammadi-Anaei, Marziye; Ahmadzadeh, Ahmad; Shariati, Gholamreza

2014-07-01

158

Bullous congenital ichthyosiform erythroderma: a sporadic case produced by a new KRT10 gene mutation.  

PubMed

Bullous congenital ichthyosiform erythroderma is an unusual type of inherited ichthyosis by mutations in the genes that encode K1 and K10. We report the case of a girl with typical clinical and histopathologic findings of bullous congenital ichthyosiform erythroderma, who was found to have a new mutation in KRT10 gene, Glu445Lys at position 445, affecting the 2B region of the KRT10 protein, the end of the rod domain, where many other keratin mutations associated with hereditary skin disease have been reported. This new mutation contributes to add to the catalog of bullous congenital ichthyosiform erythroderma mutations known. PMID:19689541

Betlloch, Isabel; Lucas Costa, Anna; Mataix, Javier; Pérez-Crespo, Maria; Ballester, Irene

2009-01-01

159

Software and database for the analysis of mutations in the VHL gene.  

PubMed Central

VHL is a tumor suppressor gene localized on chromosome 3p25-26. Mutations of the VHL gene were described at first in the heritable von Hippel-Lindau disease and in the sporadic Renal Cell Carcinoma (RCC). More recently, VHL has also been shown to harbor mutations in mesothelioma and small cell lung carcinoma. To date more than 500 mutations have been identified. These mutations are mainly private with only one hot spot at codon 167 associated with pheochromocytoma. The germline mutations are essentially missense while somatic mutations include deletions, insertions and nonsense. To standardize the collection of these informations, facilitate the mutational analysis of the VHL gene and promote the genotype-phenotype analysis, a software package along with a computerized database have been created. The current database and the analysis software are accessible via the internet and world wide web interface at the URL:http://www.umd.necker.fr

Beroud, C; Joly, D; Gallou, C; Staroz, F; Orfanelli, M T; Junien, C

1998-01-01

160

Polarity of amber mutations in ribosomal protein genes of Escherichia coli.  

PubMed Central

Two amber mutations have been mapped inside the spcA-strA region (now called rpsE-rpsL) on the bacterial genome. Derivatives of the transducing phage lambda fus3 carrying each mutation were constructed and assayed in ultraviolet-irradiated bacteria to identify the mutated genes and measure the polarity of the mutations. The data indicated that both mutations, 3162(Am) and 3161(Am), affect genes coding for ribosomal proteins: rplC (L3) and rpsN (S14), respectively. It was shown also that each mutation exerts, inside of its respective operon (S10 and spc units), a relatively strong polar effect on genes distal to the mutated locus.

Cabezon, T; Delcuve, G; Faelen, M; Desmet, L; Bollen, A

1980-01-01

161

PCSK9 gene mutations and low-density lipoprotein cholesterol.  

PubMed

Proprotein convertase subtilisin-like/kexin type 9 (PCSK9) is a newly-identified circulating protein in cholesterol metabolism in mammals, including humans, which has emerged as a new pharmacological target for hypocholesterolemia. It has been demonstrated that PCSK9 gene mutations are associated with hyper- or hypocholesterolemia. In the latter case, the incidence of coronary heart disease (CHD) is markedly reduced, suggesting that low level of low-density lipoprotein cholesterol (LDL-C) at birth is highly beneficial. Loss-of-function PCSK9 mutations will result in lower LDL-C levels and protect against CHD. Conversely, patients harboring gain-of-function PCSK9 mutations will suffer from familial autosomal dominant hypercholesterolemia (ADH), a disease characterized by elevated LDL-C plasma concentration. Although compelling evidence has suggested that PCSK9 can impair the LDL receptor (LDLR) pathway, its biological role in cholesterol metabolism remains to be defined. According to data from previous studies, PCSK9 appears to be a promising therapeutic target due to its role as a major LDLR regulator. Specific pharmacological inhibitors of PCSK9 have demonstrated a significant impact on plasma LDL-C concentrations. Therefore, understanding the relationship between PCSK9 and its genetic variants, on one hand, and the level of plasma LDL-C, on the other hand, may be clinically useful due to the fact that this protein has become a key target of lipid-lowering therapy. In this manuscript we mainly review recent data with regard to the association between PCSK9 genetic variants and plasma LDL-C concentrations, and outline the clinical implications. PMID:24518357

Wu, Na-Qiong; Li, Jian-Jun

2014-04-20

162

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

163

Heterozygous germ-line mutations in the NBN gene predispose to medulloblastoma in pediatric patients  

Microsoft Academic Search

The NBN (NBS1) gene belongs to a group of double-strand break repair genes. Mutations in any of these genes cause genome instability syndromes\\u000a and contribute to carcinogenesis. NBN gene mutations cause increased tumor risk in Nijmegen breakage syndrome (NBS) homozygotes as well as in NBN heterozygotes. NBS patients develop different types of malignancies; among solid tumors, medulloblastoma (MB), an embryonal

El?bieta Ciara; Dorota Piekutowska-Abramczuk; Ewa Popowska; Wies?awa Grajkowska; S?awomir Barszcz; Danuta Perek; Bo?enna Dembowska-Bagi?ska; Marta Perek-Polnik; Ewa Kowalewska; Aneta Czaj?ska; Ma?gorzata Syczewska; Kamila Czornak; Ma?gorzata Krajewska-Walasek; Marcin Roszkowski; Krystyna H. Chrzanowska

2010-01-01

164

Gene mutations in primary ciliary dyskinesia related to otitis media.  

PubMed

Otitis media with effusion (OME) is the most common cause of conductive hearing loss in children and is strongly associated with primary ciliary dyskinesia (PCD). Approximately half of the children with PCD require otolaryngology care, posing a major problem in this population. Early diagnosis of PCD is critical in these patients to minimise the collateral damage related to OME. The current gold standard for PCD diagnosis requires determining ciliary structure defects by transmission electron microscopy (TEM) or clearly documenting ciliary dysfunction via digital high-speed video microscopy (DHSV). Although both techniques are useful for PCD diagnosis, they have limitations and need to be supported by new methodologies, including genetic analysis of genes related to PCD. In this article, we review classical and recently associated mutations related to ciliary alterations leading to PCD, which can be useful for early diagnosis of the disease and subsequent early management of OME. PMID:24459089

Mata, Manuel; Milian, Lara; Armengot, Miguel; Carda, Carmen

2014-03-01

165

Surface plasmon resonance imaging (SPRI) system and real-time monitoring of DNA biochip for human genetic mutation diagnosis of DNA amplified samples  

Microsoft Academic Search

Nucleic acid-based biochips represent a promising tool for gene sequence analysis, especially for mutation detection. Surface plasmon resonance imaging (SPRI) technique allows kinetic monitoring of molecular interaction, such as DNA–DNA, in real-time and without any prior labelling step. SPRI was applied to developing a DNA sensor for the detection of gene mutations accounting for human cystic fibrosis and specifically some

I. Mannelli; V. Courtois; P. Lecaruyer; G. Roger; M. C. Millot; M. Goossens; M. Canva

2006-01-01

166

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

Microsoft Academic Search

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

L. Peltonen; L. Karttunen; T. Rantamaeki

1994-01-01

167

Three independent mutations in the TSC2 gene in a family with tuberous sclerosis  

Microsoft Academic Search

Tuberous sclerosis complex (TSC) is a rare autosomal dominant disorder characterized by hamartomas and hamartias in multiple organs. TSC is caused by a wide spectrum of mutations within the TSC1 and TSC2 genes. Here, we report a unique family with three independent pathological mutations in TSC2. A c.1322G>A mutation in exon 12 created a stop codon, whereas a second mutation

Cédric Le Caignec; David J Kwiatkowski; Sébastien Küry; Jean-Benoit Hardouin; Judith Melki; Albert David

2009-01-01

168

Frameshift mutations in coding repeats of protein tyrosine phosphatase genes in colorectal tumors with microsatellite instability  

Microsoft Academic Search

BACKGROUND: Protein tyrosine phosphatases (PTPs) like their antagonizing protein tyrosine kinases are key regulators of signal transduction thereby assuring normal control of cellular growth and differentiation. Increasing evidence suggests that mutations in PTP genes are associated with human malignancies. For example, mutational analysis of the tyrosine phosphatase (PTP) gene superfamily uncovered genetic alterations in about 26% of colorectal tumors. Since

Sebastian Korff; Stefan M. Woerner; Yan P Yuan; Peer Bork; Magnus von Knebel Doeberitz; Johannes Gebert

2008-01-01

169

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

170

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

171

The First Japanese Familial Sotos Syndrome with a Novel Mutation of the NSD1 Gene  

Microsoft Academic Search

Sotos syndrome is caused by the haploinsufficiency of the NSD1 gene located in 5q35. More than 70% of the Japanese cases carry microdeletions encompassing of this gene, while point mutations are common in Caucasians. Only 15 familial cases of Sotos syndrome have been reported and all cases shown to have not microdeletions but point mutations. We identified the first Japanese

SATOSHI TEI; SYUICHI TSUNEISHI; MASAFUMI MATSUO

172

Mutation screening of theARX gene in patients with autism  

Microsoft Academic Search

Mutations in the ARX gene are associated with a broad spectrum of disorders, including nonsyndromic X-linked mental retardation, sometimes associated with epilepsy, as well as syndromic forms with brain abnormalities and abnormal genitalia. Furthermore, ARX mutations have been described in a few patients with autism or autistic features. In this study, we screened the ARX gene in 226 male patients

Pauline Chaste; Gudrun Nygren; Henrik Anckarsäter; Maria Råstam; Mary Coleman; Marion Leboyer; Christopher Gillberg; Catalina Betancur

2007-01-01

173

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

Microsoft Academic Search

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

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

2010-01-01

174

Inherited and de novo Mutations in the Cardiac Actin Gene Cause Hypertrophic Cardiomyopathy  

Microsoft Academic Search

T. M. Olson, T. P. Doan, N. Y. Kishimoto, F. G. Whitby, M. J. Ackerman and L. Fananapazir. Inherited andde novo Mutations in the Cardiac Actin Gene Cause Hypertrophic Cardiomyopathy. Journal of Molecular and Cellular Cardiology (2000) 32, 1687–1694. Mutations in genes encoding sarcomeric proteins cause hypertrophic cardiomyopathy (HCM). The sarcomeric protein actin plays a central, dual role in cardiac

Timothy M Olson; Thao P Doan; Nina Y Kishimoto; Frank G Whitby; Michael J Ackerman; Lameh Fananapazir

2000-01-01

175

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

Microsoft Academic Search

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

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

2005-01-01

176

The Human Secretin Gene in Children With Autistic Spectrum Disorder: Screening for Polymorphisms and Mutations  

Microsoft Academic Search

We screened 29 children with autism for mutation in the human secretin gene using single-strand conformation polymorphism. No mutation was detected in exon 2, 3, or 4. Polymerase chain reaction and DNA sequence of 5' variable number of tandem repeats showed two polymorphisms with deletion or duplication of a repeat unit that failed to show any gene expression with transient

Samuel S. M. Ng; Billy K. C. Chow; Virginia C. N. Wong

2005-01-01

177

Novel mutations in the muscle chloride channel CLCN1 gene causing myotonia congenita in Spanish families  

Microsoft Academic Search

Mutations in the muscular voltage-dependent chloride channel gene (CLCN1), located at 7q35, lead to recessive and dominant myotonia congenita. We report four novel mutations identified in this gene,\\u000a after clinical, electromyographic, and genetic studies performed on 13 unrelated families. Two of the four mutations (2512insCTCA\\u000a and A218T) were identified in families with Thomsen’s disease, one (Q658X) in a family with

C. de Diego; J. Gámez; E. Plassart-Schiess; A. Lasa; E. Del Río; C. Cervera; M. Baiget; P. Gallano; B. Fontaine

1999-01-01

178

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

Microsoft Academic Search

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

H. Ümit Lüleyap; Davut Alptekin; Ayfer Pazarba??; Mulkiye Kasap; Halil Kasap; Hakan Demirhindi; Neslihan Mungan; Güler Özer; Ursula G. Froster

2006-01-01

179

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

Microsoft Academic Search

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

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

1998-01-01

180

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

181

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

Microsoft Academic Search

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

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

182

Papillon–Lefèvre Syndrome: Mutations and Polymorphisms in the Cathepsin C Gene  

Microsoft Academic Search

The Papillon–Lefèvre syndrome, inherited in an autosomal recessive pattern, manifests with palmoplantar keratoderma and early, destructive periodontitis. Recently, mutations in the gene encoding cathepsin C have been disclosed in a limited number of families with Papillon–Lefèvre syndrome. We have examined two multiplex families with Papillon–Lefèvre syndrome, and evaluated the gene encoding cathepsin C for mutations. The mutation detection strategy consisted

Aoi Nakano; Kazuo Nomura; Hajime Nakano; Yoshio Ono; Sal LaForgia; Leena Pulkkinen; Isao Hashimoto; Jouni Uitto

2001-01-01

183

A Unique Profile of Adenomatous Polyposis Coli Gene Mutations in Iranian Patients Suffering Sporadic Colorectal Cancer  

PubMed Central

Objective: Colorectal cancer (CRC) is one of the most common and aggressive cancers worldwide. The majority of CRC cases are sporadic that caused by somatic mutations. The Adenomatous Polyposis Coli (APC; OMIM 611731) is a tumor suppressor gene of Wnt pathway and is frequently mutated in CRC cases. This study was designed to investigate the spectrum of APC gene mutations in Iranian patients with sporadic colorectal cancer. Materials and Methods: In this descriptive study, Tumor and normal tissue samples were obtained from thirty randomly selected and unrelated sporadic CRC patients. We examined the hotspot region of the APC gene in all patients. Our mutation detection method was direct DNA sequencing. Results: We found a total of 8 different APC mutations, including two nonsense mutations (c.4099C>T and c.4348C>T), two missense mutations (c.3236C>G and c.3527C>T) and four frame shift mutations (c.2804dupA, c.4317delT, c.4464_4471delATTACATT and c.4468_4469dupCA). The c.3236C>G and c.4468_4469dupCA are novel mutations. The overall frequency of APC mutation was 26.7% (8 of 30 patients). Conclusion: This mutation rate is lower in comparison with previous studies from other countries. The findings of present study demonstrate a different APC mutation spectrum in CRC patients of Iranian origin compared with other populations.

Hasanpour, Mojtaba; Galehdari, Hamid; Masjedizadeh, Abdolrahim; Ajami, Naser

2014-01-01

184

DPY19L2 gene mutations are a major cause of globozoospermia: identification of three novel point mutations.  

PubMed

Globozoospermia, characterized by round-headed spermatozoa without acrosomes, is a rare and severe teratozoospermia causing primary male infertility. Homozygous DPY19L2 deletions have been identified as the main cause of globozoospermia, blocking sperm head elongation and acrosome formation. Several previous studies showed a very different prevalence of DPY19L2 gene deletions among globozoospermic patients in cohorts with different sample sizes and in different ethnic background. And all the patients previously analyzed were mainly of European, North African and Middle Eastern origins. So far, only 11 different point mutations of the DPY19L2 gene have been reported. To investigate the prevalence of DPY19L2 gene mutations in Chinese patients with globozoospermia and whether we can identify new sequence variants in this study, we recruited a total of 16 globozoospermic patients. Excluding one of two brothers, molecular analysis for deletions and mutations in the DPY19L2 gene was performed on 15 genetically independent individuals. Four of the 15 genetically independent patients with globozoospermia were homozygous for the DPY19L2 deletion, 5 were homozygous for a point mutation including a nucleotide deletion c.1532delA (two patients), a multi-mutation consisting of a nucleotide deletion c.1679delT and a two-nucleotide deletion c.1681_1682delAC (c.[1679delT; 1681_1682delAC]) (one patient), a recurrent missense mutation R290H (one patient) and a missense mutation L330P (one patient). One additional patient had a heterozygous deletion in one allele but with no mutation identified in another allele. Overall, 60% of the patients (9/15) have a sequence variant of DPY19L2 in both alleles. This study confirms that the DPY19L2 mutations are the major cause of globozoospermia. Three novel point mutations and a recurrent missense mutation were found in this study, further broadening the spectrum of DPY19L2 mutations. PMID:23512994

Zhu, Fuxi; Gong, Fei; Lin, Ge; Lu, Guangxiu

2013-06-01

185

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

PubMed Central

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

2011-01-01

186

Reduced selection and accumulation of deleterious mutations in genes exclusively expressed in men.  

PubMed

Sex-limited selection can moderate the elimination of deleterious mutations from the population and contribute to the high prevalence of common human diseases. Accordingly, deleterious mutations in autosomal genes that are exclusively expressed in only one of the sexes undergo sex-limited selection and can reach higher frequencies than mutations similarly selected in both sexes. Here we show that the number of deleterious SNPs in genes exclusively expressed in men is twofold higher than in genes that are selected in both sexes. Additional analyses suggest that the increased number of damaging mutations we found in male-specific genes is due to reduced selection in females. These results are noteworthy since many of these male-specific genes are known to be crucial for male reproduction, and are thus likely to be under strong purifying selection. We suggest that inheritance of male-infertility-causative mutations through unaffected female lineages contributes to the high incidence of male infertility. PMID:25014762

Gershoni, Moran; Pietrokovski, Shmuel

2014-01-01

187

In vivo cII, gpt, and Spi? gene mutation assays in transgenic mice and rats.  

PubMed

Transgenic mutation assays are used to identify and characterize genotoxic hazards and for determining the mode of action for carcinogens. The three most popular transgenic mutational models are Big Blue® (rats or mice), Muta™ mouse (mice), and gpt-delta (rats or mice). The Big Blue® and Muta™ mouse models use the cII gene as a reporter of mutation whereas gpt-delta rodents use the gpt gene and the red/gam genes (Spi? selection) as mutation reporter genes. Here we describe methodology for conducting mutation assays with these transgenes. Transgenes recovered from tissue DNA are packaged into infectious lambda phage, bacteria are infected with the phage, and cII-mutant and Spi? plaques and gpt-mutant colonies are isolated using selective conditions and quantified. Selected mutants can be further analyzed for identification of small sequence alterations in the cII and gpt genes and large deletions at the Spi? locus. PMID:23896873

Manjanatha, Mugimane G; Cao, Xuefei; Shelton, Sharon D; Mittelstaedt, Roberta A; Heflich, Robert H

2013-01-01

188

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.

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

189

Mutation analysis of the GALT gene in Czech and Slovak galactosemia populations: identification of six novel mutations, including a stop codon mutation (X380R).  

PubMed

A study of the galactose-1-phosphate uridyltransferase (GALT) gene from 37 unrelated galactosemia families is reported here. A total of 16 sequence variations in eleven mutated alleles was found. The two most common molecular defects were the mutations Q188R (46.0%) and K285N (25.7%). Six novel mutations in the GALT gene, X380R, Y209S, E340K, L74fsdelCT, Q169K and L256/P257delGCC, were detected. Three mutations, V151A, L195P and R204X that were previously described in other populations, were also found. The mutation X380R, which breaks the stop codon of the GALT gene, causes elongation of the GALT enzyme's protein chain. A deletion of four nucleotides in the 5' promoter region, in a position 116 - 119 nucleotides upstream from the initiate codon (5'UTR-119delGTCA), was revealed in Duarte (D2) alleles, in addition to N314D, IVS4nt-27g-->c, IVS5nt+62g-->a, and IVS5nt-24g-->a. An unusual molecular genotype was observed on 2 types of classical galactosemia alleles, with six variations from the normal nucleotide sequence presented in cis (mutation V151A or E340K plus five Duarte (D2) characteristic variations). In summary, galactosemia is a heterogeneous disorder at the molecular level, and mutation N314D, appears to be an ancient genetic variant of the GALT gene. Hum Mutat 15:206, 2000. PMID:10649501

Kozák, L; Francová, H; Fajkusová, L; Pijácková, A; Macku, J; Stastná, S; Peskovová, K; Martincová, O; Krijt, J; Bzdúch, V

2000-02-01

190

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.

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

191

A proportion of patients with lymphoma may harbor mutations of the perforin gene.  

PubMed

Perforin mutations have been demonstrated in a proportion of patients diagnosed with the familial form of hemophagocytic lymphohistiocytosis (HLH). In the present study, we evaluated whether some patients with lymphoma sharing clinical characteristics with HLH might harbor mutations of the perforin gene. We analyzed 29 patients and found that 4 patients, who developed either Hodgkin or non-Hodgkin lymphoma, had biallelic mutations of the perforin gene. One of these 4 patients, a 19-year-old female with T-cell lymphoma, had a brother carrying the same mutations who developed HLH. In 2 of the 4 patients with biallelic mutations of the perforin gene, we evaluated perforin expression by flow cytometry and natural killer (NK) activity and both were found to be absent. Moreover, we documented the presence of monoallelic mutations of the perforin gene in 4 more patients. One of these 4 latter patients also carried a mutation of the Fas gene. These data indicate that perforin deficiency, either alone or in combination with other mutations of genes involved in lymphocyte survival or functional activity, may be present in patients with lymphoma. These findings suggest that perforin also plays a key role in the mechanisms of immune surveillance that prevent tumor growth and/or development. PMID:15728124

Clementi, Rita; Locatelli, Franco; Dupré, Loïc; Garaventa, Alberto; Emmi, Lorenzo; Bregni, Marco; Cefalo, Graziella; Moretta, Antonia; Danesino, Cesare; Comis, Margherita; Pession, Andrea; Ramenghi, Ugo; Maccario, Rita; Aricò, Maurizio; Roncarolo, Maria Grazia

2005-06-01

192

A novel lipoprotein lipase gene missense mutation in Chinese patients with severe hypertriglyceridemia and pancreatitis  

PubMed Central

Background Alterations or mutations in the lipoprotein lipase (LPL) gene contribute to severe hypertriglyceridemia (HTG). This study reported on two patients in a Chinese family with LPL gene mutations and severe HTG and acute pancreatitis. Methods Two patients with other five family members were included in this study for DNA-sequences of hyperlipidemia-related genes (such as LPL, APOC2, APOA5, LMF1, and GPIHBP1) and 43 healthy individuals and 70 HTG subjects were included for the screening of LPL gene mutations. Results Both patients were found to have a compound heterozygote for a novel LPL gene mutation (L279V) and a known mutation (A98T). Furthermore, one HTG subject out of 70 was found to carry this novel LPL L279V mutation. Conclusions The data from this study showed that compound heterozygote mutations of A98T and L279V inactivate lipoprotein lipase enzymatic activity and contribute to severe HTG and acute pancreatitis in two Chinese patients. Further study will investigate how these LPL gene mutations genetically inactivate the LPL enzyme.

2014-01-01

193

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

PubMed

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

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

2013-04-01

194

Identification of fibrillin-1 gene mutations in Marfan syndrome by high-resolution melting analysis  

Microsoft Academic Search

Marfan syndrome has been associated with approximately 562 mutations in the fibrillin-1 (FBN1) gene. Mutation scanning of the FBN1 gene with DNA direct sequencing is time-consuming and expensive because of its large size. This study analyzed the diagnostic value of high-resolution melting analysis as an alternative method for scanning of the FBN1 gene. A total of 75 polymerase chain reaction

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

2009-01-01

195

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

Microsoft Academic Search

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

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

1999-01-01

196

Software and database for the analysis of mutations in the human FBN1 gene.  

PubMed Central

Fibrillin is the major component of extracellular microfibrils. Mutations in the fibrillin gene on chromosome 15 (FBN1) were described at first in the heritable connective tissue disorder, Marfan syndrome (MFS). More recently, FBN1 has also been shown to harbor mutations related to a spectrum of conditions phenotypically related to MFS and many mutations will have to be accumulated before genotype/phenotype relationships emerge. To facilitate mutational analysis of the FBN1 gene, a software package along with a computerized database (currently listing 63 entries) have been created.

Collod, G; Beroud, C; Soussi, T; Junien, C; Boileau, C

1996-01-01

197

Novel Mutations of the Autoimmune Regulator Gene in Two Siblings with Autoimmune Polyendocrinopathy- Candidiasis-Ectodermal Dystrophy  

Microsoft Academic Search

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystro- phy (APECED) is the first multiple autoimmune disease that has been shown to be caused by mutations of a single gene named autoimmune regulator (AIRE). Fourteen different mutations of the AIRE gene have been identified in 61 patients from 55 families with APECED. However, there has been no report documenting AIRE gene mutations in the Asian population.

TOMOHIRO ISHII; YOSHIMI SUZUKI; NAOKI ANDO; NOBUTAKE MATSUO; TSUTOMU OGATA

2010-01-01

198

Polymorphisms, haplotypes and mutations in the protamine 1 and 2 genes.  

PubMed

Protamines are the most abundant nuclear proteins and alterations in their expression have been described in infertile patients. Also, protamine haplo-insufficient mice have been described as infertile. Therefore, the protamine 1 and 2 genes have been considered important candidates in different mutational studies. In this article, we review all published articles related to protamine gene mutations and report new data on mutations from patients and controls drawn from the Spanish and Swedish populations. Sequencing of the protamine 1 and 2 genes in a total of 209 infertile patients and 152 fertility-proven controls from the Spanish and Swedish populations identified two novel and rare non-pathogenic missense mutations (R17C and R38M) in the protamine 1 gene and several additional polymorphisms. Furthermore, we have identified and we report for the first time five novel rare haplotypes encompassing the protamine 1 and 2 genes. A review of all available protamine gene mutational studies indicates that none of the reported missense mutations can be considered of proven pathogenicity. However, it is interesting to note that rare protamine 1 promoter variants have been reported only in infertile patients, but not in fertile control groups. Pathogenic high penetrance protamine gene missense mutations, if any, must be extremely rare. However, the detected presence of rare variants and haplotypes in infertile patients deserves further investigation. PMID:21029114

Jodar, M; Oriola, J; Mestre, G; Castillo, J; Giwercman, A; Vidal-Taboada, J M; Ballescà, J L; Oliva, R

2011-10-01

199

Whole Exome Sequencing Identifies Novel Recurrently Mutated Genes in Patients with Splenic Marginal Zone Lymphoma  

PubMed Central

The pathogenesis of splenic marginal zone lymphoma (SMZL) remains largely unknown. Recent high-throughput sequencing studies have identified recurrent mutations in key pathways, most notably NOTCH2 mutations in >25% of patients. These studies are based on small, heterogeneous discovery cohorts, and therefore only captured a fraction of the lesions present in the SMZL genome. To identify further novel pathogenic mutations within related biochemical pathways, we applied whole exome sequencing (WES) and copy number (CN) analysis to a biologically and clinically homogeneous cohort of seven SMZL patients with 7q abnormalities and IGHV1-2*04 gene usage. We identified 173 somatic non-silent variants, affecting 160 distinct genes. In additional to providing independent validation of the presence of mutation in several previously reported genes (NOTCH2, TNFAIP3, MAP3K14, MLL2 and SPEN), our study defined eight additional recurrently mutated genes in SMZL; these genes are CREBBP, CBFA2T3, AMOTL1, FAT4, FBXO11, PLA2G4D, TRRAP and USH2A. By integrating our WES and CN data we identified three mutated putative candidate genes targeted by 7q deletions (CUL1, EZH2 and FLNC), with FLNC positioned within the well-characterized 7q minimally deleted region. Taken together, this work expands the reported directory of recurrently mutated cancer genes in this disease, thereby expanding our understanding of SMZL pathogenesis. Ultimately, this work will help to establish a stratified approach to care including the possibility of targeted therapy.

Ennis, Sarah; Walewska, Renata; Forster, Jade; Parker, Helen; Davis, Zadie; Gardiner, Anne; Collins, Andrew; Oscier, David G.; Strefford, Jonathan C.

2013-01-01

200

Relevance of Ras gene mutations in the context of the molecular heterogeneity of multiple myeloma.  

PubMed

Ras gene mutations are a recurrent genetic lesion in multiple myeloma (MM). Here, we report a mutation analysis of N- and K-Ras genes in purified plasma cell populations from a panel of 81 newly diagnosed MM patients stratified according to the most frequent genetic and molecular features associated with the neoplasia. Ras gene mutations, mostly involving the N-Ras gene, were detected in 20% of the patients. Ras mutations did not correlate with the presence of chromosome 13q deletion, trisomy of chromosome 11, 1q amplification or hyperdiploidy. In addition, despite an appreciable association with tumours overexpressing Cyclin D1, Ras mutations did not correlate at significant levels with any of the proposed groups in the TC classification, based on the presence of the major IgH chromosomal translocations and expression of Cyclin D genes. Finally, transcription analyses revealed the presence of differentially expressed transcripts in human multiple myeloma cell lines carrying the Ras gene mutations but not in primary tumours. Overall, these data suggest that Ras gene mutations are not likely to represent a master lesion in MM but its relevance needs to be considered in the context of other genetic abnormalities. PMID:17036375

Intini, Daniela; Agnelli, Luca; Ciceri, Gabriella; Ronchetti, Domenica; Fabris, Sonia; Nobili, Lucia; Lambertenghi-Deliliers, Giorgio; Lombardi, Luigia; Neri, Antonino

2007-03-01

201

Isolation and characterization of mutations in the bacteriophage lambda terminase genes.  

PubMed Central

The terminase enzyme of bacteriophage lambda is a hetero-oligomeric protein which catalyzes the site-specific endonucleolytic cleavage of lambda DNA and its packaging into phage proheads; it is composed of the products of the lambda Nul and A genes. We have developed a simple method to select mutations in the terminase genes carried on a high-copy-number plasmid, based on the ability of wild-type terminase to kill recA strains of Escherichia coli. Sixty-three different spontaneous mutations and 13 linker insertion mutations were isolated by this method and analyzed. Extracts of cells transformed by mutant plasmids displayed variable degrees of reduction in the activity of one or both terminase subunits as assayed by in vitro lambda DNA packaging. A method of genetically mapping plasmid-borne mutations in the A gene by measuring their ability to rescue various lambda Aam phages showed that the A mutations were fairly evenly distributed across the gene. Mutant A genes were also subcloned into overproducing plasmid constructs, and it was determined that more than half of them directed the synthesis of normal amounts of full-length A protein. Three of the A gene mutants displayed dramatically reduced in vitro packaging activity only when immature (uncut) lambda DNA was used as the substrate; therefore, these mutations may lie in the endonuclease domain of terminase. Interestingly, the putative endonuclease mutations mapped in two distinct locations in the A gene separated by a least 400 bp. Images

Davidson, A; Yau, P; Murialdo, H; Gold, M

1991-01-01

202

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

PubMed Central

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

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

1996-01-01

203

Mutations in the fibrinogen gene cluster accounting for congenital afibrinogenemia: an update and report of 10 novel mutations.  

PubMed

Fibrinogen is synthesized in hepatocytes in the form of a hexamer composed of two sets of three polypeptides (Aalpha, Bbeta, and gamma). Each polypeptide is encoded by a distinct gene, FGA, FGB, and FGG, all three clustered in a region of 50 kb on 4q31. Congenital afibrinogenemia is characterized by the complete absence of fibrinogen, the precursor of the major protein constituent of the blood clot, fibrin. Although the disease was first described in 1920, the genetic defect responsible for this disorder long remained unknown. We identified the gene and the first causative mutations for this disease in a nonconsanguineous Swiss family in 1999. Since this first report, 61 additional mutations, the majority in FGA, have been identified in patients with afibrinogenemia (in homozygosity or in compound heterozygosity) or in heterozygosity in hypofibrinogenemia, since many of these patients are in fact asymptomatic carriers of afibrinogenemia mutations. Mutations in the fibrinogen genes may lead to deficiency of fibrinogen by several mechanisms: these can act at the DNA level, at the RNA level by affecting mRNA splicing or stability, or at the protein level by affecting protein synthesis, assembly, or secretion. The expression of selected mutations has shown that mechanisms acting at all three levels play a role in the molecular basis of this disease. We report here the identification of 10 novel mutations, of which eight are localized in FGA, thus increasing the total number of causative mutations identified to 72 and confirming the relative importance of FGA in the molecular basis of fibrinogen deficiency. PMID:17295221

Neerman-Arbez, Marguerite; de Moerloose, Philippe

2007-06-01

204

Mutation screening of the EXT1 and EXT2 genes in patients with hereditary multiple exostoses.  

PubMed Central

Hereditary multiple exostoses (HME), the most frequent of all skeletal dysplasias, is an autosomal dominant disorder characterized by the presence of multiple exostoses localized mainly at the end of long bones. HME is genetically heterogeneous, with at least three loci, on 8q24.1 (EXT1), 11p11-p13 (EXT2), and 19p (EXT3). Both the EXT1 and EXT2 genes have been cloned recently and define a new family of potential tumor suppressor genes. This is the first study in which mutation screening has been performed for both the EXT1 and EXT2 genes prior to any linkage analysis. We have screened 17 probands with the HME phenotype, for alterations in all translated exons and flanking intronic sequences, in the EXT1 and EXT2 genes, by conformation-sensitive gel electrophoresis. We found the disease-causing mutation in 12 families (70%), 7 (41%) of which have EXT1 mutations and 5 (29%) EXT2 mutations. Together with the previously described 1-bp deletion in exon 6, which is present in 2 of our families, we report five new mutations in EXT1. Two are missense mutations in exon 2 (G339D and R340C), and the other three alterations (a nonsense mutation, a frameshift, and a splicing mutation) are likely to result in truncated nonfunctional proteins. Four new mutations are described in EXT2. A missense mutation (D227N) was found in 2 different families; the other three alterations (two nonsense mutations and one frameshift mutation) lead directly or indirectly to premature stop codons. The missense mutations in EXT1 and EXT2 may pinpoint crucial domains in both proteins and therefore give clues for the understanding of the pathophysiology of this skeletal disorder. Images Figure 2A Figure 2C

Philippe, C; Porter, D E; Emerton, M E; Wells, D E; Simpson, A H; Monaco, A P

1997-01-01

205

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

206

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.

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

2014-01-01

207

New mutations of EXT1 and EXT2 genes in German patients with Multiple Osteochondromas.  

PubMed

Mutations in either the EXT1 or EXT2 genes lead to Multiple Osteochondromas (MO), an autosomal dominantly inherited disorder. This is a report on clinical findings and results of molecular analyses of both genes in 23 German patients affected by MO. Mutation screening was performed by using denaturing high performance liquid chromatography (dHPLC) and automated sequencing. In 17 of 23 patients novel pathogenic mutations have been identified; eleven in the EXT1 and six in the EXT2 gene. Five patients were carriers of recurrent mutations in the EXT2 gene (p.Asp227Asn, p.Gln172X, p.Gln258X) and one patient had no detectable mutation. To demonstrate their pathogenic effect on transcription, two complex mutations in EXT1 and EXT2 and three splice site mutations were characterized by mRNA investigations. The results obtained provide evidence for different aberrant splice effects - usage of new cryptic splice sites and exon skipping. Our study extends the mutational spectrum and understanding of pathogenic effects of mutations in EXT1 and EXT2. PMID:19344451

Heinritz, Wolfram; Hüffmeier, Ulrike; Strenge, Sibylle; Miterski, Bianca; Zweier, Christiane; Leinung, Steffen; Bohring, Axel; Mitulla, Beate; Peters, Usha; Froster, Ursula G

2009-05-01

208

Mutations in genes involved in nonsense mediated decay ameliorate the phenotype of sel-12 mutants with amber stop mutations in Caenorhabditis elegans  

PubMed Central

Background Presenilin proteins are part of a complex of proteins that can cleave many type I transmembrane proteins, including Notch Receptors and the Amyloid Precursor Protein, in the middle of the transmembrane domain. Dominant mutations in the human presenilin genes PS1 and PS2 lead to Familial Alzheimer's disease. Mutations in the Caenorhabditis elegans sel-12 presenilin gene cause a highly penetrant egg-laying defect due to reduction of signalling through the lin-12/Notch receptor. Mutations in six spr genes (for suppressor of presenilin) are known to strongly suppress sel-12. Mutations in most strong spr genes suppress sel-12 by de-repressing the transcription of the largely functionally equivalent hop-1 presenilin gene. However, how mutations in the spr-2 gene suppress sel-12 is unknown. Results We show that spr-2 mutations increase the levels of sel-12 transcripts with Premature translation Termination Codons (PTCs) in embryos and L1 larvae. mRNA transcripts from sel-12 alleles with PTCs undergo degradation by a process known as Nonsense Mediated Decay (NMD). However, spr-2 mutations do not appear to affect NMD. Mutations in the smg genes, which are required for NMD, can restore sel-12(PTC) transcript levels and ameliorate the phenotype of sel-12 mutants with amber PTCs. However, the phenotypic suppression of sel-12 by smg genes is nowhere near as strong as the effect of previously characterized spr mutations including spr-2. Consistent with this, we have identified only two mutations in smg genes among the more than 100 spr mutations recovered in genetic screens. Conclusion spr-2 mutations do not suppress sel-12 by affecting NMD of sel-12(PTC) transcripts and appear to have a novel mechanism of suppression. The fact that mutations in smg genes can ameliorate the phenotype of sel-12 alleles with amber PTCs suggests that some read-through of sel-12(amber) alleles occurs in smg backgrounds.

Gontijo, Alisson M; Aubert, Sylvie; Roelens, Ingele; Lakowski, Bernard

2009-01-01

209

Overview of Cytochrome P450 1B1 gene mutations in patients with primary congenital glaucoma.  

PubMed

The objective of this study was to investigate the distribution of mutations in the Cytochrome P450 1B1 gene (CYP1B1) in patients with primary congenital glaucoma (PCG) among different populations. All identifiable original studies on CYP1B1 gene mutations of patients with PCG were reviewed. Finally, DNA mutations within the CYP1B1 gene were identified in 542 patients with PCG according to 52 scientific articles and 147 distinct mutations were found. The 3987G>A (G61E) missense mutation is a founder mutation in Middle Eastern population, responsible for 45.52% of CYP1B1 mutations. In Gypsies, missense mutation 7996G>A (E387K) seems to be a founder mutation, accounting for 79.63% of CYP1B1 mutations. It seems that there is no founder mutation in Asian or Caucasian population, but also accumulates in some spots. Mutations 7927G>A (V364M), 7990C>T (L385F) and 8006G>A (R390H) are common in Asian population. In Caucasians, 7940G>A (R368H), 8037dup10, 8006G>A (R390H), 7901del13, 4340delG, 3987G>A (G61E), 7996G>A (E387K), 4490G>A (E229K) and 8005C>T/A (R390C/S) are common mutations. The findings suggest that ethnic differences and the geographical distribution of PCG may be associated with different CYP1B1 mutation patterns. Such information may be useful in developing strategies for reliable clinical genetic testing of patients with PCG and their families. PMID:21854771

Li, Ni; Zhou, Yong; Du, Liang; Wei, Maoling; Chen, Xiaoming

2011-11-01

210

Interleukin-7 receptor-? gene mutations are not detected in adult T-cell acute lymphoblastic leukemia  

PubMed Central

Somatic mutations in cancer cell genes are classified according to their functional significance. Those that provide the malignant cells with significant advantage are collectively referred to as driver mutations and those that do not, are the passenger mutations. Accordingly, analytical criteria to distinguish driver mutations from passenger mutations have been recently suggested. Recent studies revealed mutations in interleukin-7 receptor-? (IL7R) gene in 10% of pediatric T-cell acute lymphoblastic leukemia (T-ALL) patients and in only a few cases of pediatric B-ALL. IL7R mutations are also frequently found in patients with lung cancer, but whereas in pediatric T-ALL IL7R mutations are “drivers” (consisting of gain-of-function mutations within a narrow 50-base pair interval at exon 6 that confer cytokine-independent cell growth and promote tumor transformation), in lung cancer, mutations are substitution mutations randomly distributed across the gene and are probably only “passenger” events. Because the treatment response of adult T-ALL is significantly poorer than that of childhood T-ALL and because exon 6 IL7R mutations play a role in the pathogenesis of childhood T-ALL, we sought to determine how the pattern of IL7R mutations varies between adult and childhood T-ALL. To that end, we sequenced the 50-base pair interval in exon 6 of the IL7R of DNA obtained from bone marrow samples of 35 randomly selected adult patients with T-ALL. Our analysis revealed that none of these 35 samples carried an IL7R mutation in exon 6. Whether differences in the genetic makeup of adult and childhood T-ALL explain the differential response to therapy remains to be determined.

Rozovski, Uri; Li, Ping; Harris, David; Ohanian, Maro; Kantarjian, Hagop; Estrov, Zeev

2014-01-01

211

New mutation in periaxin gene causing Charcot Marie Tooth disease in a Puerto Rican young male.  

PubMed

Charcot-Marie-Tooth (CMT) disease is an inherited peripheral neuropathy caused by mutations in more than 30 different genes. One of the genes encodes for periaxin (PRX) protein, which is required for the maintenance of peripheral nerve myelin. Individuals with PRX gene mutations have been described to present early-onset, autosomal recessive, demyelinating CMT disease or CMT4F subtype. Only 23 mutations involving the PRX gene have been reported in patients throughout the world. We describe a case of a Puerto Rican adolescent with history, neurologic examination, electromyographic data, and laboratory tests consistent with CMT4F. Genetic analysis of this individual showed a heterozygous transversion resulting in amino acid change from arginine to glycine in the PRX gene, suggesting CMT4F. We report this novel PRX mutation to expand the clinical spectrum of CMT disease. PMID:24263033

Noriega, Elizabeth; Ramos, Edwardo

2013-12-01

212

Excess of De Novo Deleterious Mutations in Genes Associated with Glutamatergic Systems in Nonsyndromic Intellectual Disability  

PubMed Central

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

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

2011-01-01

213

Separation of mutational and transcriptional enhancers in immunoglobulin genes  

PubMed Central

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

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

2011-01-01

214

Mutations in the Cystic Fibrosis Transmembrane Regulator Gene and In Vivo Transepithelial Potentials  

PubMed Central

Aim: To examine the relationship between cystic fibrosis transmembrane regulator gene mutations (CFTR) and in vivo transepithelial potentials. Methods: We prospectively evaluated 162 men including 31 healthy subjects, 21 obligate heterozygotes, 60 with congenital bilateral absence of the vas deferens (CBAVD) and 50 with CF by extensive CFTR genotyping, sweat chloride and nasal potential difference testing. Results: Six (10%) men with CBAVD carried no CFTR mutations, 18 (30%) carried one mutation, including the 5T variant, and 36 (60%) carried mutations on both alleles, for a significantly higher rate carrying one or more mutations than healthy controls (90% versus 19%, p < 0.001). There was an overlapping spectrum of ion channel measurements among the men with CBAVD, ranging from values in the control and obligate heterozygote range at one extreme, to values in the CF range at the other. All pancreatic-sufficient patients with CF and 34 of 36 patients with CBAVD with mutations on both alleles carried at least one mild mutation. However, the distribution of mild mutations in the two groups differed greatly. Genotyping, sweat chloride and nasal potential difference (alone or in combination) excluded CF in all CBAVD men with no mutations. CF was confirmed in 56% and 67% of CBAVD men carrying 1 and 2 CFTR mutations, respectively. Conclusion: Abnormalities of CFTR transepithelial function correlate with the number and severity of CFTR gene mutations.

Wilschanski, Michael; Dupuis, Annie; Ellis, Lynda; Jarvi, Keith; Zielenski, Julian; Tullis, Elizabeth; Martin, Sheelagh; Corey, Mary; Tsui, Lap-Chee; Durie, Peter

2006-01-01

215

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

PubMed Central

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

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

1997-01-01

216

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.)

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

217

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

218

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

PubMed Central

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

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

2013-01-01

219

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

PubMed

Recurrent gene mutations contribute to the pathogenesis of chronic lymphocytic leukaemia (CLL). We developed a next-generation sequencing (NGS) platform to determine the genetic profile, intratumoural heterogeneity, and clonal structure of two independent CLL cohorts. TP53, SF3B1, and NOTCH1 were most frequently mutated (16.3%, 16.9%, 10.7%). We found evidence for subclonal mutations in 67.5% of CLL cases with mutations of cancer consensus genes. We observed selection of subclones and found initial evidence for convergent mutations in CLL. Our data suggest that assessment of (sub)clonal structure may need to be integrated into analysis of the mutational profile in CLL. PMID:24032483

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

2013-11-01

220

Nemaline myopathy caused by mutations in the nebulin gene may present as a distal myopathy.  

PubMed

Mutations in the nebulin gene are the main cause of autosomal recessive nemaline myopathy, with clinical presentations ranging from mild to severe disease. We have previously reported a nonspecific distal myopathy caused by homozygous missense mutations in the nebulin gene in six Finnish patients from four different families. Here we describe three non-Finnish patients in two unrelated families with distal nemaline myopathy caused by four different compound heterozygous nebulin mutations, only one of which is a missense mutation. One of the mutations has previously been identified in one family with the severe form of nemaline myopathy. We conclude that nemaline myopathy and distal myopathy caused by nebulin mutations form a clinical and histological continuum. Nemaline myopathy should be considered as a differential diagnosis in patients presenting with an early-onset predominantly distal myopathy. PMID:21724397

Lehtokari, Vilma-Lotta; Pelin, Katarina; Herczegfalvi, Agnes; Karcagi, Veronika; Pouget, Jean; Franques, Jerôme; Pellissier, Jean François; Figarella-Branger, Dominique; von der Hagen, Maja; Huebner, Angela; Schoser, Benedikt; Lochmüller, Hanns; Wallgren-Pettersson, Carina

2011-08-01

221

[New mutation in Saccharomyces cerevisiae SRM genes and some features of their phenotypic effects].  

PubMed

The effects of the previously identified mutations in nuclear genes SRM8, SRM12, SRM15, and SRM17 on the maintenance of chromosomes and recombinant plasmids in Saccharomyces cerevisiae cells and on cell sensitivity to ionizing radiation were studied. The srm8 mutation caused instability of chromosome maintenance in diploid cells. In yeast cells with the intact mitochondrial genome, all examined srm mutations decreased the mitotic stability of a centromeric recombinant plasmid with the chromosomal ARS element. Mutations srm12, srm15, and srm17 also decreased the mitotic stability of a centromereless plasmid containing the same ARS element, whereas the srm8 mutation did not markedly affect the maintenance of this plasmid. Mutations srm8, srm12, and srm17 were shown to increase cell sensitivity to gamma-ray irradiation. The SRM8 gene was mapped, cloned, and found to correspond to the open reading frame YJLO76w in chromosome X. PMID:11642124

Koltovaia, N A; Ma?orova, E S; Rzianina, A V; Gerasimova, A S; Devin, A B

2001-09-01

222

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

PubMed

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 F C C; Peng, Roujun; Georgiou, Konstantinos; Wu, Chenglin; Falk Sörqvist, Elin; Berglund, Mattias; Chen, Longyun; Gao, Zhibo; Lagerstedt, Kristina; Lisboa, Susana; Roos, Fredrik; van Wezel, Tom; Teixeira, Manuel R; Rosenquist, Richard; Sundström, Christer; Enblad, Gunilla; Nilsson, Mats; Zeng, Yixin; Kipling, David; Pan-Hammarström, Qiang

2013-08-26

223

Frameshift mutations in coding repeats of protein tyrosine phosphatase genes in colorectal tumors with microsatellite instability  

PubMed Central

Background Protein tyrosine phosphatases (PTPs) like their antagonizing protein tyrosine kinases are key regulators of signal transduction thereby assuring normal control of cellular growth and differentiation. Increasing evidence suggests that mutations in PTP genes are associated with human malignancies. For example, mutational analysis of the tyrosine phosphatase (PTP) gene superfamily uncovered genetic alterations in about 26% of colorectal tumors. Since in these studies tumors have not been stratified according to genetic instability status we hypothesized that colorectal tumors characterized by high-level of microsatellite instability (MSI-H) might show an increased frequency of frameshift mutations in those PTP genes that harbor long mononucleotide repeats in their coding region (cMNR). Results Using bioinformatic analysis we identified 16 PTP candidate genes with long cMNRs that were examined for genetic alterations in 19 MSI-H colon cell lines, 54 MSI-H colorectal cancers, and 17 MSI-H colorectal adenomas. Frameshift mutations were identified only in 6 PTP genes, of which PTPN21 show the highest mutation frequency at all in MSI-H tumors (17%). Conclusion Although about 32% of MSI-H tumors showed at least one affected PTP gene, and cMNR mutation rates in PTPN21, PTPRS, and PTPN5 are higher than the mean mutation frequency of MNRs of the same length, mutations within PTP genes do not seem to play a common role in MSI tumorigenesis, since no cMNR mutation frequency reached statistical significance and therefore, failed prediction as a Positive Selective Target Gene.

Korff, Sebastian; Woerner, Stefan M; Yuan, Yan P; Bork, Peer; von Knebel Doeberitz, Magnus; Gebert, Johannes

2008-01-01

224

Campomelic dysplasia and autosomal sex reversal caused by mutations in an SRY-related gene  

Microsoft Academic Search

Induction of testis development in mammals requires the presence of the Y-chromosome gene SPY. This gene must exert its effect by interacting with other genes in the sex-determination pathway. Cloning of a translocation chromosome breakpoint from a sex-reversed patient with campomelic dysplasia, followed by mutation analysis of an adjacent gene, indicates that SOX9, an SRY-related gene, is involved in both

Jamie W. Foster; Marina A. Dominguez-Steglich; Silvana Guioli; Cheni Kwok; Polly A. Weller; Milena Stevanovic; Jean Weissenbach; Sahar Mansour; Ian D. Young; Peter N. Goodfellow; J. David Brook; Alan J. Schafer

1994-01-01

225

Mutations in the SLC3A1 Transporter Gene in Cystinuria  

PubMed Central

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. ImagesFigure 2Figure 3Figure 4

Pras, Elon; Raben, Nina; Golomb, Eliahu; Arber, Nadir; Aksentijevich, Ivona; Schapiro, Jonathan M.; Harel, Daniela; Katz, Giora; Liberman, Uri; Pras, Mordechai; Kastner, Daniel L.

1995-01-01

226

A null mutation in the rhodopsin gene causes rod photoreceptor dysfunction and autosomal recessive retinitis pigmentosa.  

PubMed

Mutations within the rhodopsin gene are known to give rise to autosomal dominant retinitis pigmentosa (RP), a common hereditary form of retinal degeneration. We now describe a patient with autosomal recessive RP who is homozygous for a nonsense mutation at codon 249 within exon 4 of the rhodopsin gene. This null mutation, the first gene defect identified in autosomal recessive retinitis pigmentosa, should result in a functionally inactive rhodopsin protein that is missing the sixth and seventh transmembrane domains including the 11-cis-retinal attachment site. We also found a different null mutation carried heterozygously by an unrelated unaffected individual. Heterozygous carriers of either mutation had normal ophthalmologic examinations but their electroretinograms revealed an abnormality in rod photoreceptor function. PMID:1303237

Rosenfeld, P J; Cowley, G S; McGee, T L; Sandberg, M A; Berson, E L; Dryja, T P

1992-06-01

227

C1824T mutation in the LMNA gene has no association with senile cataract.  

PubMed

Mutations in the LMNA gene encoding lamins A/C are responsible for Hutchinson-Gilford syndrome (HGS), a disorder of premature aging. Cataract is 1 of the main manifestations. The most prevalent mutation in Hutchinson-Gilford syndrome is C1824T, which activates a cryptic splice donor site to produce an abnormal lamin A protein. The purpose of this study was to investigate a possible association of the C1824T mutation with age-related cataract. Anterior lens capsule material was collected during cataract extraction surgery from 178 patients with senile cataract during 2007-2008. DNA and mRNA were extracted and sequenced for the LMNA gene. DNA and cDNA were screened for the C1824T mutation, which was not detected. Messenger RNA (mRNA) expression was normal, with no truncation. We found that human age-related nuclear cataract is not associated with LMNA gene mutations or truncation of lamin A. PMID:22079058

Sadikov, Tamilla; Simon, Amos J; Avraham-Lubin, Bat-Chen R; Dratviman-Storobinsky, Olga; Cohen, Yoram; Goldenberg-Cohen, Nitza

2012-07-01

228

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

229

PAH Gene Mutations in the Sicilian Population: Association with Minihaplotypes and Expression Analysis  

Microsoft Academic Search

The molecular basis of PAH deficiency in the Sicilian population is characterized by a marked heterogeneity, with 44 mutations at a single locus identified by a “gene-scanning” approach and accounting for a detection rate of 91%. The remaining 9% of PAH alleles does not bear mutations in any of the 13 exons and 24 exon\\/intron junctions. Three mutations IVS10nt-11 G

Mario G. Mirisola; Francesco Cali; Angelo Gloria; Pietro Schinocca; Monica D'Amato; Georgia Cassara; Giacomo De Leo; Letizia Palillo; Concetta Meli; Valentino Romano

2001-01-01

230

Fibrillin gene ( FBN1 ) mutations in Japanese patients with Marfan syndrome  

Microsoft Academic Search

Marfan syndrome (MFS; MIM #154700) is a connective tissue disorder characterized by cardiovascular, skeletal, and ocular\\u000a abnormalities. The fibrillin-1 gene (FBN1; MIM no. 134797) on chromosome 15 was revealed to be the cause of Marfan syndrome. To date over 137 types of FBN1 mutations have been reported. In this study, two novel mutations and a recurrent de-novo mutation were identified

Hiroki Chikumi; Toshiyuki Yamamoto; Yasutoshi Ohta; Eiji Nanba; Keiko Nagata; Haruaki Ninomiya; Kohshi Narasaki; Tatsuo Katoh; Ichiro Hisatome; Kimiyo Ono; Noriyuki Tanaka; Hiroaki Kuroda; Shigetsugu Ohgi

2000-01-01

231

Functional Analysis of PIK3CA Gene Mutations in Human Colorectal Cancer  

Microsoft Academic Search

Mutations in the PIK3CA gene, which encodes the p110A catalytic subunit of phosphatidylinositol 3-kinase (PI3K), have been reported in human cancers, including colorectal cancer. Most of the mutations cluster at hotspots within the helical and kinase domains. Whereas H1047R, one of the hotspot mutants, is reported to have elevated lipid kinase activity, the functional consequences of other mutations have not

Tsuneo Ikenoue; Fumihiko Kanai; Yohko Hikiba; Toshiyuki Obata; Yasuo Tanaka; Jun Imamura; Miki Ohta; Amarsanaa Jazag; Bayasi Guleng; Keisuke Tateishi; Yoshinari Asaoka; Masayuki Matsumura; Takao Kawabe; Masao Omat

2005-01-01

232

Novel mutations in the CDKL5 gene, predicted effects and associated phenotypes  

Microsoft Academic Search

It has been found that CDKL5 gene mutations are responsible for early-onset epilepsy and drug resistance. We screened a population\\u000a of 92 patients with classic\\/atypical Rett syndrome, 17 Angelman\\/Angelman-like patients and six idiopathic autistic patients\\u000a for CDKL5 mutations and exon deletions and identified seven novel mutations: six in the Rett subset and one in an Angelman\\u000a patient. This last, an

S. Russo; M. Marchi; F. Cogliati; M. T. Bonati; M. Pintaudi; E. Veneselli; V. Saletti; M. Balestrini; B. Ben-Zeev; L. Larizza

2009-01-01

233

Clinical and pathologic features of focal segmental glomerulosclerosis with mitochondrial tRNALeu(UUR) gene mutation  

Microsoft Academic Search

Clinical and pathologic features of focal segmental glomerulosclerosis with mitochondrial tRNALeu(UUR) gene mutation.BackgroundSeveral families have been described in which an A to G transition mutation at position 3243 (A3243G) of the mitochondrial DNA (mtDNA) is associated with focal and segmental glomerulosclerosis (FSGS). However, the prevalence, clinical features, and pathophysiology of FSGS carrying mtDNA mutations are largely undefined.MethodsAmong 11 biopsy-proven primary

Osamu Hotta; Chiyoko N. Inoue; Shigeaki Miyabayashi; Takashi Furuta; Akihiko Takeuchi; Yoshio Taguma

2001-01-01

234

Novel Donor Splice Site Mutation of ABCG5 Gene in Sitosterolemia  

Microsoft Academic Search

In a patient with sitosterolemia, we found two different mutations of the ATP-binding cassette, subfamily G, member 5 (ABCG5) gene. The first is a missense mutation that changes the amino acid residue at position 419 from arginine to histidine, i.e., R419H. The second is a novel splicing mutation affecting the invariant guanine at the first base of the donor splice

Ching-Wan Lam; Anna Wai-Fun Cheng; Sui-Fan Tong; Yan-Wo Chan

2002-01-01

235

TP53 mutation status and gene expression profiles are powerful prognostic markers of breast cancer  

Microsoft Academic Search

INTRODUCTION: Gene expression profiling of breast carcinomas has increased our understanding of the heterogeneous biology of this disease and promises to impact clinical care. The aim of this study was to evaluate the prognostic value of gene expression-based classification along with established prognostic markers and mutation status of the TP53 gene (tumour protein p53) in a group of breast cancer

Anita AL Langerod; Hongjuan HZ Zhao; Ørnulf Borgan; Jahn JMN Nesland; Ida IKB Bukholm; Tone TI Ikdahl; Rolf RK Kaaresen; Anne-Lise ALBD Borresen-Dale; Stefanie SSJ Jeffrey

2007-01-01

236

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.

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

2013-01-01

237

Splicing defects in the ataxia-telangiectasia gene, ATM: underlying mutations and consequences.  

PubMed Central

Mutations resulting in defective splicing constitute a significant proportion (30/62 [48%]) of a new series of mutations in the ATM gene in patients with ataxia-telangiectasia (AT) that were detected by the protein-truncation assay followed by sequence analysis of genomic DNA. Fewer than half of the splicing mutations involved the canonical AG splice-acceptor site or GT splice-donor site. A higher percentage of mutations occurred at less stringently conserved sites, including silent mutations of the last nucleotide of exons, mutations in nucleotides other than the conserved AG and GT in the consensus splice sites, and creation of splice-acceptor or splice-donor sites in either introns or exons. These splicing mutations led to a variety of consequences, including exon skipping and, to a lesser degree, intron retention, activation of cryptic splice sites, or creation of new splice sites. In addition, 5 of 12 nonsense mutations and 1 missense mutation were associated with deletion in the cDNA of the exons in which the mutations occurred. No ATM protein was detected by western blotting in any AT cell line in which splicing mutations were identified. Several cases of exon skipping in both normal controls and patients for whom no underlying defect could be found in genomic DNA were also observed, suggesting caution in the interpretation of exon deletions observed in ATM cDNA when there is no accompanying identification of genomic mutations.

Teraoka, S N; Telatar, M; Becker-Catania, S; Liang, T; Onengut, S; Tolun, A; Chessa, L; Sanal, O; Bernatowska, E; Gatti, R A; Concannon, P

1999-01-01

238

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

239

Mutation status of somatic EGFR and KRAS genes in Chinese patients with prostate cancer (PCa).  

PubMed

Activating mutations of the epidermal growth factor receptor (EGFR) confers sensitivity to tyrosine kinase inhibitors (TKIs). In colorectal cancer and in lung adenocarcinomas, clinical trials have shown a lack of response to anti-EGFR therapy when KRAS gene mutations are present. In this study, the mutation status of specified exons of the EGFR and KRAS genes was profiled in patients with prostate cancer (PCa). Direct Sanger sequencing was used to screen for mutations in exons 19-21 of EGFR and in exon 2 of KRAS in 88 Chinese patients diagnosed with prostate adenocarcinomas. Mutations were detected in 11 patients. In nine cases (10 %), activating mutations in the region of EGFR encoding the tyrosine kinase (TK) domain were present. Deletions in exon 19 and the L858R substitution in exon 21 were "hotspot" mutations, together accounting for five (55 %) of nine cases. Many synonymous substitutions were also detected. KRAS mutations were found in two cases (2.3 % of 88). There were no cases with mutations in both EGFR and KRAS, suggesting that mutations in the two genes might be mutually exclusive. Although prognostic relevance of EGFR expression by immunohistochemistry (IHC) was observed in PCa patients in previous studies, we found no statistically significant association between EGFR or KRAS mutations and clinicopathological features (including age, smoking status, preoperative prostate-specific antigen, Gleason scores, and tumor stage). We contend that accurate profiling of the mutation status of EGFR and KRAS could improve prognostic stratification, and we suggest a potential anti-EGFR therapy for patients with PCa with EGFR mutations. PMID:24595526

Fu, Meng; Zhang, Wei; Shan, Ling; Song, Jian; Shang, Donghao; Ying, Jianming; Zhao, Jimao

2014-05-01

240

[Clinical significance of common leukemia gene mutations in patients with acute promyelocytic leukemia].  

PubMed

This study was aimed to explore whether multiple common gene mutations of leukemia synergistically involved in acute promyelocytic leukemia (APL) pathogenesis, and to investigate their relevance to clinical features, cytogenetics and molecular risk stratification. 84 specimens of admitted de novo APL patients from February 2005 to October 2010 were collected, the gene mutations of bone marrow mononuclear cells and clinical features of mutation-positive patients were analyzed by genomic DNA-PCR. The results indicated that the prevalence of mutations was 60.7% (51/84), in which the mutations with the highest incidence were found as FLT3-ITD, reaching 27.4% (23/84). Next, there were 12 cases WT1 mutation, 9 for FLT3-TKD, 7 for TET2, 5 for N-RAS, 4 for ASXL1, 2 for EZH2 mutation and 1 positive case in MLL-PTD, IDH1 and CBL mutation respectively. No mutation was found in other JAK1, DNMT3, c-Kit, NPM1, IDH2, RUNX1 and JAK2 (V617F) common leukemia-related genes. Combined analysis with clinical data demonstrated that the patients with FLT3-ITD mutation displayed higher white blood cell counts, while the patients with N-RAS mutation showed lower platelet counts. Overall survival of these patients was obviously shorten as compared with patients with wild-type. This difference between mutant and wild-type of all above mentioned cases was statistically significant (P < 0.05). The difference between APL with simple t (15;17) and additional abnormal karyotype was not statistically significant. It is concluded that the FLT3-ITD mutation is recurrent genetic change in APL, and together with N-RAS mutation indicates poor prognosis. Additional abnormal karyotype does not associate with prognosis of APL. PMID:23484688

Yin, Jia; Sun, Ai-Ning; Tian, Xiao-Peng; Tian, Hong; Wang, Rong-Xian; Yang, Zhen; Wang, Xiu-Li; Wu, De-Pei; Qiu, Hui-Ying; Pan, Jin-Lan; Cen, Jian-Nong; Liang, Jian-Ying; Chen, Su-Ning

2013-02-01

241

Lymphatic Mapping Establishes the Role of BRAF Gene Mutation in Papillary Thyroid Carcinoma  

PubMed Central

Objective: To define the role of BRAF gene mutation in the progression of papillary thyroid carcinoma. Summary Background Data: BRAF gene mutation is frequently detected in papillary thyroid carcinoma. Its role in pathogenesis or progression is under investigation. Methods: Patients who underwent thyroidectomy and sentinel lymph node biopsy for papillary thyroid cancer were accrued. BRAF mutation was assessed in primary tumors and matched sentinel lymph nodes by a quantitative real-time PCR assay. Results: Tissue specimens from 103 consecutive patients were evaluated. BRAF mutation of the primary tumor was detected in 34 (33%) patients. In 26 of 34 (76%) patients with BRAF mutation, concomitant lymph node metastasis was detected. On the contrary, in 69 patients with BRAF mutation-negative primary tumors, only 12 (17%) patients had lymph node metastasis (?2, P < 0.0001). BRAF mutation was detected in 20 of 26 (77%) lymph node metastases matched to BRAF mutation-positive primary tumors; it was not detected in lymph node metastases matched to BRAF mutation-negative primary tumors. Univariate analysis identified age, stage, tumor size, and BRAF mutation as prognostic factors for lymph node metastasis. In multivariate analysis, only BRAF mutation remained a significant prognostic factor for lymph node metastasis (odds ratio = 10.8, 95% confidence interval, 3.5–34.0, P < 0.0001). Conclusions: BRAF mutation may be a key genetic factor for the metastatic progression of papillary thyroid carcinoma. The study demonstrates that this gene mutation is a significant risk factor for locoregional lymph node metastasis and has potential utility as a surrogate marker.

Kim, Joseph; Giuliano, Armando E.; Turner, Roderick R.; Gaffney, Robyn E.; Umetani, Naoyuki; Kitago, Minoru; Elashoff, David; Hoon, Dave S. B.

2006-01-01

242

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

PubMed Central

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

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

2010-01-01

243

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

PubMed

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

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

2013-01-01

244

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.

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

2014-01-01

245

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

PubMed Central

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

Iengar, Prathima

2012-01-01

246

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

247

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

PubMed

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

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

2011-01-01

248

A novel elastin gene mutation in a vietnamese patient with cutis laxa.  

PubMed

We report a 3-year-old girl from Vietnam with severe congenital cutis laxa; no cardiovascular, pulmonary, neurologic, or visceral involvement; and no family history of cutis laxa. Mutational analysis of the elastin gene identified heterozygosity for a previously unreported de novo c.2184delT mutation in exon 30 not present in either parent. PMID:24758204

Siefring, Mark L; Lawrence, Elizabeth C; Nguyen, Tom C; Lu, Doanh; Pham, Giang; Lorenchick, Christa; Levine, Kara L; Urban, Zsolt

2014-05-01

249

A Novel Elastin Gene Mutation in a Vietnamese Patient with Cutis Laxa  

PubMed Central

We report a 3-year-old girl from Vietnam with severe congenital cutis laxa, no cardiovascular, pulmonary, neurological or visceral involvement and no family history of cutis laxa. Mutational analysis of the elastin (ELN) gene identified heterozygosity for a previously unreported, de novo c.2184delT mutation in exon 30, not present in either parent.

Siefring, Mark L.; Lawrence, Elizabeth C.; Nguyen, Tom C.; Lu, Doanh; Pham, Giang; Lorenchick, Christa; Levine, Kara L.; Urban, Zsolt

2014-01-01

250

?-Galactosidase Gene Mutations in Patients With Slowly Progressive GM1 Gangliosidosis  

Microsoft Academic Search

Three unrelated North American cases with slowly progressive forms of GM1 gangliosidosis were found to have two unique point mutations and a 9 bp insertion in the coding region of the gene encoding ?-galactosidase. Case 1 was noted to have a 9 bp insertion {CAGAATTTT} on one allele between nucleotides 730 and 731 with no other mutations identified in the

Edward M. Kaye; Christo Shalish; James Livermore; Harold A. Taylor; Roger E. Stevenson; Xandra O. Breakefield

1997-01-01

251

APC gene: database of germline and somatic mutations in human tumors and cell lines.  

PubMed Central

A database is described in which over 700 mutations in the human APC gene of tumors (colon cancer predominantly) are compiled from the literature. It includes both molecular informations about the mutations and also clinical data about the patients. A software have been designed in order to analyse all these informations in the database.

Beroud, C; Soussi, T

1996-01-01

252

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.

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

253

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

254

Mutation patterns of 16 genes in primary and secondary acute myeloid leukemia (AML) with normal cytogenetics.  

PubMed

Acute myeloid leukemia patients with normal cytogenetics (CN-AML) account for almost half of AML cases. We aimed to study the frequency and relationship of a wide range of genes previously reported as mutated in AML (ASXL1, NPM1, FLT3, TET2, IDH1/2, RUNX1, DNMT3A, NRAS, JAK2, WT1, CBL, SF3B1, TP53, KRAS and MPL) in a series of 84 CN-AML cases. The most frequently mutated genes in primary cases were NPM1 (60.8%) and FLT3 (50.0%), and in secondary cases ASXL1 (48.5%) and TET2 (30.3%). We showed that 85% of CN-AML patients have mutations in at least one of ASXL1, NPM1, FLT3, TET2, IDH1/2 and/or RUNX1. Serial samples from 19 MDS/CMML cases that progressed to AML were analyzed for ASXL1/TET2/IDH1/2 mutations; seventeen cases presented mutations of at least one of these genes. However, there was no consistent pattern in mutation acquisition during disease progression. This report concerns the analysis of the largest number of gene mutations in CN-AML studied to date, and provides insight into the mutational profile of CN-AML. PMID:22912701

Fernandez-Mercado, Marta; Yip, Bon Ham; Pellagatti, Andrea; Davies, Carwyn; Larrayoz, María José; Kondo, Toshinori; Pérez, Cristina; Killick, Sally; McDonald, Emma-Jane; Odero, María Dolores; Agirre, Xabier; Prósper, Felipe; Calasanz, María José; Wainscoat, James S; Boultwood, Jacqueline

2012-01-01

255

Brain cysts associated with mutation in the Aristaless related homeobox gene, ARX  

Microsoft Academic Search

The novel Aristaless related homeobox gene, ARX, is widely expressed in the brain and is thought to play a key role in the regulation of brain development. Neurological phenotypes caused by ARX mutations have recently started to unfold. We describe a 72 year old man with X-linked mental retardation due to a 24 bp duplication mutation in exon 2 of

P Strømme; S J Bakke; A Dahl; J Ge?cz

2003-01-01

256

Mutations in the nebulin gene in a child with nemaline (rod) myopathy.  

PubMed

Nemaline myopathy, also called rod myopathy, is a relatively common congenital myopathy and probably second in incidence only to central core disease. The mainstay of diagnosis is histopathology, but detection of the causative mutation is mandatory for determining the mode of inheritance and for prenatal diagnosis. The authors report two siblings with nemaline myopathy caused by mutations in the nebulin gene. PMID:22941215

Kapoor, Seema; Singh, Ankur; Lehtokari, Vilma-Lotta; Wallgren-Pettersson, Carina; Batra, Vineeta Vijay

2013-08-01

257

Mutations in the sulonylurea receptor gene are associated with familial hyperinsulinism in Ashkenazi Jews  

Microsoft Academic Search

Familial hyperinsulinism (HI) is a disorder of pancreatic ?-cell function characterized by persistent hyperinsulinism despite severe hypoglycemia. To define the molecular genetic basis of HI in Ashkenazi Jews, 25 probands were screened for mutations in the sulfonylurea receptor (SUR1) gene by single-strand conformation polymorphism (SSCP) analysis of genomic DNA and subsequent nucleotide sequence analyses. Two common mutations were identified: (i)

Ann Nestorowicz; Beth Anne Wilson; Kathleen P. Schoor; Hiroshi Inoue; Benjamin Glaser; Heddy Landau; Charles A. Stanley; Paul S. Thornton; John P. Clement; Joseph Bryan; Lydia Aguilar-Bryan; M. Alan Permutt

1996-01-01

258

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

PubMed Central

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

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

2012-01-01

259

A Mutation in the Myostatin Gene Increases Muscle Mass and Enhances Racing Performance in Heterozygote Dogs  

Microsoft Academic Search

Double muscling is a trait previously described in several mammalian species including cattle and sheep and is caused by mutations in the myostatin (MSTN) gene (previously referred to as GDF8). Here we describe a new mutation in MSTN found in the whippet dog breed that results in a double-muscled phenotype known as the “bully” whippet. Individuals with this phenotype carry

Dana S Mosher; Pascale Quignon; Carlos D Bustamante; Nathan B Sutter; Cathryn S Mellersh; Heidi G Parker; Elaine A Ostrander

2007-01-01

260

Somatic gene mutation in the human in relation to radiation risk  

SciTech Connect

This report discusses the measurement of somatic gene-mutation frequencies in the human. We ask the following questions. How well can they be measured? Do they respond to radiation? Can they also function as a dosimeter? What do they tell us about the somatic mutation theory of carcinogenesis?

Mendelsohn, M.L.

1992-01-01

261

Somatic gene mutation in the human in relation to radiation risk  

SciTech Connect

This report discusses the measurement of somatic gene-mutation frequencies in the human. We ask the following questions. How well can they be measured Do they respond to radiation Can they also function as a dosimeter What do they tell us about the somatic mutation theory of carcinogenesis

Mendelsohn, M.L.

1992-01-01

262

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

Microsoft Academic Search

The most common human leukemia is B cell chronic lymphocytic leukemia (CLL), a malig- nancy 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

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

2001-01-01

263

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

Microsoft Academic Search

The most common human leukemia is B cell chronic lymphocytic leukemia (CLL), a malig- nancy 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

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

264

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

Microsoft Academic Search

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

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

1998-01-01

265

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

Microsoft Academic Search

Both epidermal growth factor receptor (EGFR) and RAS gene mutations contribute to the development of non-small cell lung cancer (NSCLC). Because RAS is one of the downstream molecules in the EGFR signal transduction, the association between the somatic mutations of EGFR and RAS may be important in the pathogenesis of NSCLC . However, to date, such data are lacking. In

Young Hwa Soung; Jong Woo Lee; Su Young Kim; Si Hyung Seo; Won Sang Park; Suk Woo Nam; Sang Yong Song; Joung Ho Han; Cheol Keun Park; Jung Young Lee; Nam Jin Yoo; Sug Hyung Lee

2005-01-01

266

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

Microsoft Academic Search

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

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

1999-01-01

267

Somatic mutations of the CD95 gene in Hodgkin and Reed-Sternberg cells.  

PubMed

Hodgkin and Reed-Sternberg (H/RS) cells in classical Hodgkin's disease (cHD) are thought to be derived from preapoptotic germinal center B cells. However, little is known about the transforming events rescuing the precursor of the H/RS cells from apoptosis. Given the importance of CD95 (Apo-1/Fas)-mediated apoptosis for negative selection within the germinal center, single micromanipulated H/RS cells from 10 cases of cHD were analyzed for somatic mutations within the CD95 gene. Three clonal mutations within the 5' regions were amplified from single H/RS cells in one case. From H/RS cells of another case, two mutations within the last exon coding for the death domain were detected. About half of these H/RS cells carried a monoallelic stop-codon; the remaining tumor cells harbored a monoallelic replacement mutation. Both mutations likely impair CD95 function. Because all these H/RS cells also bear clonal mutations inactivating the IkappaB alpha gene, the IkappaB alpha mutations occurred earlier than those of the CD95 gene in the sequence of transforming events leading to cHD. In conclusion, somatic mutations of the CD95 gene occur in a fraction of cHD cases and may favor the escape of the precursor of the H/RS clone from apoptosis. PMID:11059754

Müschen, M; Re, D; Bräuninger, A; Wolf, J; Hansmann, M L; Diehl, V; Küppers, R; Rajewsky, K

2000-10-15

268

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

269

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

PubMed

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

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

2013-01-01

270

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

PubMed Central

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

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

2013-01-01

271

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

272

[BRAF gene mutation in wild-type KRAS patients with colorectal cancers].  

PubMed

Background: In colorectal cancer, BRAF and KRAS mutation are mutually exclusive, but both are independent prognostic factors for the disease. Aim: To determine the frequency of BRAF V600E mutation in colorectal cancer. Material and Methods: A KRAS mutation study was carried out in 100 tissue samples of primary and metastatic adenocarcinomas of colon and rectum from patients aged 61.1 ± 62 years (56 women). Negative KRAS mutation cases underwent study of BRAF V600E mutation by restriction fragment length polymorphism (RFLP) and direct sequencing. Results: Primary tumors were located in the colon and rectum in 88 and six cases respectively. Five were liver metastases and in one case, the sample location was undetermined. Forty two samples were KRAS positive (mutated). In 12 of the 58 KRAS negative (wild type) samples, the V600E mutation in codon 15 of the BRAF gene was demonstrated. No differences in the frequency and distribution of mutations, stratified by gender, age, primary tumor versus metastasis, or tumor location were observed. Conclusions: Twelve percent of KRAS negative colorectal cancer samples showed BRAF gene mutation. Considering that 42% of samples have a KRAS mutation, 54% of patients should not respond to therapies with monoclonal antibodies directed against epidermic growth factor (EGFR) pathway. PMID:24861115

Roa, Iván; Game, Anakaren; Bizama, Carolina; Schalper, Kurt

2014-01-01

273

Further characterization of a non-essential mutator gene in Escherichia coli K-12.  

PubMed Central

The properties of mutR, a mutator closely linked to thyA, have been further characterized. We have found that the mutator gene is carried on a specialized transducing phage (lambdapcI857 thyA) generated by the excision of lambdacI857 integrated at a secondary attachment site between lysA and thyA. We present three lines of evidence indicating that mutR is a nonessential gene. (i) Deletions of the mutator can be found amoung survivors of heat induction of lambdacI857 when the phage is integrated between lysA and thyA. (ii) Mutations in mutR can be induced with the frameshift mutagen ICR-191. (iii) An amber mutant in mutR has been found. Viable strains could be made by combining the mutator with polB, polA polR, ligts7, and uvrA mutations. The mutator was still able to increase the spontaneous mutation frequency in these genetic backgrounds. When the reversion patterns of a series of well-characterized trpA mutations were analyzed, the results suggested that mutR is more efficient at causing transitions than transversion mutations.

Hoess, R H; Fan, D P

1975-01-01

274

Mutational pattern of the nurse shark antigen receptor gene (NAR) is similar to that of mammalian Ig genes and to spontaneous mutations in evolution: the translesion synthesis model of somatic hypermutation  

Microsoft Academic Search

The pattern of somatic mutations of shark and frog Ig is distinct from somatic hypermutation of Ig in mammals in that there is a bias to mutate GC base pairs and a low frequency of mutations. Previous analysis of the new antigen receptor gene in nurse sharks (NAR), however, revealed no bias to mutate GC base pairs and the frequency

Marilyn Diaz; Jovanna Velez; Mallika Singh; Jan Cern; Martin F. Flajnik

1999-01-01

275

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.

276

Novel SOST gene mutation in a sclerosteosis patient from Morocco: A case report.  

PubMed

Sclerosteosis (OMIM 269500) is a rare autosomal recessive condition characterized by increased bone density associated with syndactyly. It is linked to a genetic defect in the SOST gene coding for sclerostin. So far, seven different loss-of-function mutations in SOST have been reported in patients with sclerosteosis. Recently, two mutations in LRP4 gene underlying sclerosteosis were identified, reflecting the genetic heterogeneity of this disease. We report here a 30-years-old Moroccan man presented with typical clinical and radiological features of sclerosteosis who carries a novel homozygous mutation in the SOST gene, characterized as a nonsense mutation (c.79C > T; p.Gln27?) in exon 1 of the SOST gene. This is to our knowledge the first case of sclerosteosis reported from Morocco and North Africa. PMID:24594238

Belkhribchia, Mohamed Reda; Collet, Corinne; Laplanche, Jean-Louis; Hassani, Redouane

2014-03-01

277

A novel mutation of coproporphyrinogen oxidase (CPO) gene in a Japanese family.  

PubMed

Hereditary coproporphyria (HCP) is an autosomal dominant disease characterized by a deficiency of coproporphyrinogen oxidase (CPO). Only 11 mutations of the gene have been reported to date as the mutations responsible for HCP. We report here a novel mutation of the gene responsible for the disease in a Japanese family. Analysis of the polymerase chain reaction (PCR) amplified DNA fragments of the gene by direct-sequencing and/or cloning-based sequencing methods revealed the gene abnormality responsible for the disease. The mutation found was a single base deletion of T at nt position 526, which results in frame shift and truncation of coded protein at amino acid position 204. Screening of pre-symptomatic cases seemed to be possible by PCR restriction analysis using restriction enzyme Xcm I. PMID:9747031

Susa, S; Daimon, M; Yamamori, I; Kondo, M; Yamatani, K; Sasaki, H; Kato, T

1998-01-01

278

Novel mutations in the TBX5 gene in patients with Holt-Oram Syndrome.  

PubMed

The Holt-Oram syndrome (HOS) is an autosomal dominant condition characterized by upper limb and cardiac malformations. Mutations in the TBX5 gene cause HOS and have also been associated with isolated heart and arm defects. Interactions between the TBX5, GATA4 and NKX2.5 proteins have been reported in humans. We screened the TBX5, GATA4, and NKX2.5 genes for mutations, by direct sequencing, in 32 unrelated patients presenting classical (8) or atypical HOS (1), isolated congenital heart defects (16) or isolated upper-limb malformations (7). Pathogenic mutations in the TBX5 gene were found in four HOS patients, including two new mutations (c.374delG; c.678G > T) in typical patients, and the hotspot mutation c.835C > T in two patients, one of them with an atypical HOS phenotype involving lower-limb malformations. Two new mutations in the GATA4 gene were found in association with isolated upper-limb malformations, but their clinical significance remains to be established. A previously described possibly pathogenic mutation in the NKX2.5 gene (c.73C > 7) was detected in a patient with isolated heart malformations and also in his clinically normal father. PMID:21637475

Porto, Marianna P R; Vergani, Naja; Carvalho, Antonio Carlos C; Cernach, Mirlene C S P; Brunoni, Decio; Perez, Ana Beatriz A

2010-04-01

279

Osteopoikilosis and multiple exostoses caused by novel mutations in LEMD3 and EXT1 genes respectively - coincidence within one family  

PubMed Central

Background Osteopoikilosis is a rare autosomal dominant genetic disorder, characterised by the occurrence of the hyperostotic spots preferentially localized in the epiphyses and metaphyses of the long bones, and in the carpal and tarsal bones [1]. Heterozygous LEMD3 gene mutations were shown to be the primary cause of the disease [2]. Association of the primarily asymptomatic osteopokilosis with connective tissue nevi of the skin is categorized as Buschke-Ollendorff syndrome (BOS) [3]. Additionally, osteopoikilosis can coincide with melorheostosis (MRO), a more severe bone disease characterised by the ectopic bone formation on the periosteal and endosteal surface of the long bones [4-6]. However, not all MRO affected individuals carry germ-line LEMD3 mutations [7]. Thus, the genetic cause of MRO remains unknown. Here we describe a familial case of osteopoikilosis in which a novel heterozygous LEMD3 mutation coincides with a novel mutation in EXT1, a gene involved in aetiology of multiple exostosis syndrome. The patients affected with both LEMD3 and EXT1 gene mutations displayed typical features of the osteopoikilosis. There were no additional skeletal manifestations detected however, various non-skeletal pathologies coincided in this group. Methods We investigated LEMD3 and EXT1 in the three-generation family from Poland, with 5 patients affected with osteopoikilosis and one child affected with multiple exostoses. Results We found a novel c.2203C > T (p.R735X) mutation in exon 9 of LEMD3, resulting in a premature stop codon at amino acid position 735. The mutation co-segregates with the osteopoikilosis phenotype and was not found in 200 ethnically matched controls. Another new substitution G > A was found in EXT1 gene at position 1732 (cDNA) in Exon 9 (p.A578T) in three out of five osteopoikilosis affected family members. Evolutionary conservation of the affected amino acid suggested possible functional relevance, however no additional skeletal manifestations were observed other then those specific for osteopoikilosis. Finally in one member of the family we found a splice site mutation in the EXT1 gene intron 5 (IVS5-2 A > G) resulting in the deletion of 9 bp of cDNA encoding three evolutionarily conserved amino acid residues. This child patient suffered from a severe form of exostoses, thus a causal relationship can be postulated. Conclusions We identified a new mutation in LEMD3 gene, accounting for the familial case of osteopoikilosis. In the same family we identified two novel EXT1 gene mutations. One of them A598T co-incided with the LEMD3 mutation. Co-incidence of LEMD3 and EXT1 gene mutations was not associated with a more severe skeletal phenotype in those patients.

2010-01-01

280

Mutations of CD40 gene cause an autosomal recessive form of immunodeficiency with hyper IgM  

PubMed Central

CD40 is a member of the tumor necrosis factor receptor superfamily, expressed on a wide range of cell types including B cells, macrophages, and dendritic cells. CD40 is the receptor for CD40 ligand (CD40L), a molecule predominantly expressed by activated CD4+ T cells. CD40/CD40L interaction induces the formation of memory B lymphocytes and promotes Ig isotype switching, as demonstrated in mice knocked-out for either CD40L or CD40 gene, and in patients with X-linked hyper IgM syndrome, a disease caused by CD40L/TNFSF5 gene mutations. In the present study, we have identified three patients with an autosomal recessive form of hyper IgM who fail to express CD40 on the cell surface. Sequence analysis of CD40 genomic DNA showed that one patient carried a homozygous silent mutation at the fifth base pair position of exon 5, involving an exonic splicing enhancer and leading to exon skipping and premature termination; the other two patients showed a homozygous point mutation in exon 3, resulting in a cysteine to arginine substitution. These findings show that mutations of the CD40 gene cause an autosomal recessive form of hyper IgM, which is immunologically and clinically undistinguishable from the X-linked form.

Ferrari, Simona; Giliani, Silvia; Insalaco, Antonella; Al-Ghonaium, Abdulaziz; Soresina, Anna R.; Loubser, Michael; Avanzini, Maria A.; Marconi, Massimo; Badolato, Raffaele; Ugazio, Alberto G.; Levy, Yves; Catalan, Nadia; Durandy, Anne; Tbakhi, Abdelghani; Notarangelo, Luigi D.; Plebani, Alessandro

2001-01-01

281

Mutation to Herbicide Resistance Maps within the psbA Gene of Anacystis nidulans R2  

Microsoft Academic Search

A psbA gene encoding the target of photosystem II herbicide inhibition the 32,000-dalton thylakoid membrane protein, has cloned from a mutant of Anacystis nidulans R2, Which is resistant to 3-(3,4-dicholorophenyl)-1,1-dimethylurea-(diuron). A cloned DNA fragnebt from within the coding region of this gene transforms wild-type cells to herbicide resistance, proving that mutation within psbA is responsible for that phenotype. The mutation

Susan S. Golden; Robert Haselkorn

1985-01-01

282

Genotype–phenotype correlations analysis of mutations in the phenylalanine hydroxylase ( PAH ) gene  

Microsoft Academic Search

The aims of our research were to define the genotype–phenotype correlations of mutations in the phenylalanine hydroxylase\\u000a (PAH) gene that cause phenylketonuria (PKU) among the Israeli population. The mutation spectrum of the PAH gene in PKU patients in Israel is described, along with a discussion on genotype–phenotype correlations. By using polymerase\\u000a chain reaction\\/denaturing high-performance liquid chromatography (PCR\\/dHPLC) and DNA sequencing,

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

2008-01-01

283

Somatic mutations of the histone H3K27 demethylase gene UTX in human cancer.  

PubMed

Somatically acquired epigenetic changes are present in many cancers. Epigenetic regulation is maintained via post-translational modifications of core histones. Here, we describe inactivating somatic mutations in the histone lysine demethylase gene UTX, pointing to histone H3 lysine methylation deregulation in multiple tumor types. UTX reintroduction into cancer cells with inactivating UTX mutations resulted in slowing of proliferation and marked transcriptional changes. These data identify UTX as a new human cancer gene. PMID:19330029

van Haaften, Gijs; Dalgliesh, Gillian L; Davies, Helen; Chen, Lina; Bignell, Graham; Greenman, Chris; Edkins, Sarah; Hardy, Claire; O'Meara, Sarah; Teague, Jon; Butler, Adam; Hinton, Jonathan; Latimer, Calli; Andrews, Jenny; Barthorpe, Syd; Beare, Dave; Buck, Gemma; Campbell, Peter J; Cole, Jennifer; Forbes, Simon; Jia, Mingming; Jones, David; Kok, Chai Yin; Leroy, Catherine; Lin, Meng-Lay; McBride, David J; Maddison, Mark; Maquire, Simon; McLay, Kirsten; Menzies, Andrew; Mironenko, Tatiana; Mulderrig, Lee; Mudie, Laura; Pleasance, Erin; Shepherd, Rebecca; Smith, Raffaella; Stebbings, Lucy; Stephens, Philip; Tang, Gurpreet; Tarpey, Patrick S; Turner, Rachel; Turrell, Kelly; Varian, Jennifer; West, Sofie; Widaa, Sara; Wray, Paul; Collins, V Peter; Ichimura, Koichi; Law, Simon; Wong, John; Yuen, Siu Tsan; Leung, Suet Yi; Tonon, Giovanni; DePinho, Ronald A; Tai, Yu-Tzu; Anderson, Kenneth C; Kahnoski, Richard J; Massie, Aaron; Khoo, Sok Kean; Teh, Bin Tean; Stratton, Michael R; Futreal, P Andrew

2009-05-01

284

Cystic fibrosis with three mutations in the cystic fibrosis transmembrane conductance regulator gene  

Microsoft Academic Search

Three mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene were discovered in a pancreas-insufficient patient with cystic fibrosis (CF) who displayed an uncommon combination of almost normal chloride concentration in sweat tests and typical symptoms of gastrointestinal and pulmonary disease. The R553Q mutation was found on the maternal ?F508-CFTR gene. Codon 553 is located within a consensus motif

Thilo Dörk; Ulrich Wulbrand; Thomas Richter; Thomas Neumann; Heiner Wolfes; Brigitte Wulf; Günter Maass; Burkhard Tümmler

1991-01-01

285

High frequency hearing loss correlated with mutations in the GJB2 gene  

Microsoft Academic Search

Genetic hearing impairment affects approximately 1\\/2000 live births. Mutations in one gene, GJB2, coding for connexin 26 cause 10%-20% of all genetic sensorineural hearing loss. Mutation analysis in the GJB2 gene and audiology were performed on 106 families presenting with at least one child with congenital hearing loss. The families were recruited from a hospital-based multi-disciplinary clinic, which functions to

Stephen A Wilcox; Kerryn Saunders; Amelia H Osborn; Angela Arnold; Julia Wunderlich; Therese Kelly; Veronica Collins; Leah J Wilcox; RJ McKinlay Gardner; Maria Kamarinos; Barbara Cone-Wesson; Robert Williamson; Hans-Henrik M. Dahl

2000-01-01

286

Molecular pathology of expanded polyalanine tract mutations in the Aristaless-related homeobox gene  

Microsoft Academic Search

The Aristaless-related homeobox gene (ARX) is one of the major genes causing X-linked mental retardation. We have been interested in the pathogenic mechanism of expanded polyalanine tract mutations in ARX. We showed that the c.304ins(GCG)7 mutation causing an increase from 16 to 23 alanines increased the propensity of ARX protein aggregation and a shift from nuclear to cytoplasmic localization. We

Cheryl Shoubridge; Desiree Cloosterman; Douglas Brooks; Jozef Gécz

2007-01-01

287

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.

2014-01-01

288

HFE Gene Mutation, Chronic Liver Disease, and Iron Overload In Turkey  

Microsoft Academic Search

We aimed to determine the relationships between iron overload and HFE gene mutation in chronic liver disease in Turkey. One\\u000a hundred thirteen chronic liver disease patients and 138 healthy controls were evaluated regarding their clinical, biochemical,\\u000a and genetic parameters. Each group was divided into two subgroups according to transferrin saturation (TS) (45% and >45%).\\u000a HFE gene mutation was analyzed by

Oya Yönal; Özden Hat?rnaz; Filiz Akyüz; Ugur Özbek; Kadir Demir; Sabahattin Kaymakoglu; Atilla Ökten; Zeynel Mungan

2007-01-01

289

First report of a de novo germline mutation in the MLH1 gene  

PubMed Central

Hereditary non-polyposis colorectal carcinoma (HNPCC) is an autosomal dominant disorder associated with colorectal and endometrial cancer and a range of other tumor types. Germline mutations in the DNA mismatch repair (MMR) genes, particularly MLH1, MSH2, and MSH6, underlie this disorder. The vast majority of these HNPCC-associated mutations have been proven, or assumed, given the family history of cancer, to be transmitted through several generations. To the best of our knowledge, only a single case of a de novo germline MMR gene mutation (in MSH2) has been reported till now. Here, we report a patient with a de novo mutation in MLH1. We identified a MLH1 Q701X truncating mutation in the blood lymphocytes of a male who had been diagnosed with rectal cancer at the age of 35. His family history of cancer was negative for the first- and second-degree relatives. The mutation could not be detected in the patient’s parents and sibling and paternity was confirmed with a set of highly polymorphic markers. Non-penetrance and small family size is the common explanation of verified negative family histories of cancer in patients with a germline MMR gene mutation. However, in addition to some cases explained by non-paternity, de novo germline mutations should be considered as a possible explanation as well. As guidelines that stress not to restrict MMR gene mutation testing to patients with a positive family history are more widely introduced, more cases of de novo MMR gene germline mutations may be revealed.

Stulp, Rein P; Vos, Yvonne J; Mol, Bart; Karrenbeld, Arend; de Raad, Monique; van der Mijle, Huub JC; Sijmons, Rolf H

2006-01-01

290

Dystrophin Gene Mutation Location and the Risk of Cognitive Impairment in Duchenne Muscular Dystrophy  

PubMed Central

Background A significant component of the variation in cognitive disability that is observed in Duchenne muscular dystrophy (DMD) is known to be under genetic regulation. In this study we report correlations between standardised measures of intelligence and mutational class, mutation size, mutation location and the involvement of dystrophin isoforms. Methods and Results Sixty two male subjects were recruited as part of a study of the cognitive spectrum in boys with DMD conducted at the Sydney Children's Hospital (SCH). All 62 children received neuropsychological testing from a single clinical psychologist and had a defined dystrophin gene (DMD) mutation; including DMD gene deletions, duplications and DNA point mutations. Full Scale Intelligence Quotients (FSIQ) in unrelated subjects with the same mutation were found to be highly correlated (r?=?0.83, p?=?0.0008), in contrast to results in previous publications. In 58 cases (94%) it was possible to definitively assign a mutation as affecting one or more dystrophin isoforms. A strong association between the risk of cognitive disability and the involvement of groups of DMD isoforms was found. In particular, improvements in the correlation of FSIQ with mutation location were identified when a new classification system for mutations affecting the Dp140 isoform was implemented. Significance These data represent one of the largest studies of FSIQ and mutational data in DMD patients and is among the first to report on a DMD cohort which has had both comprehensive mutational analysis and FSIQ testing through a single referral centre. The correlation between FSIQ results with the location of the dystrophin gene mutation suggests that the risk of cognitive deficit is a result of the cumulative loss of central nervous system (CNS) expressed dystrophin isoforms, and that correct classification of isoform involvement results in improved estimates of risk.

Maroulis, Sarah; Gilissen, Christian; Pedersen, Robyn L.; Mowat, David R.; Johnston, Heather M.; Buckley, Michael F.

2010-01-01

291

Changes in auxin response from mutations in an AUX/IAA gene.  

PubMed

Transcription of the AUX/IAA family of genes is rapidly induced by the plant hormone auxin, but evidence that AUX/IAA genes mediate further responses to auxin has been elusive. Changes in diverse auxin responses result from mutations in the Arabidopsis AXR3 gene. AXR3 was shown to be a member of the AUX/IAA family, providing direct evidence that AUX/IAA genes are central in auxin signaling. Molecular characterization of axr3 gain-of-function and loss-of-function mutations established the functional importance of domains conserved among AUX/IAA proteins. PMID:9478901

Rouse, D; Mackay, P; Stirnberg, P; Estelle, M; Leyser, O

1998-02-27

292

CDH1 gene mutations do not contribute in hereditary diffuse gastric cancer in Poland  

PubMed Central

Hereditary diffuse gastric cancer (HDGC) is a cancer susceptibility syndrome characterized by a high risk of diffuse stomach cancer and lobular breast cancer. HDGC is caused by germline mutations in the CDH1 gene encoding the E-cadherin which is a member of the transmembrane glycoprotein family responsible for calcium-dependent, cell-to-cell adhesion and plays a fundamental role in the maintenance of cell differentiation and the normal architecture of epithelial tissues. Mutations in the CDH1 gene are detected in 30–46% of families that fulfil strong clinical criteria for HDGC and in about 11% of families fulfilling the modified criteria. In the present study, we investigated germline mutations in the CDH1 gene in Polish patients with HDGC. The entire coding sequence of CDH1 gene was analyzed by sequencing in 86 Polish cancer patients from families fulfilling the modified criteria of HDGC. We found several silent mutations including one common variant (c.2076T>C) present in 56 patients, and three rare variants (c.2253C>T, c.1896C>T, c.2634C>T) detected in 2 patients. In addition, we found four rare sequence variants of unknown significance localized in introns. We did not detect any deleterious mutations of the CDH1 gene. CDH1 gene mutations are not present in Polish families with HDGC defined by the modified clinical criteria. Further studies of families with HDGC matching the restrictive criteria for HDGC are needed.

Lawniczak, Malgorzata; Wojnarska, Beata; Cybulski, Cezary; Huzarski, Tomasz; Byrski, Tomasz; Toloczko-Grabarek, Aleksandra; Jaworska, Katarzyna; Durda, Katarzyna; Starzynska, Teresa; Lubinski, Jan

2010-01-01

293

PIG-A gene mutations in four Taiwanese patients with paroxysmal nocturnal haemoglobinuria following aplastic anaemia.  

PubMed

Paroxysmal nocturnal haemoglobinuria (PNH) is an acquired haemolytic disorder caused by deficient biosynthesis of the glycosyl phosphatidylinositol (GPI) anchor in haemopoietic stem cells. PIG-A, an X-linked gene that participates in the first step of GPI-anchor synthesis, is responsible for PNH. Various abnormalities of the PIG-A gene have been demonstrated in all patients with PNH so far examined. In this study we characterized the somatic mutations in PIG-A gene in four Taiwanese patients with PNH. We identified five novel mutations in the PIG-A gene, three single nucleotide substitution mutations (-342, C-->G, codon 335, GGT-->AGT and codon 405, GCT-->GTT) and two frameshift mutations (codon 22, GGA-->G-A and codon 356, TGT-->TGTT) in the PIG-A gene. The -342 mutation was judged to be a polymorphism. Furthermore, three patients had previous clinicopathologic evidence which suggested aplastic anaemia (AA), before the development of PNH. One of these was found to have thrombocytopenia during follow-up. We suggest that the somatic PIG-A gene mutations highlight a subgroup of AA having a pathogenetic link with PNH. PMID:9163589

Lin, L I; Liu, C H; Chen, Y C; Shen, M C; Wang, C H; Huang, Y L; Lin, J K

1997-05-01

294

Screening for germline mutations in the neurofibromatosis type 2 (NF2) gene in NF2 patients  

SciTech Connect

Neurofibromatosis type 2 (NF2) is an autosomal dominant disease with over 95% penetrance which predisposes gene carriers to develop multiple tumors of the central nervous system. The NF2 gene is a putative tumor suppressor gene which was previously mapped to the long arm of chromosome 22, and has recently been identified, using positional cloning techniques. The gene encodes a protein, schwannomin (SCH), which is highly homologous to the band 4.1 protein family. In an attempt to identify and characterize mutations which lead to the manifestation of the disease, we have used single strand conformation analysis (SSCA) to screen for germline mutations in all 17 exons of the NF2 gene in 59 unrelated NF2 patients, representing both familial and new mutations. A total of 27 migration abnormalities was found in 26 patients. Using direct sequencing analysis, the majority of these variants were found to result in nonsense, splice-site or frameshift mutations. Mutations identified in familial NF2 patients segregate in the family, and may prove to be useful tools for a simple and direct SSCA-based technique of presymptomatic or prenatal diagnosis in relatives of patients with NF2. This may be of particular importance in children of patients who have new mutations in the NF2 gene, where linkage analysis may not be feasible.

Andermann, A.A.; Ruttledge, M.H.; Rangaratnam, A. [McGill Univ. and Montreal General Hospital Research Institute, Quebec (Canada)] [and others

1994-09-01

295

Gain-of-function mutations of platelet-derived growth factor receptor ? gene in gastrointestinal stromal tumors  

Microsoft Academic Search

Background & Aims: Most gastrointestinal stromal tumors (GISTs) have gain-of-function mutations of c-kit receptor tyrosine kinase (KIT) gene, but some GISTs do not. We investigated the cause of GISTs without KIT mutations. Because GISTs apparently expressed platelet-derived growth factor receptor (PDGFR) ?, we examined whether GISTs without KIT mutations had a mutation of PDGFR ?. Methods: Whole coding region of

Seiichi Hirota; Akiko Ohashi; Toshirou Nishida; Koji Isozaki; Kazuo Kinoshita; Yasuhisa Shinomura; Yukihiko Kitamura

2003-01-01

296

Infantile spasms, dystonia, and other X-linked phenotypes caused by mutations in Aristaless related homeobox gene, ARX  

Microsoft Academic Search

Clinical data from 50 mentally retarded (MR) males in nine X-linked MR families, syndromic and non-specific, with mutations (duplication, expansion, missense, and deletion mutations) in the Aristaless related homeobox gene, ARX, were analysed. Seizures were observed with all mutations and occurred in 29 patients, including one family with a novel myoclonic epilepsy syndrome associated with the missense mutation. Seventeen patients

Petter Strømme; Marie E Mangelsdorf; Ingrid E Scheffer; Jozef Gécz

2002-01-01

297

Patterns of Epistasis between Beneficial Mutations in an Antibiotic Resistance Gene  

PubMed Central

Understanding epistasis is central to biology. For instance, epistatic interactions determine the topography of the fitness landscape and affect the dynamics and determinism of adaptation. However, few empirical data are available, and comparing results is complicated by confounding variation in the system and the type of mutations used. Here, we take a systematic approach by quantifying epistasis in two sets of four beneficial mutations in the antibiotic resistance enzyme TEM-1 ?-lactamase. Mutations in these sets have either large or small effects on cefotaxime resistance when present as single mutations. By quantifying the epistasis and ruggedness in both landscapes, we find two general patterns. First, resistance is maximal for combinations of two mutations in both fitness landscapes and declines when more mutations are added due to abundant sign epistasis and a pattern of diminishing returns with genotype resistance. Second, large-effect mutations interact more strongly than small-effect mutations, suggesting that the effect size of mutations may be an organizing principle in understanding patterns of epistasis. By fitting the data to simple phenotype resistance models, we show that this pattern may be explained by the nonlinear dependence of resistance on enzyme stability and an unknown phenotype when mutations have antagonistically pleiotropic effects. The comparison to a previously published set of mutations in the same gene with a joint benefit further shows that the enzyme's fitness landscape is locally rugged but does contain adaptive pathways that lead to high resistance.

Schenk, Martijn F.; Szendro, Ivan G.; Salverda, Merijn L.M.; Krug, Joachim; de Visser, J. Arjan G.M.

2013-01-01

298

Human gene mutation database-a biomedical information and research resource.  

PubMed

Although 20 years have elapsed since the first single basepair substitution underlying an inherited disease in humans was characterised at the DNA level, the initiative has only recently been taken to establish central database resources for pathological genetic variants. Disease-associated gene lesions are currently collected and publicised by the Human Gene Mutation Database (HGMD) in Cardiff, locus-specific mutation databases, and to some extent also by the Genome Database (GDB) and Online Mendelian Inheritance in Man (OMIM). To date, HGMD represents the only comprehensive and publicly available database of gene lesions underlying human inherited disease. By July 1999, HGMD contained over 18,000 different mutations from some 900 human genes, the majority being single basepair substitutions. In addition to its potential as an information resource for clinicians and genetic counsellors, HGMD has allowed molecular geneticists to address a variety of biological questions through meta-analysis of the collated data. HGMD also promises to assist research workers in optimising mutation search strategies for a given gene. A questionnaire sent out to, and answered by, the editors of 20 key journals revealed that human genetics journals are increasingly reluctant to publish mutation reports. Electronic data submission and publication facilities are therefore urgently required. The World Wide Web (WWW) provides an excellent medium within which to combine the centralised management of basic mutation data, including rigorous quality control, with the possibility of publishing additional mutation-related information. In response to these needs, HGMD has both instituted a collaboration with Springer-Verlag GmbH, Heidelberg, to potentiate free online submission and electronic publication of human gene mutation data and developed links with the curators of locus-specific mutation databases. PMID:10612821

Krawczak, M; Ball, E V; Fenton, I; Stenson, P D; Abeysinghe, S; Thomas, N; Cooper, D N

2000-01-01

299

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

300

Detection of six novel mutations in WASP gene in fifteen Iranian Wiskott-Aldrich patients.  

PubMed

Wiskott-Aldrich syndrome (WAS) is a life-threatening X-linked recessive immunodeficiency disease described as a clinical triad of thrombocytopenia, eczema, and recurrent infections, caused by mutations of the WAS protein (WASP) gene. The milder form of this disease is X-linked thrombocytopenia (XLT) that presents only as platelet abnormalities. Mutation analysis for 15 boys with Wiskott-Aldrich syndrome was performed. Five previously reported mutations and six novel mutations including G8X, R41X, D283E, P412fsX446, E464X, and AfsX358 were detected. PMID:23264413

Safaei, Sepideh; Fazlollahi, Mohammad Reza; Houshmand, Masoud; Hamidieh, Amir Ali; Bemanian, Mohammad Hassan; Alavi, Samin; Mousavi, Farideh; Pourpak, Zahra; Moin, Mostafa

2012-12-01

301

Constitutional RB1-gene mutations in patients with isolated unilateral retinoblastoma.  

PubMed Central

In most patients with isolated unilateral retinoblastoma, tumor development is initiated by somatic inactivation of both alleles of the RB1 gene. However, some of these patients can transmit retinoblastoma predisposition to their offspring. To determine the frequency and nature of constitutional RB1-gene mutations in patients with isolated unilateral retinoblastoma, we analyzed DNA from peripheral blood and from tumor tissue. The analysis of tumors from 54 (71%) of 76 informative patients showed loss of constitutional heterozygosity (LOH) at intragenic loci. Three of 13 uninformative patients had constitutional deletions. For 39 randomly selected tumors, SSCP, hetero-duplex analysis, sequencing, and Southern blot analysis were used to identify mutations. Mutations were detected in 21 (91%) of 23 tumors with LOH. In 6 (38%) of 16 tumors without LOH, one mutation was detected, and in 9 (56%) of the tumors without LOH, both mutations were found. Thus, a total of 45 mutations were identified in tumors of 36 patients. Thirty-nine of the mutations-including 34 small mutations, 2 large structural alterations, and hypermethylation in 3 tumors-were not detected in the corresponding peripheral blood DNA. In 6 (17%) of the 36 patients, a mutation was detected in constitutional DNA, and 1 of these mutations is known to be associated with reduced expressivity. The presence of a constitutional mutation was not associated with an early age at treatment. In 1 patient, somatic mosaicism was demonstrated by molecular analysis of DNA and RNA from peripheral blood. In 2 patients without a detectable mutation in peripheral blood, mosaicism was suggested because 1 of the patients showed multifocal tumors and the other later developed bilateral retinoblastoma. In conclusion, our results emphasize that the manifestation and transmissibility of retinoblastoma depend on the nature of the first mutation, its time in development, and the number and types of cells that are affected. Images Figure 2 Figure 3 Figure 4

Lohmann, D R; Gerick, M; Brandt, B; Oelschlager, U; Lorenz, B; Passarge, E; Horsthemke, B

1997-01-01

302

FGFR3 Mutations and the Skin: Report of a Patient with a FGFR3 Gene Mutation, Acanthosis Nigricans, Hypochondroplasia and Hyperinsulinemia and Review of the Literature  

Microsoft Academic Search

Fibroblast growth factor receptor 3 (FGFR3) gene mutations in the germline are well-known causes of skeletal syndromes. Somatic FGFR3 mutations have been found in malignant neoplasms and more recently in several cutaneous elements. We present a 14-year-old girl with mild hypochondroplasia who developed acanthosis nigricans. The report of a K650Q mutation in the FGFR3 gene in a similar case prompted

M. Blomberg; E. M. Jeppesen; F. Skovby; E. Benfeldt

2010-01-01

303

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

Microsoft Academic Search

Marfan syndrome is a dominantly inherited connective tissue disorder with a wide range of phenotypic severity. The condition is the result of mutations in FBN1, a large gene composed of 65 exons encoding the fibrillin-1 protein. While mutations causing classic manifestations of Marfan syndrome have been identified throughout the FBN1 gene, the six previously characterized mutations resulting in the severe,

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

1996-01-01

304

Haemochromatosis gene mutations in a clustered Italian population: evidence of high prevalence in people of Celtic ancestry  

Microsoft Academic Search

Hereditary haemochromatosis is an inherited disorder characterised by an excessive iron absorption from the diet and is associated with several HFE gene mutations. One hypothesis is that these genetic mutations originated in the Celtic populations. The aim of this study is to determine the frequency of HFE gene mutations in a clustered Italian population of Celtic ancestry (Cimbri, Asiago plateau).

Gabriele Pozzato; Francesca Zorat; Fabiana Nascimben; Michela Gregorutti; Consuelo Comar; Stefano Baracetti; Serena Vatta; Elena Bevilacqua; Anna Belgrano; Sergio Crovella; Antonio Amoroso

2001-01-01

305

Genes, patients, families, doctors-mutation analysis in clinical practice.  

PubMed

Developments in mutation analysis have led to significant benefits for patients with inherited metabolic disorders and their families. This is particularly the case where new methodologies have prevented the need for invasive tissue biopsies or have allowed carrier detection or first trimester prenatal testing to be undertaken. Whereas in the past it may have only been possible to identify specific 'common' mutations, the availability of techniques, such as automated sequencing, and novel technologies including mutation scanning techniques, multiplex ligation dependent probe amplification, and array technologies, have vastly improved the diagnostic efficiency of molecular testing. PMID:19306072

Walter, J H

2009-06-01

306

A cluster of mutations within a short triplet repeat in the C1 inhibitor gene.  

PubMed Central

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 8460. This short segment of DNA contains three direct repeats of the triplet CAA and is immediately preceded by a similar adenosine-rich sequence (CAAGAACAC). These triplet repeats make this region susceptible to mutation by a slipped mispairing mechanism. There are two other short triplet repeat elements in the coding region for this gene, but they have not become mutated in any kindred examined. This suggests that the apparent enhanced mutation rate in this region of exon 5 may be influenced by DNA structural characteristics. Images

Bissler, J J; Cicardi, M; Donaldson, V H; Gatenby, P A; Rosen, F S; Sheffer, A L; Davis, A E

1994-01-01

307

Epidermolytic hyperkeratosis in a Hispanic family resulting from a mutation in the keratin 1 gene.  

PubMed

Epidermolytic hyperkeratosis (EHK; bullous congenital ichthyosiform erythroderma) is a genodermatosis resulting from mutations in either the keratin 1 (K1) or keratin 10 (K10) genes. It is characterized by erythroderma and blistering at birth, and the development of ichthyotic hyperkeratosis and palmoplantar keratoderma. A wide variety of mutations within the highly conserved helix initiation and termination motifs of the central rod domains of the K1 or K10 genes correlate with the highly variable phenotypic severity observed in EHK. We report a novel missense mutation designated L214P in a large Hispanic pedigree with EHK. The mutation is located in the highly conserved 1A segment of the alpha-helical rod domain. The presence of this mutation underscores the importance of sequence alterations located in the central rod domain in the pathogenesis of EHK. PMID:10844506

Cserhalmi-Friedman, P B; Squeo, R; Gordon, D; Garzon, M; Schneiderman, P; Grossman, M E; Christiano, A M

2000-05-01

308

De novo mutations in histone modifying genes in congenital heart disease  

PubMed Central

Congenital heart disease (CHD) is the most frequent birth defect, affecting 0.8% of live births1. Many cases occur sporadically and impair reproductive fitness, suggesting a role for de novo mutations. By analysis of exome sequencing of parent-offspring trios, we compared the incidence of de novo mutations in 362 severe CHD cases and 264 controls. CHD cases showed a significant excess of protein-altering de novo mutations in genes expressed in the developing heart, with an odds ratio of 7.5 for damaging mutations. Similar odds ratios were seen across major classes of severe CHD. We found a marked excess of de novo mutations in genes involved in production, removal or reading of H3K4 methylation (H3K4me), or ubiquitination of H2BK120, which is required for H3K4 methylation2–4. There were also two de novo mutations in SMAD2; SMAD2 signaling in the embryonic left-right organizer induces demethylation of H3K27me5. H3K4me and H3K27me mark `poised' promoters and enhancers that regulate expression of key developmental genes6. These findings implicate de novo point mutations in several hundred genes that collectively contribute to ~10% of severe CHD.

Zaidi, Samir; Choi, Murim; Wakimoto, Hiroko; Ma, Lijiang; Jiang, Jianming; Overton, John D.; Romano-Adesman, Angela; Bjornson, Robert D.; Breitbart, Roger E.; Brown, Kerry K.; Carriero, Nicholas J.; Cheung, Yee Him; Deanfield, John; DePalma, Steve; Fakhro, Khalid A.; Glessner, Joseph; Hakonarson, Hakon; Italia, Michael; Kaltman, Jonathan R.; Kaski, Juan; Kim, Richard; Kline, Jennie K.; Lee, Teresa; Leipzig, Jeremy; Lopez, Alexander; Mane, Shrikant M.; Mitchell, Laura E.; Newburger, Jane W.; Parfenov, Michael; Pe'er, Itsik; Porter, George; Roberts, Amy; Sachidanandam, Ravi; Sanders, Stephan J.; Seiden, Howard S.; State, Mathew W.; Subramanian, Sailakshmi; Tikhonova, Irina R.; Wang, Wei; Warburton, Dorothy; White, Peter S.; Williams, Ismee A.; Zhao, Hongyu; Seidman, Jonathan G.; Brueckner, Martina; Chung, Wendy K.; Gelb, Bruce D.; Goldmuntz, Elizabeth; Seidman, Christine E.; Lifton, Richard P.

2013-01-01

309

Identification of candidate genes for lung cancer somatic mutation test kits  

PubMed Central

Over the past three decades, mortality from lung cancer has sharply and continuously increased in China, ascending to the first cause of death among all types of cancer. The ability to identify the actual sequence of gene mutations may help doctors determine which mutations lead to precancerous lesions and which produce invasive carcinomas, especially using next-generation sequencing (NGS) technology. In this study, we analyzed the latest lung cancer data in the COSMIC database, in order to find genomic “hotspots” that are frequently mutated in human lung cancer genomes. The results revealed that the most frequently mutated lung cancer genes are EGFR, KRAS and TP53. In recent years, EGFR and KRAS lung cancer test kits have been utilized for detecting lung cancer patients, but they presented many disadvantages, as they proved to be of low sensitivity, labor-intensive and time-consuming. In this study, we constructed a more complete catalogue of lung cancer mutation events including 145 mutated genes. With the genes of this list it may be feasible to develop a NGS kit for lung cancer mutation detection.

Chen, Yong; Shi, Jian-Xin; Pan, Xu-Feng; Feng, Jian; Zhao, Heng

2013-01-01

310

Iron overload and HFE gene mutations in Czech patients with chronic liver diseases.  

PubMed

The aim of the study was to identify the prevalence of HFE gene mutations in Czech patients with chronic liver diseases and the influence of the mutations on iron status. The presence of HFE gene mutations (C282Y, H63D, and S65C) analyzed by the PCR-RFLP method, presence of cirrhosis, and serum iron indices were compared among 454 patients with different chronic liver diseases (51 with chronic hepatitis B, 122 with chronic hepatitis C, 218 with alcoholic liver disease, and 63 patients with hemochromatosis). Chronic liver diseases patients other than hemochromatics did not have an increased frequency of HFE gene mutations compared to controls. Although 33.3% of patients with hepatitis B, 43% of patients with hepatitis C, and 73.2% of patients with alcoholic liver disease had elevated transferrin saturation or serum ferritin levels, the presence of HFE gene mutations was not significantly associated with iron overload in these patients. Additionally, patients with cirrhosis did not have frequencies of HFE mutations different from those without cirrhosis. This study emphasizes the importance, not only of C282Y, but also of the H63D homozygous genetic constellation in Czech hemochromatosis patients. Our findings show that increased iron indices are common in chronic liver diseases but {\\it HFE} mutations do not play an important role in the pathogenesis of chronic hepatitis B, chronic hepatitis C, and alcoholic liver disease. PMID:22297603

Dostalikova-Cimburova, Marketa; Kratka, Karolina; Stransky, Jaroslav; Putova, Ivana; Cieslarova, Blanka; Horak, Jiri

2012-01-01

311

Comprehensive characterization of HNPCC-related colorectal cancers reveals striking molecular features in families with no germline mismatch repair gene mutations  

Microsoft Academic Search

A considerable fraction of families with HNPCC shows no germline mismatch repair (MMR) gene mutations. We previously detected ‘hidden’ MMR gene defects in 42% of such families, leaving the remaining 58% ‘truly’ mutation negative. Here, we characterized 50 colorectal carcinomas and five adenomas arising in HNPCC families; 24 truly MMR gene mutation negative and 31 MMR gene mutation positive. Among

Wael M Abdel-Rahman; Miina Ollikainen; Reetta Kariola; Heikki J Järvinen; Jukka-Pekka Mecklin; Minna Nyström-Lahti; Sakari Knuutila; Päivi Peltomäki

2005-01-01

312

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.

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

313

Mitochondrial DNA Mutations in Respiratory Complex-I in Never-Smoker Lung Cancer Patients Contribute to Lung Cancer Progression and associated with EGFR gene mutation  

PubMed Central

Mitochondrial DNA (mtDNA) mutations were reported in different cancers. However, the nature and role of mtDNA mutation in never-smoker lung cancer patients including patients with EGFR and KRAS gene mutation are unknown. In the present study, we sequenced entire mitochondrial genome (16.5 kb) in matched normal and tumors obtained from 30 never-smoker and 30 current-smoker lung cancer patients, and determined the mtDNA content. All the patients’ samples were sequenced for KRAS (exon 2) and EGFR (exon 19 and 21) gene mutation. The impact of forced overexpression of a respiratory complex-I gene mutation was evaluated in a lung cancer cell line. We observed significantly higher (P=0.006) mtDNA mutation in the never-smokers compared to the current-smoker lung cancer patients. MtDNA mutation was significantly higher (P=0.026) in the never-smoker Asian compared to the current-smoker Caucasian patients’ population. MtDNA mutation was significantly (P=0.007) associated with EGFR gene mutation in the never-smoker patients. We also observed a significant increase (P=0.037) in mtDNA content among the never-smoker lung cancer patients. The majority of the coding mtDNA mutations targeted respiratory complex-I and forced overexpression of one of these mutations resulted in increased in vitro proliferation, invasion and superoxide production in lung cancer cells. We observed a higher prevalence and new relationship between mtDNA alterations among never-smoker lung cancer patients and EGFR gene mutation. Moreover, a representative mutation produced strong growth effects after forced overexpression in lung cancer cells. Signature mtDNA mutations provide a basis to develop novel biomarkers and therapeutic strategies for never-smoker lung cancer patients.

Dasgupta, Santanu; Soudry, Ethan; Mukhopadhyay, Nitai; Shao, Chunbo; Yee, John; Lam, Stephan; Lam, Wan; Zhang, Wei; Gazdar, Adi F; Fisher, Paul B; Sidransky, David

2011-01-01

314

Cell surface fucosylation does not affect development of colon tumors in mice with germline Smad3 mutation  

PubMed Central

Background/Aims: Neoplasia-related alterations in cell surface ?(1,2)fucosylated glycans have been reported in multiple tumors including colon, pancreas, endometrium, cervix, bladder, lung, and choriocarcinoma. Spontaneous colorectal tumors from mice with a germline null mutation of transforming growth factor-? signaling gene Smad3 (Madh3) were tested for ?(1,2)fucosylated glycan expression. Methods: Ulex Europaeus Agglutinin-I lectin staining, fucosyltransferase gene northern blot analysis, and a cross of mutant mice with Fut2 and Smad3 germline mutations were performed. Results: Spontaneous colorectal tumors from Smad3 (-/-) homozygous null mice were found to express ?(1,2)fucosylated glycans in an abnormal pattern compared to adjacent nonneoplastic colon. Northern blot analysis of ?(1,2)fucosyltransferase genes Fut1 and Fut2 revealed that Fut2, but not Fut1, steady-state mRNA levels were significantly increased in tumors relative to adjacent normal colonic mucosa. Mutant mice with a Fut2-inactivating germline mutation were crossed with Smad3 targeted mice. In Smad3 (-/-)/Fut2 (-/-) double knock-out mice, UEA-I lectin staining was eliminated from colon and colon tumors, however, the number and size of tumors present by 24 weeks of age did not vary regardless of the Fut2 genotype. Conclusions: In this model of colorectal cancer, cell surface ?(1,2)fucosylation does not affect development of colon tumors.

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

2006-01-01

315

A common mutation site in the beta-galactosidase gene originates in Puerto Rico.  

PubMed

Several mutation sites have been found in the beta-galactosidase gene of patients with GM1 gangliosidosis. In a previous report we found a common point mutation site in American patients with GM1 gangliosidosis resulting in a 208Arg --> Cys amino acid substitution. From the patients' family history, we suggested that this mutation may have come to South and North America via Puerto Rico. Four new patients with infantile GM1 gangliosidosis have been analyzed with allele-specific hybridization. Two siblings from Puerto Rico of Spanish ancestry are homozygous for this mutation. Another patient also from Puerto Rico is heterozygous for this allele, and another black patient does not have this mutation. These results support our initial hypothesis that this mutation has probably arisen in Puerto Rico. PMID:8652017

Chiu, N C; Qian, W H; Shanske, A L; Brooks, S S; Boustany, R M

1996-01-01

316

Exome Sequencing Reveals Cubilin Mutation as a Single-Gene Cause of Proteinuria  

PubMed Central

In two siblings of consanguineous parents with intermittent nephrotic-range proteinuria, we identified a homozygous deleterious frameshift mutation in the gene CUBN, which encodes cubulin, using exome capture and massively parallel re-sequencing. The mutation segregated with affected members of this family and was absent from 92 healthy individuals, thereby identifying a recessive mutation in CUBN as the single-gene cause of proteinuria in this sibship. Cubulin mutations cause a hereditary form of megaloblastic anemia secondary to vitamin B12 deficiency, and proteinuria occurs in 50% of cases since cubilin is coreceptor for both the intestinal vitamin B12-intrinsic factor complex and the tubular reabsorption of protein in the proximal tubule. In summary, we report successful use of exome capture and massively parallel re-sequencing to identify a rare, single-gene cause of nephropathy.

Ovunc, Bugsu; Otto, Edgar A.; Vega-Warner, Virginia; Saisawat, Pawaree; Ashraf, Shazia; Ramaswami, Gokul; Fathy, Hanan M.; Schoeb, Dominik; Chernin, Gil; Lyons, Robert H.; Yilmaz, Engin

2011-01-01

317

Generation of a monkey with MECP2 mutations by TALEN-based gene targeting.  

PubMed

Gene editing in model organisms has provided critical insights into brain development and diseases. Here, we report the generation of a cynomolgus monkey (Macaca fascicularis) carrying MECP2 mutations using transcription activator-like effector nucleases (TALENs)-mediated gene targeting. After injecting TALENs mRNA into monkey zygotes achieved by in vitro fertilization and embryo transplantation into surrogate monkeys, we obtained one male newborn monkey with an MECP2 deletion caused by frameshifting mutation in various tissues. The monkey carrying the MECP2 mutation failed to survive after birth, due to either the toxicity of TALENs or the critical requirement of MECP2 for neural development. The level of MeCP2 protein was essentially depleted in the monkey's brain. This study demonstrates the feasibility of introducing genetic mutations in non-human primates by site-specific gene-editing methods. PMID:24838303

Liu, Zhen; Zhou, Xue; Zhu, Ying; Chen, Zhi-Fang; Yu, Bin; Wang, Yan; Zhang, Chen-Chen; Nie, Yan-Hong; Sang, Xiao; Cai, Yi-Jun; Zhang, Yue-Fang; Zhang, Chen; Zhou, Wen-Hao; Sun, Qiang; Qiu, Zilong

2014-06-01

318

No evidence for oncogenic mutations in the adrenocorticotropin receptor gene in human adrenocortical neoplasms  

SciTech Connect

The mechanism(s) of tumorigenesis for the majority of adrenocortical neoplasms remain unknown. G-Protein-coupled receptors were recently proposed as candidate protooncogenes. That activating mutations of this class of receptors might be important for tumor induction or progression of endocrine neoplasms was strengthened by the recent identification of such mutations in hyperfunctioning thyroid adenomas. To examine whether the ACTH receptor (ACTH-R) gene could be an oncogene in human adrenocortical tumors, we amplified by the polymerase chain reaction and directly sequenced the entire exon of the ACTH-R gene in 25 adrenocortical tumors (17 adenomas and 8 carcinomas) and 2 adrenocortical cancer cell lines. We found no missense point mutations or even silent polymorphisms in any of the tumors and cell lines studied. We conclude that activating mutations of the ACTH-R gene do not represent a frequent mechanism of human adrenocortical tumorigenesis. 15 refs., 2 tabs.

Latronico, A.C.; Reincke, M.; Mendonca, B.B. [National Inst. of Child Health and Human Development, Bethesda, MD (United States)] [and others] [National Inst. of Child Health and Human Development, Bethesda, MD (United States); and others

1995-03-01

319

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.

2013-01-01

320

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

321

Absence of c-Ki-ras gene mutation in malignant and premalignant Barrett's oesophagus  

PubMed Central

Aims—To establish the prevalence of c-Ki-ras gene mutations in codons 12 and 13 in 28 surgically resected Barrett's adenocarcinomas and 18 associated preneoplastic lesions in Barrett's oesophagus. Methods—Mutations were detected using the polymerase chain reaction followed by restriction fragment length polymorphism analysis. Human colon carcinoma cell lines with well characterised mutations in codons 12 and 13 were used as positive controls and to test the sensitivity of the method. Results—c-Ki-ras gene mutations were not detected in any of the 28 specimens of Barrett's adenocarcinoma or in the 18 specimens of Barrett's oesophagus (nine non-dysplastic cases, three cases with low and six with high grade dysplasia). Conclusions—These results suggest that the c-Ki-ras gene is not involved in the development of cancer in Barrett's oesophagus. Images

Lagorce, C; Flejou, J-F; Muzeau, F; Henin, D; Potet, F

1995-01-01

322

Absence of c-Ki-ras gene mutation in malignant and premalignant Barrett's oesophagus.  

PubMed

Aims-To establish the prevalence of c-Ki-ras gene mutations in codons 12 and 13 in 28 surgically resected Barrett's adenocarcinomas and 18 associated preneoplastic lesions in Barrett's oesophagus.Methods-Mutations were detected using the polymerase chain reaction followed by restriction fragment length polymorphism analysis. Human colon carcinoma cell lines with well characterised mutations in codons 12 and 13 were used as positive controls and to test the sensitivity of the method.Results-c-Ki-ras gene mutations were not detected in any of the 28 specimens of Barrett's adenocarcinoma or in the 18 specimens of Barrett's oesophagus (nine non-dysplastic cases, three cases with low and six with high grade dysplasia).Conclusions-These results suggest that the c-Ki-ras gene is not involved in the development of cancer in Barrett's oesophagus. PMID:16696006

Lagorce, C; Fléjou, J F; Muzeau, F; Hénin, D; Potet, F

1995-08-01

323

Mutations in the EXT1 and EXT2 genes in hereditary multiple exostoses.  

PubMed Central

Hereditary multiple exostoses (EXT; MIM 133700) is an autosomal dominant bone disorder characterized by the presence of multiple benign cartilage-capped tumors (exostoses). Besides suffering complications caused by the pressure of these exostoses on the surrounding tissues, EXT patients are at an increased risk for malignant chondrosarcoma, which may develop from an exostosis. EXT is genetically heterogeneous, and three loci have been identified so far: EXT1, on chromosome 8q23-q24; EXT2, on 11p11-p12; and EXT3, on the short arm of chromosome 19. The EXT1 and EXT2 genes were cloned recently, and they were shown to be homologous. We have now analyzed the EXT1 and EXT2 genes, in 26 EXT families originating from nine countries, to identify the underlying disease-causing mutation. Of the 26 families, 10 families had an EXT1 mutation, and 10 had an EXT2 mutation. Twelve of these mutations have never been described before. In addition, we have reviewed all EXT1 and EXT2 mutations reported so far, to determine the nature, frequency, and distribution of mutations that cause EXT. From this analysis, we conclude that mutations in either the EXT1 or the EXT2 gene are responsible for the majority of EXT cases. Most of the mutations in EXT1 and EXT2 cause premature termination of the EXT proteins, whereas missense mutations are rare. The development is thus mainly due to loss of function of the EXT genes, consistent with the hypothesis that the EXT genes have a tumor- suppressor function.

Wuyts, W; Van Hul, W; De Boulle, K; Hendrickx, J; Bakker, E; Vanhoenacker, F; Mollica, F; Ludecke, H J; Sayli, B S; Pazzaglia, U E; Mortier, G; Hamel, B; Conrad, E U; Matsushita, M; Raskind, W H; Willems, P J

1998-01-01

324

Novel mutations in the calreticulin gene core promoter and coding sequence in schizoaffective disorder.  

PubMed

We have recently reported the first case of mutation in the core promoter sequence of the human calreticulin gene in a family case of schizoaffective disorder. Remarkably, this gene coincides with a region of suggested linkage at 19p13.2, identified in a whole genome scan [Hamshere et al. (2005); Arch Gen Psychiatry 62;1081-1088]. The identified mutation was located at the conserved position -48 from the transcription start site, and was shown to be of functional effect, resulting in the aberrant expression of the gene. Following screening of the gene in 60 independent cases of schizoaffective disorder, we report novel germ-line mutations at positions -205 C > T and the conserved exon 5 (c: 682 C > T, pro228ser) in two unrelated cases of schizoaffective disorder. These mutations were disease-specific, and as for the -48 G > C mutation, neither was detected in a control population of 370 individuals, indicating a contribution of 3.17% in this sample series. To our knowledge, this is the first instance of disease-specific mutations in schizoaffective disorder, which warrants systematic screening of the regulatory and coding regions of the calreticulin gene in this disorder. PMID:19760677

Nabi, M Olad; Mirabzadeh, A; Feizzadeh, G; Khorshid, H R Khorram; Karimlou, M; Yeganeh, M Zarif; Asgharian, A M; Najmabadi, H; Ohadi, M

2010-03-01

325

Dominant lethal mutations in the plasma membrane H(+)-ATPase gene of Saccharomyces cerevisiae.  

PubMed

The plasma membrane H(+)-ATPase of Saccharomyces cerevisiae is an essential protein that is required to establish cellular membrane potential and maintain a normal internal pH. An Asp-378 to Asn substitution at the residue phosphorylated during catalysis is dominant lethal when the pma1-D378N mutation is expressed along with a wild-type plasma membrane H(+)-ATPase (PMA1) gene. Several mutations in the first two putative transmembrane domains are also dominant lethal. However, these dominant lethal mutants often appear to be innocuous, because they are frequently lost by gene conversion to the wild-type sequence during the process of introducing the mutant sequence and subsequently removing the wild-type gene. Loss of the mutation by gene conversion does not occur while introducing recessive lethal mutations. Cells carrying the wild-type PMA1 gene on the chromosome and a dominant lethal mutation under the control of a GAL1 promoter on a centromere-containing plasmid exhibit a galactose-dependent lethality. Indirect immunofluorescence staining using anti-Pma1 antibodies shows that induction of dominant lethal PMA1 mutations leads to the accumulation of a number of intensely staining cytoplasmic structures that are not coincident with the nucleus and its immediately surrounding endoplasmic reticulum. These structures also accumulate the endoplasmic reticulum protein Kar2. Expression of the dominant lethal protein also prevents transport of the wild-type ATPase to the plasma membrane. PMID:7937988

Harris, S L; Na, S; Zhu, X; Seto-Young, D; Perlin, D S; Teem, J H; Haber, J E

1994-10-25

326

Mutations and Polymorphisms in GUSB Gene in Mucopolysaccharidosis VII (Sly Syndrome)  

PubMed Central

Mucopolysaccharidosis VII (MPS VII; Sly syndrome) is an autosomal recessive disorder caused by a deficiency of ?-glucuronidase (GUS, EC 3.2.1.31; GUSB). GUS is required to degrade glycosaminoglycans (GAGs), including heparan sulfate (HS), dermatan sulfate (DS), and chondroitin-4,6-sulfate (CS). Accumulation of undegraded GAGs in lysosomes of affected tissues leads to mental retardation, short stature, hepatosplenomegaly, bone dysplasia, and hydrops fetalis. We summarize information on the 49 unique, disease-causing mutations determined so far in the GUS gene, including nine novel mutations (eight missense and one splice-site). This heterogeneity in GUS gene mutations contributes to the extensive clinical variability among patients with MPS VII. One pseudodeficiency allele, one polymorphism causing an amino acid change, and one silent variant in the coding region are also described. Among the 103 analyzed mutant alleles, missense mutations accounted for 78.6%; nonsense mutations, 12.6%; deletions, 5.8%; and splice-site mutations, 2.9%. Transitional mutations at CpG dinucleotides made up 40.8% of all the described mutations. The five most frequent mutations (accounting for 44/103 alleles) were exonic point mutations, p.L176F, p.R357X, p.P408S, p.P415L, and p.A619 V. Genotype/phenotype correlation was attempted by correlating the effects of certain missense mutations or enzyme activity and stability within phenotypes. These were in turn correlated with the location of the mutation in the tertiary structure of GUS. A total of seven murine, one feline, and one canine model of MPS VII have been characterized for phenotype and genotype.

Tomatsu, Shunji; Montano, Adriana M.; Dung, Vu Chi; Grubb, Jeffrey H.; Sly, William S.

2011-01-01

327

Nucleophosmin gene mutations are predictors of favorable prognosis in acute myelogenous leukemia with a normal karyotype.  

PubMed

Nucleophosmin (NPM1) exon-12 gene mutations are the hallmark of a large acute myelogenous leukemia (AML) subgroup with normal karyotype, but their prognostic value in this AML subset has not yet been determined. We screened 401 AML patients with normal karyotype treated within the German AML Cooperative Group Protocol 99 (AMLCG99) study for NPM1 mutations. Results were related with partial tandem duplications within the MLL gene (MLL-PTD), Fms-like tyrosine kinase 3-length mutations (FLT3-LM), the tyrosine kinase domain of FLT3 (FLT3-TKD), NRAS, KIT, and CEBPA mutations and with clinical characteristics and outcome. NPM1 mutations were detected in 212 (52.9%) of 401 patients. Fourteen mutations, including 8 new variants, were identified. NPM1-mutated cases associated frequently with FLT3 mutations but rarely with other mutations. The NPM1-mutated group had a higher complete remission (CR) rate (70.5% vs 54.7%, P = .003), a trend to a longer overall survival (OS; median 1012 vs 549 days, P = .076), and significantly longer event-free survival (EFS; median 428 vs 336 days; P = .012). The favorable impact of NPM1 mutations on OS and EFS clearly emerged in the large group (264 [66.8%] of 395 cases) of normal-karyotype AML without FLT3-LM. This positive effect was lost in the presence of a concomitant FLT3-LM, since survival of the NPM1+/FLT3-LM+ double positive was similar to NPM1-/FLT3-LM+ cases. In conclusion, this study demonstrates that NPM1+/FLT3-LM- mutations are an independent predictor for a favorable outcome in AML with normal karyotype. PMID:16076867

Schnittger, Susanne; Schoch, Claudia; Kern, Wolfgang; Mecucci, Cristina; Tschulik, Claudia; Martelli, Massimo F; Haferlach, Torsten; Hiddemann, Wolfgang; Falini, Brunangelo

2005-12-01

328

A novel mutation in the gene for canine acid ?-galactosidase that causes GM1-gangliosidosis in Shiba dogs  

Microsoft Academic Search

A homozygous recessive mutation, causing GM1-gangliosidosis in Shiba dogs, was identified as a deletion of C nucleotide 1668 in the gene for canine acid ß-galactosidase, which was a novel mutation in canine GM1-gangliosidosis.

O. Yamato; D. Endoh; A. Kobayashi; Y. Masuoka; M. Yonemura; A. Hatakeyama; H. Satoh; M. Tajima; M. Yamasaki; Y. Maede

2002-01-01

329

Disruption Mutations of ADA2b and GCN5 Transcriptional Adaptor Genes Dramatically Affect Arabidopsis Growth, Development, and Gene Expression  

Microsoft Academic Search

We previously identified Arabidopsis genes homologous with the yeast ADA2 and GCN5 genes that encode components of the ADA and SAGA histone acetyltransferase complexes. In this report, we explore the biological roles of the Arabidopsis ADA2b and GCN5 genes. T-DNA insertion mutations in ADA2b and GCN5 were found to have pleiotropic effects on plant growth and development, including dwarf size,

Konstantinos E. Vlachonasios; Michael F. Thomashow; Steven J. Triezenberg

2003-01-01

330

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

331

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.

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

332

Identification of APC gene mutations in Italian adenomatous polyposis coli patients by PCR-SSCP analysis  

SciTech Connect

The APC gene is a putative human tumor-suppressor gene responsible for adenomatous polyposis coli (APC), an inherited, autosomal dominant predisposition to colon cancer. It is also implicated in the development of sporadic colorectal tumors. The characterization of APC gene mutations in APC patients is clinically important because DNA-based tests can be applied for presymptomatic diagnosis once a specific mutation has been identified in a family. Moreover, the identification of the spectrum of APC gene mutations in patients is of great interest in the study of the biological properties of the APC gene product. The authors analyzed the entire coding region of the APC gene by the PCR-single-strand conformation polymorphism method in 42 unrelated Italian APC patients. Mutations were found in 12 cases. These consist of small (5-14 bp) base-pair deletions leading to frameshifts; all are localized within exon 15. Two of these deletions, a 5-bp deletion at position 3183-3187 and a 5-bp deletion at position 3926-3930, are present in 3/42 and 7/42 cases of the series, respectively, indicating the presence of mutational hot spots at these two sites. 17 refs., 2 figs., 1 tab.

Varesco, L.; Gismondi, V.; James, R.; Casarino, L.; De Benedetti, L.; Bafico, A.; Allegretti, A.; Aste, H. (Istituto Nazionale per la Ricerca sul Cancro, Genoa (Italy)); Robertson, M.; Groden, J.; White, R. (Univ. of Utah, Salt Lake City (United States)); Grammatico, P.; De Sanctis, S.; Sciarra, A.; Del Porto, G. (Universita di Roma, Rome (Italy)); Bertario, L.; Sala, P.; Rossetti, C.; Illeni, M.T. (Istituto Nazionale Tumori, Milan (Italy)); Sassatelli, R.; Ponz de Leon, M. (Universita di Modena (Italy)); Biasco, G. (Universita di Bologna (Italy)); Ferrara, G.B. (Istituto Nazionale per la Ricerca sul Cancro, Genoa (Italy) Universita di Napoli, Naples (Italy))

1993-02-01

333

Mutation survey of candidate genes in 40 Chinese patients with congenital ectopia lentis  

PubMed Central

Purpose To identify the spectrum and frequency of five candidate genes in Chinese patients with congenital ectopia lentis (EL). Methods Forty consecutive and unrelated congenital probands with EL were collected and underwent ocular, skeletal, and cardiovascular examinations. Sanger sequencing was used to analyze all of the coding and adjacent regions of five candidate genes: FBN1, ADAMTS10, ADAMTSL4, TGFBR2, and CBS. Mutation analysis was performed to evaluate the pathogenic variants and to identify the cause of congenital EL. Results The FBN1 gene screen revealed 25 pathogenic variants in 34 of the 40 families with congenital EL, including three novel (c.1955G>T, c.2222delA, and c.4381T>C) and 22 known mutations. The ADAMTSL10 gene screen revealed a compound heterozygous variant (c.1586G>A and c.2485T>A) in a family with Weill-Marchesani syndrome (WMS). In the remaining five probands, no pathogenic variant was detected in any of the five screened genes. Conclusions In this study, we identified three novel and 22 known mutations in FBN1 in 34 of 40 EL families. The results expand the mutation spectrum of the FBN1 gene and suggest that FBN1 mutations may be the major cause of congenital EL in Chinese patients.

Li, Jie; Jia, Xiaoyun; Li, Shiqiang; Fang, Shaohua

2014-01-01

334

Ichthyosis bullosa of Siemens is caused by mutations in the keratin 2e gene.  

PubMed

Ichthyosis bullosa of Siemens is a blistering disorder with autosomal dominant inheritance. The disease resembles bullous congenital ichthyosiform erythroderma but is less severe. Keratins K1 and K10 have been implicated in bullous congenital ichthyosiform erythroderma. Linkage analysis pointed to the involvement of a keratin type II gene (12q11-13) in ichthyosis bullosa of Siemens. Mutations in the highly conserved regions of K1, a member of the type II gene cluster, were excluded. The gene coding for keratin 2e is also located in the type II gene cluster and the expression of the gene coincides with the occurrence of epidermolytic hyperkeratosis. Sequence analysis revealed the presence of mutations in the K2e gene in patients with ichthyosis bullosa of Siemens. Three different mutations were detected, one in the 1A domain and two in the 2B domain of the rod. Furthermore, histologic and ultrastructural examination of skin biopsies indicated that ichthyosis exfoliativa is identical to ichthyosis bullosa of Siemens. This was confirmed by the results of the molecular analysis. In the family diagnosed as ichthyosis exfoliativa, a mutation was detected that was identical to the mutation found in one of the families with ichthyosis bullosa of Siemens. PMID:8077693

Kremer, H; Zeeuwen, P; McLean, W H; Mariman, E C; Lane, E B; van de Kerkhof, C M; Ropers, H H; Steijlen, P M

1994-09-01

335

Increased rate of base substitution in a hamster mutator strain obtained during serial selection for gene amplification.  

PubMed Central

The pattern of mutations produced by a mutator gene (obtained during serial selection for amplification of the dihydrofolate reductase [dhfr] locus) shows a pronounced shift from that found in wild-type cells. The rate of certain types of base substitutions (particularly transitions) is dramatically increased, while gene rearrangements constitute a lower proportion of mutations. These data suggest a lower fidelity of the replication process in the mutator strain.

Caligo, M A; Armstrong, W; Rossiter, B J; Meuth, M

1990-01-01

336

A Second Common Mutation in the Methylenetetrahydrofolate Reductase Gene: An Additional Risk Factor for Neural-Tube Defects?  

Microsoft Academic Search

Summary Recently, we showed that homozygosity for the common 677(CrT) mutation in the methylenetetrahydrofolate reductase (MTHFR) gene, causing thermolability of the enzyme, is a risk factor for neural-tube defects (NTDs). We now report on another mutation in the same gene, the 1298(ArC) mutation, which changes a glutamate into an alanine residue. This mutation destroys anMboII recognition site and has an

Fons Gabreëls; Erik M. B. Stevens; Jan A. M. Smeitink; Frans J. M. Trijbels; Tom K. A. B. Eskes; Lambert P. van den Heuvel; Henk J. Blom

1998-01-01

337

Multiple Intestinal Neoplasia Caused by a Mutation in the Murine Homolog of the APC Gene  

Microsoft Academic Search

Germ-line mutations of the APC gene are responsible for familial adenomatous polyposis (FAP), an autosomal dominantly inherited disease in humans. Patients with FAP develop multiple benign colorectal tumors. Recently, a mouse lineage that exhibits an autosomal dominantly inherited predisposition to multiple intestinal neoplasia (Min) was described. Linkage analysis showed that the murine homolog of the APC gene (mApc) was tightly

Li-Kuo Su; Kenneth W. Kinzler; Bert Vogelstein; Antonette C. Preisinger; Amy Rapaich Moser; Cindy Luongo; Karen A. Gould; William F. Dove

1992-01-01

338

Lens epithelial changes and mutated gene expression in patients with myotonic dystrophy  

Microsoft Academic Search

AIMSExamination of the expression of the mutated allele of myotonic dystrophy protein kinase gene and lens epithelial cell changes in patients with myotonic dystrophy.METHODSSix eyes from three patients with myotonic dystrophy underwent cataract surgery. The lens epithelium was photographed to examine the morphological changes. mRNAs were extracted to determine myotonic dystrophy protein kinase gene expression in the lens epithelium and

Toshiaki Abe; Masami Sato; Junko Kuboki; Tetsuya Kano; Makoto Tamai

1999-01-01

339

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

Microsoft Academic Search

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 phenyl-ketonuria (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

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

1991-01-01

340

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

341

A Homozygous Missense Mutation of the Sodium\\/Iodide Symporter Gene Causing Iodide Transport Defect  

Microsoft Academic Search

Iodide transport defect is a disorder characterized by an inability of the thyroid to maintain an iodide concentration difference between the plasma and the thyroid. The recent cloning of the sodium\\/iodide symporter (NIS) gene enabled us to characterize the NIS gene in this disorder. We identified a homozygous missense mutation of A3 Ca t nucleotide 11060 in NIS complementary DNA

AKIRA MATSUDA; SHINJI KOSUGI

1997-01-01

342

Gene-targeting studies of mammalian behavior: is it the mutation or the background genotype?  

Microsoft Academic Search

Gene targeting to create null mutations in mice is a powerful new tool in biology which will allow the molecular dissection of complex phenotypes such as mammalian brain function, and learning and memory. However, the attempt to interpret the phenotypical changes which arise in null-mutant mice is subject to several caveats. For example, the ability to disrupt a single gene

Robert Gerlai

1996-01-01

343

Mutational screening of ARX gene in Brazilian males with mental retardation of unknown etiology  

Microsoft Academic Search

ARX gene mutations have been known as important causes of developmental and neurological disorders and are responsible for a large spectrum of abnormal phenotypes, includeing syndromic as well as nonsyndromic forms of mental retardation. We have screened the entire coding and flanking intronic sequences of ARX gene in 143 mentally impaired males in order to investigate the contribution of ARX

Raquel de Souza Gestinari-Duarte; Cíntia Barros Santos-Rebouças; Márcia Mattos Gonçalves Pimentel

2006-01-01

344

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

Microsoft Academic Search

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

Ivaylo Stoilov; Michael W. Kilpatrick; Petros Tsipouras

1995-01-01

345

Predicting a clinical\\/biochemical phenotype for PKU\\/MHP patients with PAH gene mutations  

Microsoft Academic Search

Phenylketonuria (PKU) and mild hyperphenylalaninemia (MHP) are allelic disorders caused by mutations in the gene encoding\\u000a phenylalanine hydroxylase (PAH). In this study, a total of 218 independent PAH chromosomes (109 unrelated patients with PKU residing in Lithuania) were investigated. All 13 exons of the PAH gene of all PKU probands were scanned for DNA alterations by denaturing gradient gel electrophoresis

J. Kasnauskien?; L. Cimbalistien?; V. Ku?inskas

2008-01-01

346

Mutations in the cardiac troponin I gene associated with hypertrophic cardiomyopathy.  

PubMed

Hypertrophic cardiomyopathy (HCM), the most common cause of sudden death in the young, is an autosomal dominant disease characterized by ventricular hypertrophy accompanied by myofibrillar disarrays. Linkage studies and candidate-gene approaches have demonstrated that about half of the patients have mutations in one of six disease genes: cardiac beta-myosin heavy chain (c beta MHC), cardiac troponin T (cTnT), alpha-tropomyosin (alpha TM), cardiac myosin binding protein C (cMBPC), ventricular myosin essential light chain (vMLC1) and ventricular myosin regulatory light chain (vMLC2) genes. Other disease genes remain unknown. Because all the known disease genes encode major contractile elements in cardiac muscle, we have systematically characterized the cardiac sarcomere genes, including cardiac troponin I (cTnI), cardiac actin (cACT) and cardiac troponin C (cTnC) in 184 unrelated patients with HCM and found mutations in the cTnI gene in several patients. Family studies showed that an Arg145Gly mutation was linked to HCM and a Lys206Gln mutation had occurred de novo, thus strongly suggesting that cTnI is the seventh HCM gene. PMID:9241277

Kimura, A; Harada, H; Park, J E; Nishi, H; Satoh, M; Takahashi, M; Hiroi, S; Sasaoka, T; Ohbuchi, N; Nakamura, T; Koyanagi, T; Hwang, T H; Choo, J A; Chung, K S; Hasegawa, A; Nagai, R; Okazaki, O; Nakamura, H; Matsuzaki, M; Sakamoto, T; Toshima, H; Koga, Y; Imaizumi, T; Sasazuki, T

1997-08-01

347

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

348

Chromosomal changes in colorectal adenomas: relationship to gene mutations and potential for clinical utility.  

PubMed

Although the occurrence of both chromosomal aberrations and specific gene mutations in colorectal tumorigenesis is firmly established, the relationship between these different forms of genetic abnormality remains poorly understood. We have previously demonstrated, in colorectal adenocarcinomas, that mutations of APC, KRAS, and TP53 are each specifically associated with certain chromosomal aberrations. Using comparative genomic hybridization and mutational analysis of APC, KRAS, and TP53 to evaluate 78 colorectal adenomas, we have shown that several of the significant relationships between gene mutations and chromosomal abnormalities reported in colorectal adenocarcinomas also exist at the adenomatous stage. KRAS mutation correlated with 12p gain (P < 0.001) and TP53 mutation with both 20q gain and 18q loss (P = 0.03 for both). In addition, we have identified two chromosomal aberrations, gain of 13q and loss of 11q, that correlate with the presence of synchronous adenomas (P = 0.049 and P = 0.03, respectively) and several chromosomal changes (20p+, 20q+, 17p-, and 18q-) that are related to the onset of high-grade dysplasia. These data strengthen our previous contention that the co-occurrence of specific gene mutations and chromosomal changes is not random and significant relationships do exist. Our findings also raise the possibility that certain chromosomal aberrations may act as important clinical biomarkers. PMID:16235243

Leslie, Amy; Stewart, Arlene; Baty, David U; Mechan, Dorothy; McGreavey, Louise; Smith, Gillian; Wolf, C Roland; Sales, Mark; Pratt, Norman R; Steele, Robert J C; Carey, Francis A

2006-02-01

349

Mutations in the MESP2 Gene Cause Spondylothoracic Dysostosis/Jarcho-Levin Syndrome  

PubMed Central

Spondylothoracic dysostosis (STD), also known as Jarcho-Levin syndrome (JLS), is an autosomal-recessive disorder characterized by abnormal vertebral segmentation and defects affecting spine formation, with complete bilateral fusion of the ribs at the costovertebral junction producing a “crab-like” configuration of the thorax. The shortened spine and trunk can severely affect respiratory function during early childhood. The condition is prevalent in the Puerto Rican population, although it is a panethnic disorder. By sequencing a set of candidate genes involved in mouse segmentation, we identified a recessive E103X nonsense mutation in the mesoderm posterior 2 homolog (MESP2) gene in a patient, of Puerto Rican origin and from the Boston area, who had been diagnosed with STD/JLS. We then analyzed 12 Puerto Rican families with STD probands for the MESP2 E103X mutation. Ten patients were homozygous for the E103X mutation, three patients were compound heterozygous for a second nonsense mutation, E230X, or a missense mutation, L125V, which affects a conserved leucine residue within the bHLH region. Thus, all affected probands harbored the E103X mutation. Our findings suggest a founder-effect mutation in the MESP2 gene as a major cause of the classical Puerto Rican form of STD/JLS.

Cornier, Alberto S.; Staehling-Hampton, Karen; Delventhal, Kym M.; Saga, Yumiko; Caubet, Jean-Francois; Sasaki, Nobuo; Ellard, Sian; Young, Elizabeth; Ramirez, Norman; Carlo, Simon E.; Torres, Jose; Emans, John B.; Turnpenny, Peter D.; Pourquie, Olivier

2008-01-01

350

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.

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

351

Mutation of the PAX6 gene in patients with autosomal dominant keratitis.  

PubMed Central

Autosomal dominant keratitis (ADK) is an eye disorder chiefly characterized by corneal opacification and vascularization and by foveal hypoplasia. Aniridia (shown recently to result from mutations in the PAX6 gene) has overlapping clinical findings and a similar pattern of inheritance with ADK. On the basis of these similarities, we used a candidate-gene approach to investigate whether mutations in the PAX6 gene also result in ADK. Significant linkage was found between two polymorphic loci in the PAX6 region and ADK in a family with 15 affected members in four generations (peak LOD score = 4.45; theta = .00 with D11S914), consistent with PAX6 mutations being responsible for ADK. SSCP analysis and direct sequencing revealed a mutation in the PAX6 exon 11 splice-acceptor site. The predicted consequent incorrect splicing results in truncation of the PAX6 proline-serine-threonine activation domain. The SeyNeu mouse results from a mutation in the Pax-6 exon 10 splice-donor site that produces a PAX6 protein truncated from the same point as occurs in our family with ADK. Therefore, the SeyNeu mouse is an excellent animal model of ADK. The finding that mutations in PAX6 underlie ADK, along with a recent report that mutations in PAX6 also underlie Peters anomaly, implicates PAX6 broadly in human anterior segment malformations. Images Figure 2 Figure 1 Figure 3

Mirzayans, F; Pearce, W G; MacDonald, I M; Walter, M A

1995-01-01

352

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

PubMed Central

Genetic lesions affecting a number of kinases and other elements within the epidermal growth factor receptor (EGFR) signaling pathway have been implicated in the pathogenesis of human non–small-cell lung cancer (NSCLC). We performed mutational profiling of a large cohort of lung adenocarcinomas to uncover other potential somatic mutations in genes of this pathway that could contribute to lung tumorigenesis. We have identified in 2 of 207 primary lung tumors a somatic activating mutation in exon 2 of MEK1 (i.e., mitogen-activated protein kinase kinase 1 or MAP2K1) that substitutes asparagine for lysine at amino acid 57 (K57N) in the nonkinase portion of the kinase. Neither of these two tumors harbored known mutations in other genes encoding components of the EGFR signaling pathway (i.e., EGFR, HER2, KRAS, PIK3CA, and BRAF). Expression of mutant, but not wild-type, MEK1 leads to constitutive activity of extracellular signal–regulated kinase (ERK)-1/2 in human 293T cells and to growth factor–independent proliferation of murine Ba/F3 cells. A selective MEK inhibitor, AZD6244, inhibits mutant-induced ERK activity in 293T cells and growth of mutant-bearing Ba/F3 cells. We also screened 85 NSCLC cell lines for MEK1 exon 2 mutations; one line (NCI-H1437) harbors a Q56P substitution, a known transformation-competent allele of MEK1 originally identified in rat fibroblasts, and is sensitive to treatment with AZD6244. MEK1 mutants have not previously been reported in lung cancer and may provide a target for effective therapy in a small subset of patients with lung adenocarcinoma.

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

2008-01-01

353

Characterization of AQP-2 gene mutation (R254Q) in a family with dominant nephrogenic DI.  

PubMed

We identified the AQP-2 gene mutation (R254Q) in a family with dominant NDI. The patient studied here has NDI with partial response to the anti-diuretic effect of AVP and dDAVP. Hereditary NDI seems to have the uniform clinical manifestations, but this might only reflect the information on screened patients with clear clinical presentations. It may be that a milder form of NDI has been overlooked due to a lack of genetic identification. Gene mutation analysis should be considered even in patients with mild NDI symptoms. Fortunately, both V2R and AQP2 genes are small and can be easily analyzed. PMID:23409988

Shida, Yoko; Matsuoka, Hisafumi; Chiga, Motoko; Uchida, Shinichi; Sasaki, Sei; Sugihara, Shigetaka

2013-02-01

354

Missense mutations of the WASP gene cause intermittent X-linked thrombocytopenia.  

PubMed

Mutations of the WASP gene have been previously shown to be responsible for classical Wiskott-Aldrich syndrome, isolated X-linked thrombocytopenia, and severe, congenital X-linked neutropenia. We report herewith 2 families in which affected males had a history of intermittent thrombocytopenia with consistently reduced platelet volume, in the absence of other major clinical features, and carried missense mutations of the WASP gene that allowed substantial protein expression. This observation broadens the spectrum of clinical phenotypes associated with WASP gene defects, and it indicates the need for molecular analysis in males with reduced platelet volume, regardless of the platelet number. PMID:11877312

Notarangelo, Lucia D; Mazza, Cinzia; Giliani, Silvia; D'Aria, Chiara; Gandellini, Francesca; Ravelli, Chiara; Locatelli, Maria Grazia; Nelson, David L; Ochs, Hans D; Notarangelo, Luigi D

2002-03-15

355

[Hereditary sensorineural hearing impairment and macrothrombocytopenia: a rare MYH9 gene mutation].  

PubMed

We report on a rare case of an exon 16 mutation of the MYH9 gene in a 23-year-old woman. This gene encodes for non-muscular myosin IIA, which acts as a cytoskeletal contractile protein in diverse cell types. This disorder led to sensorineural hearing loss, macrothrombocytopenia, and proteinuria. MYH9 gene mutation can lead to diverse organ manifestation like pre-senile cataract or renal failure which are progressive in course. Due to the current lack of causal treatment, diagnostic steps, advice for follow-up examinations and symptomatic therapy approaches are presented. PMID:23223919

Böttcher, A; Knecht, R; Busch, C-J; Lörincz, B B; Dalchow, C V

2013-02-01

356

Muscle Protein Alterations in LGMD2I Patients With Different Mutations in the Fukutin-related Protein Gene  

PubMed Central

Fukutin-related protein (FKRP) is a protein involved in the glycosylation of cell surface molecules. Pathogenic mutations in the FKRP gene cause both the more severe congenital muscular dystrophy Type 1C and the milder Limb-Girdle Type 2I form (LGMD2I). Here we report muscle histological alterations and the analysis of 11 muscle proteins: dystrophin, four sarcoglycans, calpain 3, dysferlin, telethonin, collagen VI, ?-DG, and ?2-laminin, in muscle biopsies from 13 unrelated LGMD2I patients with 10 different FKRP mutations. In all, a typical dystrophic pattern was observed. In eight patients, a high frequency of rimmed vacuoles was also found. A variable degree of ?2-laminin deficiency was detected in 12 patients through immunofluorescence analysis, and 10 patients presented ?-DG deficiency on sarcolemmal membranes. Additionally, through Western blot analysis, deficiency of calpain 3 and dystrophin bands was found in four and two patients, respectively. All the remaining proteins showed a similar pattern to normal controls. These results suggest that, in our population of LGMD2I patients, different mutations in the FKRP gene are associated with several secondary muscle protein reductions, and the deficiencies of ?2-laminin and ?-DG on sections are prevalent, independently of mutation type or clinical severity. (J Histochem Cytochem 56:995–1001, 2008)

Yamamoto, Lydia U.; Velloso, Fernando J.; Lima, Bruno L.; Fogaca, Luciana L.Q.; de Paula, Flavia; Vieira, Natassia M.; Zatz, Mayana; Vainzof, Mariz

2008-01-01

357

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

358

Novel VANGL1 Gene Mutations in 144 Slovakian, Romanian and German Patients with Neural Tube Defects  

PubMed Central

Neural tube defects (NTDs) are a group of congenital malformations of the central nervous system occurring at an average rate of 1 per 1,000 human pregnancies worldwide. Numerous genetic and environmental factors are discussed to be relevant in their etiology. In mice, mutants in >200 genes including the planar cell polarity (PCP) pathway are known to cause NTDs, and recently, heterozygous mutations in the human VANGL1 gene have been described in a small subset of patients with NTDs. We performed a VANGL1 mutation analysis in 144 unrelated individuals with NTDs from Slovakia, Romania and Germany and identified 3 heterozygous missense mutations: c.613G>A (p.Gly205Arg) with an open spina bifida (lumbosacral meningomyelocele), c.557G>A (p.Arg186His) with a closed spina bifida (tethered cord and spinal lipoma) and c.518G>A (p.Arg173His) with an unknown NTD. The c.613G>A mutation was also found in a healthy sibling. None of the mutations were described previously. Findings support that heterozygous VANGL1 mutations represent hypomorphs or conditional mutants predisposing to NTDs and occur at a frequency of approximately 2.1% of open and closed spinal NTDs. The mutations (p.Arg173His, p.Arg186His, p.Gly205Arg) modified conserved regions of the VANGL1 protein and shared similarities with previously described mutants, providing further evidence for the presence of mutational hot spots in these patients.

Bartsch, O.; Kirmes, I.; Thiede, A.; Lechno, S.; Gocan, H.; Florian, I.S.; Haaf, T.; Zechner, U.; Sabova, L.; Horn, F.

2012-01-01

359

Identification of a novel FBN1 gene mutation in a large Pakistani family with Marfan syndrome  

PubMed Central

Purpose To describe a novel mutation in the fibrillin-1 (FBN1) gene in a large Pakistani family with autosomal dominant Marfan syndrome (MFS). Methods Blood samples were collected of 11 family members affected with Marfan syndrome, and DNA was isolated by phenol-extraction. The coding exons of FBN1 were analyzed by polymerase chain reaction (PCR) and direct sequencing. One hundred-thirty controls were screened for a mutation in the FBN1 gene that was identified in this family by restriction fragment length polymorphism (RFLP) analysis. Results A novel heterozygous missense mutation c.2368T>A; p.Cys790Ser was observed in exon 19. This mutation substitutes a highly conserved cysteine residue by serine in a calcium binding epidermal growth factor-like domain (cbEGF) of FBN1. This mutation was present in all affected members and absent from unaffected individuals of the family in addition to 130 healthy Pakistani controls. Interestingly all affected family members presented with ectopia lentis, myopia and glaucoma, but lacked the cardinal cardiovascular features of MFS. Conclusions This is a first report of a mutation in FBN1 in MFS patients of Pakistani origin. The identification of a FBN1 mutation in this family confirms the diagnosis of MFS patients and expands the worldwide spectrum of FBN1 mutations.

Micheal, Shazia; Khan, Muhammad Imran; Akhtar, Farah; Weiss, Marjan M.; Islam, Farah; Ali, Mehmood; Qamar, Raheel; Maugeri, Alessandra

2012-01-01

360

Mutations in the fibrinogen aalpha gene account for the majority of cases of congenital afibrinogenemia.  

PubMed

Congenital afibrinogenemia is a rare, autosomal, recessive disorder characterized by the complete absence of detectable fibrinogen. We previously identified the first causative mutations in a nonconsanguineous Swiss family; the 4 affected persons have homozygous deletions of approximately 11 kb of the fibrinogen alpha (FGA) gene. Haplotype data implied that these deletions occurred on distinct ancestral chromosomes, suggesting that this region may be susceptible to deletion by a common mechanism. We subsequently showed that all the deletions were identical to the base pair and probably resulted from a nonhomologous recombination mediated by 7-bp direct repeats. In this study, we have collected data on 13 additional unrelated patients to identify the causative mutations and to determine the prevalence of the 11-kb deletion. A common recurrent mutation, at the donor splice site of FGA intron 4 (IVS4 + 1 G > T), accounted for 14 of the 26 (54%) alleles. One patient was heterozygous for the previously identified deletion. Three more frameshift mutations, 2 nonsense mutations, and a second splice site mutation were also identified. Consequently, 86% of afibrinogenemia alleles analyzed to date have truncating mutations of FGA, though mutations in all 3 fibrinogen genes, FGG, FGA, and FGB, might be predicted to cause congenital afibrinogenemia. PMID:10891444

Neerman-Arbez, M; de Moerloose, P; Bridel, C; Honsberger, A; Schönbörner, A; Rossier, C; Peerlinck, K; Claeyssens, S; Di Michele, D; d'Oiron, R; Dreyfus, M; Laubriat-Bianchin, M; Dieval, J; Antonarakis, S E; Morris, M A

2000-07-01

361

HFE gene mutation, chronic liver disease, and iron overload In Turkey.  

PubMed

We aimed to determine the relationships between iron overload and HFE gene mutation in chronic liver disease in Turkey. One hundred thirteen chronic liver disease patients and 138 healthy controls were evaluated regarding their clinical, biochemical, and genetic parameters. Each group was divided into two subgroups according to transferrin saturation (TS) (45% and >45%). HFE gene mutation was analyzed by the PCR-RFLP method. C282Y homozygote, heterozygote, and wild-type mutation rates were 1.7%, 0%, and 98.3% in patients and 0%, 1.4%, and 98.6% in controls, respectively. H63D homozygote, heterozygote, and wild-type mutation rates were 1.8%, 24.7%, and 73.5% in patients and 1.4%, 24%, and 74.6% in controls, respectively. Mutation rates were not statistically different in patients with high and normal TS. Iron overload was positively correlated with biochemical activity and Child-Pugh score (P < 0.05). In multivariate analysis, H63D homozygotic mutation was an independent factor for the development of hepatocellular carcinoma (P = 0.004). We conclude that C282Y mutation is very rare in Turkey. Iron overload is not related to H63D mutation but is positively correlated with biochemical activity and Child-Pugh score in chronic liver diseases. PMID:17410459

Yönal, Oya; Hatirnaz, Ozden; Akyüz, Filiz; Ozbek, Ugur; Demir, Kadir; Kaymakoglu, Sabahattin; Okten, Atilla; Mungan, Zeynel

2007-11-01

362

Tay-Sachs disease-causing mutations and neutral polymorphisms in the Hex A gene.  

PubMed

Tay-Sachs disease is an autosomal recessive disorder affecting the central nervous system. The disorder results from mutations in the gene encoding the alpha-subunit of beta-hexosaminidase A, a lysosomal enzyme composed of alpha and beta polypeptides. Seventy-eight mutations in the Hex A gene have been described and include 65 single base substitutions, one large and 10 small deletions, and two small insertions. Because these mutations cripple the catalytic activity of beta-hexosaminidase to varying degrees, Tay-Sachs disease displays clinical heterogeneity. Forty-five of the single base substitutions cause missense mutations; 39 of these are disease causing, three are benign but cause a change in phenotype, and three are neutral polymorphisms. Six nonsense mutations and 14 splice site lesions result from single base substitutions, and all but one of the splice site lesions cause a severe form of Tay-Sachs disease. Eight frameshift mutations arise from six deletion- and two insertion-type lesions. One of these insertions, consisting of four bases within exon 11, is found in 80% of the carriers of Tay-Sachs disease from the Ashkenazi Jewish population, an ethnic group that has a 10-fold higher gene frequency for a severe form of the disorder than the general population. A very large deletion, 7.5 kilobases, including all of exon 1 and portions of DNA upstream and downstream from that exon, is the major mutation found in Tay-Sachs disease carriers from the French Canadian population, a geographic isolate displaying an elevated carrier frequency. Most of the other mutations are confined to single pedigrees. Identification of these mutations has permitted more accurate carrier information, prenatal diagnosis, and disease prognosis. In conjunction with a precise tertiary structure of the enzyme, these mutations could be used to gain insight into the structure-function relationships of the lysosomal enzyme. PMID:9090523

Myerowitz, R

1997-01-01

363

HAEdb: a novel interactive, locus-specific mutation database for the C1 inhibitor gene.  

PubMed

Hereditary angioneurotic edema (HAE) is an autosomal dominant disorder characterized by episodic local subcutaneous and submucosal edema and is caused by the deficiency of the activated C1 esterase inhibitor protein (C1-INH or C1INH; approved gene symbol SERPING1). Published C1-INH mutations are represented in large universal databases (e.g., OMIM, HGMD), but these databases update their data rather infrequently, they are not interactive, and they do not allow searches according to different criteria. The HAEdb, a C1-INH gene mutation database (http://hae.biomembrane.hu) was created to contribute to the following expectations: 1) help the comprehensive collection of information on genetic alterations of the C1-INH gene; 2) create a database in which data can be searched and compared according to several flexible criteria; and 3) provide additional help in new mutation identification. The website uses MySQL, an open-source, multithreaded, relational database management system. The user-friendly graphical interface was written in the PHP web programming language. The website consists of two main parts, the freely browsable search function, and the password-protected data deposition function. Mutations of the C1-INH gene are divided in two parts: gross mutations involving DNA fragments >1 kb, and micro mutations encompassing all non-gross mutations. Several attributes (e.g., affected exon, molecular consequence, family history) are collected for each mutation in a standardized form. This database may facilitate future comprehensive analyses of C1-INH mutations and also provide regular help for molecular diagnostic testing of HAE patients in different centers. PMID:15580551

Kalmár, Lajos; Hegedüs, Tamás; Farkas, Henriette; Nagy, Melinda; Tordai, Attila

2005-01-01

364

A mutation in the MATP gene causes the cream coat colour in the horse.  

PubMed

In horses, basic colours such as bay or chestnut may be partially diluted to buckskin and palomino, or extremely diluted to cream, a nearly white colour with pink skin and blue eyes. This dilution is expected to be controlled by one gene and we used both candidate gene and positional cloning strategies to identify the "cream mutation". A horse panel including reference colours was established and typed for different markers within or in the neighbourhood of two candidate genes. Our data suggest that the causal mutation, a G to A transition, is localised in exon 2 of the MATP gene leading to an aspartic acid to asparagine substitution in the encoded protein. This conserved mutation was also described in mice and humans, but not in medaka. PMID:12605854

Mariat, Denis; Taourit, Sead; Guérin, Gérard

2003-01-01

365

Mutations in the Human Ca2+-Sensing-Receptor Gene That Cause Familial Hypocalciuric Hypercalcemia  

PubMed Central

We report five novel mutations in the human Ca2+-sensing-receptor gene that cause familial hypocalciuric hypercalcemia (FHH) or neonatal severe hyperparathyroidism. Each gene defect is a missense mutation (228Arg?Gln, 139Thr?Met, 144Gly?Glu, 63Arg?Met, and 67Arg?Cys) that encodes a nonconservative amino acid alteration. These mutations are each predicted to be in the Ca2+-sensing receptor's large extracellular domain. In three families with FHH linked to the Ca2+-sensing-receptor gene on chromosome 3 and in unrelated individuals probands with FHH, mutations were not detected in protein-coding sequences. On the basis of these data and previous analyses, we suggest that there are a wide range of mutations that cause FHH. Mutations that perturb the structure and function of the extracellular or transmembrane domains of the receptor and those that affect noncoding sequences of the Ca2+-sensing-receptor gene can cause FHH. ImagesFigure 2

Chou, Yah-Huei Wu; Pollak, Martin R.; Brandi, Maria L.; Toss, Goran; Arnqvist, H.; Atkinson, A. Brew; Papapoulos, Socrates E.; Marx, Stephen; Brown, Edward M.; Seidman, J. G.; Seidman, Christine E.

1995-01-01

366

Mutation analysis of the NSD1 gene in a group of 59 patients with congenital overgrowth.  

PubMed

Sotos syndrome is characterized by pre- and post-natal overgrowth, typical craniofacial features, advanced bone age, and developmental delay. Some degree of phenotypic overlap exists with other overgrowth syndromes, in particular with Weaver syndrome. Sotos syndrome is caused by haploinsufficiency of the NSD1 (nuclear receptor SET domain containing gene 1) gene. Microdeletions involving the gene are the major cause of the syndrome in Japanese patients, whereas intragenic mutations are more frequent in non-Japanese patients. NSD1 aberrations have also been described in some patients diagnosed as Weaver syndrome. Some authors have suggested a certain degree of genotype-phenotype correlation, with a milder degree of overgrowth, a more severe mental retardation, and a higher frequency of congenital anomalies in microdeleted patients. Data on larger series are needed to confirm this suggestion. We report here on microdeletion and mutation analysis of NSD1 in 59 patients with congenital overgrowth. Fourteen novel mutations, two previously described and one microdeletion were identified. All patients with a NSD1 mutation had been clinically classified as "classical Sotos," although their phenotype analysis demonstrated that some major criteria, such as overgrowth and macrocephaly, could be absent. All patients with confirmed mutations shared the typical Sotos facial gestalt. A high frequency of congenital heart defects was present in patients with intragenic mutations, supporting the relevance of the NSD1 gene in the pathogenesis of this particular defect. PMID:15742365

Cecconi, M; Forzano, F; Milani, D; Cavani, S; Baldo, C; Selicorni, A; Pantaleoni, C; Silengo, M; Ferrero, G B; Scarano, G; Della Monica, M; Fischetto, R; Grammatico, P; Majore, S; Zampino, G; Memo, L; Cordisco, E Lucci; Neri, G; Pierluigi, M; Bricarelli, F Dagna; Grasso, M; Faravelli, Francesca

2005-04-30

367

Investigation of the Mitochondrial ATPase 6/8 and tRNALys Genes Mutations in Autism  

PubMed Central

Objective: Autism results from developmental factors that affect many or all functional brain systems. Brain is one of tissues which are crucially in need of adenosine triphosphate (ATP). Autism is noticeably affected by mitochondrial dysfunction which impairs energy metabolism. Considering mutations within ATPase 6, ATPase 8 and tRNALys genes, associated with different neural diseases, and the main role of ATPase 6/8 in energy generation, we decided to investigate mutations on these mtDNA-encoded genes to reveal their roles in autism pathogenesis. Materials and Methods: In this experimental study, mutation analysis for the mentioned genes were performed in a cohort of 24 unrelated patients with idiopathic autism by employing amplicon sequencing of mtDNA fragments. Results: In this study, 12 patients (50%) showed point mutations that represent a significant correlation between autism and mtDNA variations. Most of the identified substitutions (55.55%) were observed on MT-ATP6, altering some conserved amino acids to other ones which could potentially affect ATPase 6 function. Mutations causing amino acid replacement denote involvement of mtDNA genes, especially ATPase 6 in autism pathogenesis. Conclusion: MtDNA mutations in relation with autism could be remarkable to realize an understandable mechanism of pathogenesis in order to achieve therapeutic solutions.

Piryaei, Fahimeh; Houshmand, Massoud; Aryani, Omid; Dadgar, Sepideh; Soheili, Zahra-Soheila

2012-01-01

368

Mutation Survey of Known LCA Genes and Loci in the Saudi Arabian Population  

PubMed Central

Purpose The purpose of this study was to perform a comprehensive survey of all known Leber congenital amaurosis (LCA) genes and loci in a collection of 37 consanguineous LCA families from Saudi Arabia. Methods Direct PCR and sequencing were used to screen 13 known LCA genes (GUCY2D, CRX, RPE65, TULP1, AIPL1, CRB1, RPGRIP1, LRAT, RDH12, IMPDH1, CEP290, RD3, LCA5). In addition, families without mutations identified were further screened with STR markers around these 13 known LCA genes and two loci. Results Disease-causing mutations were identified in nine of the 37 families: five in TULP1, two in CRB1, one in RPE65, and one in GUCY2D. Mutations in known genes only accounted for 24% of the Saudi families—much less than what has been observed in the European population (65%). Phenotype-genotype analysis was carried out to investigate the LCA disease penetrance for all families whose mutations identified. All identified mutations were found to segregate perfectly with the disease phenotype. On the other hand, severity of the disease varies for different patients carrying the same mutation and even within the same family. Furthermore, based on homozygosity mapping with both STR and SNP markers, one family is likely to map to the LCA3 locus. Conclusions These results underscore the importance of studying LCA disease families from different ethnic backgrounds to identify additional novel LCA disease genes. Furthermore, perfect segregation between mutation and disease indicates that LCA is fully penetrant. However, phenotypic variations among patients carrying the same mutation suggest that at least some of the variations in the clinical phenotype is due to modification from the genetic background, environment, or other factors.

Li, Yumei; Wang, Hui; Peng, Jianlan; Gibbs, Richard A.; Lewis, Richard Alan; Lupski, James R.; Mardon, Graeme; Chen, Rui

2009-01-01

369

Mutational Analysis of Hedgehog Signaling Pathway Genes in Human Malignant Mesothelioma  

PubMed Central

Background The Hedgehog (HH) signaling pathway is critical for embryonic development and adult homeostasis. Recent studies have identified regulatory roles for this pathway in certain cancers with mutations in the HH pathway genes. The extent to which mutations of the HH pathway genes are involved in the pathogenesis of malignant mesothelioma (MMe) is unknown. Methodology/Principal Findings Real-time PCR analysis of HH pathway genes PTCH1, GLI1 and GLI2 were performed on 7 human MMe cell lines. Exon sequencing of 13 HH pathway genes was also performed in cell lines and human MMe tumors. In silico programs were used to predict the likelihood that an amino-acid substitution would have a functional effect. GLI1, GLI2 and PTCH1 were highly expressed in MMe cells, indicative of active HH signaling. PTCH1, SMO and SUFU mutations were found in 2 of 11 MMe cell lines examined. A non-synonymous missense SUFU mutation (p.T411M) was identified in LO68 cells. In silico characterization of the SUFU mutant suggested that the p.T411M mutation might alter protein function. However, we were unable to demonstrate any functional effect of this mutation on Gli activity. Deletion of exons of the PTCH1 gene was found in JU77 cells, resulting in loss of one of two extracellular loops implicated in HH ligand binding and the intracellular C-terminal domain. A 3-bp insertion (69_70insCTG) in SMO, predicting an additional leucine residue in the signal peptide segment of SMO protein was also identified in LO68 cells and a MMe tumour. Conclusions/Significance We identified the first novel mutations in PTCH1, SUFU and SMO associated with MMe. Although HH pathway mutations are relatively rare in MMe, these data suggest a possible role for dysfunctional HH pathway in the pathogenesis of a subgroup of MMe and help rationalize the exploration of HH pathway inhibitors for MMe therapy.

Lim, Chuan Bian; Prele, Cecilia M.; Cheah, Hui Min; Cheng, Yuen Yee; Klebe, Sonja; Reid, Glen; Watkins, D. Neil; Baltic, Svetlana; Thompson, Philip J.; Mutsaers, Steven E.

2013-01-01

370

Novel CHST6 gene mutations in 2 unrelated cases of macular corneal dystrophy  

PubMed Central

Purpose To investigate possible mutations in the carbohydrate sulfotransferase 6 (CHST6) gene of two unrelated cases of macular corneal dystrophy (MCD) and to report atypical stromal deposits in one of them. Methods Corneal tissues were stained with anti-sulfated keratan sulfate (KS), anti-transforming growth factor beta 1-induced protein (TGFBIp), thioflavin-T, alcian blue, and Masson trichrome. Sequencing was performed to identify potential mutations in the CHST6 gene and the fourth and twelfth exons of the TGFBI gene. Results Alcian blue staining revealed the presence of multiple subepithelial and intra-stromal mucopolysaccharide deposits, confirming the diagnosis of MCD in both cases. Immunofluorescence staining in case 1 revealed the presence of sulfated KS only in the keratocytes and select endothelial cells, consistent with MCD type IA. Preferential expression of sulfated KS was observed in keratocytes and extracellular stromal matrix in case 2, consistent with MCD type II. Atypical sub-epithelial and superficial stromal deposits were observed in case 1, which stained positively with alcian blue, eosin, Masson trichrome and thioflavin-T indicating the presence of hyaline and amyloid materials. CHST6 gene sequencing revealed two heterozygous mutations in case 1 (a p.Arg211Gln and a novel mutation of p.Arg177Gly) and a novel homozygous mutation of p.Pro186Arg in case 2. No mutations were found in exons 4 or 12 of the TGFBI gene in case 1. Conclusions Secondary hyalinosis and amyloidosis occur in a case of MCD type IA with a novel p.Arg177Gly mutation in CHST6. A novel p.Pro186Arg mutation in CHST6 is associated with MCD type II in an African American.

Patel, Dhara A.; Harocopos, George J.; Chang, Shu-Hong; Vora, Smita C.; Lubniewski, Anthony J.; Huang, Andrew J.W.

2010-01-01

371

Phenotype of cytochrome P4501B1 gene (CYP1B1) mutations in Japanese patients with primary congenital glaucoma  

PubMed Central

Aim: To investigate the phenotypes associated with cytochrome P4501B1 gene (CYP1B1) mutations in Japanese patients with primary congenital glaucoma (PCG). Methods: 66 Japanese patients with PCG were screened for sequence mutations in the CYP1B1 gene using single strand conformation polymorphism analysis followed by automated DNA sequencing. 11 cases had a CYP1B1 mutation in both alleles (the mutation group) and 21 cases did not have a CYP1B1 mutation (the “no mutation” group). The clinical features, such as age of onset, sex, intraocular pressure, and Descemet‘s membrane rupture, of the two groups were compared. Results: The clinical symptoms and signs did not differ for the two groups. The mean age at onset was 1.7 months in the mutation group and 3.1 months in the no mutation group, and the male:female ratio was 6:5 in the mutation group and 19:2 in the no mutation group. Both of these differences were statistically significant. Conclusions: In clinically diagnosed cases of PCG, a subgroup shows a CYP1B1 gene mutation. Age at onset was earlier in PCG patients with CYP1B1 mutations than in patients without mutations. Women were more prevalent among patients with mutations than those without mutations.

Ohtake, Y; Tanino, T; Suzuki, Y; Miyata, H; Taomoto, M; Azuma, N; Tanihara, H; Araie, M; Mashima, Y

2003-01-01

372

Mutation in the CYP21B gene (Ile-172----Asn) causes steroid 21-hydroxylase deficiency.  

PubMed Central

Steroid 21-hydroxylase deficiency is the most common cause of congenital adrenal hyperplasia. It results from a deficiency in a specific cytochrome P450, P450c21 (P450XXIA). The gene encoding this protein (CYP21B) and a closely linked pseudogene (CYP21A) are located in the HLA complex on chromosome 6p. Many mutant alleles are associated with deletions of CYP21B; we report the cloning and characterization of a nondeleted mutant CYP21B gene. This mutant gene is expressed on transfection into mouse Y1 adrenal cells, producing mRNA levels similar to those seen after transfection of the normal CYP21B gene. In codon 172 of the mutant gene, the normal codon ATC, encoding isoleucine, has been changed to AAC, encoding asparagine. This mutation is normally present in the CYP21A pseudogene, so that it may have been transferred to the mutant CYP21B gene by gene conversion. Hybridization of oligonucleotide probes corresponding to this and two other mutations normally present in CYP21A demonstrated that 4 out of 20 patients carried the codon 172 mutation; in one of these patients, the mutation was present as part of a larger gene conversion involving at least exons 3-6. Gene conversion may be a frequent cause of 21-hydroxylase deficiency alleles due to the presence of six chi-like sequences (GCTGGGG) in the CYP21 genes and the close proximity of the CYP21A pseudogene, which has several potentially deleterious mutations. Images

Amor, M; Parker, K L; Globerman, H; New, M I; White, P C

1988-01-01

373

VarWalker: Personalized Mutation Network Analysis of Putative Cancer Genes from Next-Generation Sequencing Data  

PubMed Central

A major challenge in interpreting the large volume of mutation data identified by next-generation sequencing (NGS) is to distinguish driver mutations from neutral passenger mutations to facilitate the identification of targetable genes and new drugs. Current approaches are primarily based on mutation frequencies of single-genes, which lack the power to detect infrequently mutated driver genes and ignore functional interconnection and regulation among cancer genes. We propose a novel mutation network method, VarWalker, to prioritize driver genes in large scale cancer mutation data. VarWalker fits generalized additive models for each sample based on sample-specific mutation profiles and builds on the joint frequency of both mutation genes and their close interactors. These interactors are selected and optimized using the Random Walk with Restart algorithm in a protein-protein interaction network. We applied the method in >300 tumor genomes in two large-scale NGS benchmark datasets: 183 lung adenocarcinoma samples and 121 melanoma samples. In each cancer, we derived a consensus mutation subnetwork containing significantly enriched consensus cancer genes and cancer-related functional pathways. These cancer-specific mutation networks were then validated using independent datasets for each cancer. Importantly, VarWalker prioritizes well-known, infrequently mutated genes, which are shown to interact with highly recurrently mutated genes yet have been ignored by conventional single-gene-based approaches. Utilizing VarWalker, we demonstrated that network-assisted approaches can be effectively adapted to facilitate the detection of cancer driver genes in NGS data.

Jia, Peilin; Zhao, Zhongming

2014-01-01

374

Hepatitis B Virus Gene Mutations in Liver Diseases: A Report from New Delhi  

Microsoft Academic Search

ObjectivesThe study was designed to characterize the surface, core promoter, precore\\/core region sequences for the presence of mutations in hepatitis B virus (HBV) associated with different liver diseases.Methods567 HBV associated patients with different liver diseases were enrolled in this study. All samples were analyzed for HBV surface, core promoter, precore\\/core region mutations and genotypes using PCR and direct sequencing.ResultsHBV genotype

Abdul Malik; Deepak Kumar Singhal; Abdulmajeed Albanyan; Syed Akhtar Husain; P. Kar

2012-01-01

375

A frequent factor XII gene mutation in Hageman trait  

Microsoft Academic Search

An additionalTaqI restriction site was mapped in intron 2 of the factor XII gene. The site was found only in subjects with total or partial factor XII deficiency and thus represents the true gene lesion or a very tightly linked restriction fragment length polymorphism. The altered gene identified by this marker is present in four (three heterozygotes and one homozygote)

F. Bernardi; G. Marchetti; S. Volinia; P. Patracchini; A. Casonato; A. Girolami; F. Conconi

1988-01-01

376

Mixed lineage kinase 3 gene mutations in mismatch repair deficient gastrointestinal tumours.  

PubMed

Mixed lineage kinase 3 (MLK3) is a serine/threonine kinase, regulating MAPkinase signalling, in which cancer-associated mutations have never been reported. In this study, 174 primary gastrointestinal cancers (48 hereditary and 126 sporadic forms) and 7 colorectal cancer cell lines were screened for MLK3 mutations. MLK3 mutations were significantly associated with MSI phenotype in primary tumours (P = 0.0005), occurring in 21% of the MSI carcinomas. Most MLK3 somatic mutations identified were of the missense type (62.5%) and more than 80% of them affected evolutionarily conserved residues. A predictive 3D model points to the functional relevance of MLK3 missense mutations, which cluster in the kinase domain. Further, the model shows that most of the altered residues in the kinase domain probably affect MLK3 scaffold properties, instead of its kinase activity. MLK3 missense mutations showed transforming capacity in vitro and cells expressing the mutant gene were able to develop locally invasive tumours, when subcutaneously injected in nude mice. Interestingly, in primary tumours, MLK3 mutations occurred in KRAS and/or BRAF wild-type carcinomas, although not being mutually exclusive genetic events. In conclusion, we have demonstrated for the first time the presence of MLK3 mutations in cancer and its association to mismatch repair deficiency. Further, we demonstrated that MLK3 missense mutations found in MSI gastrointestinal carcinomas are functionally relevant. PMID:19955118

Velho, Sérgia; Oliveira, Carla; Paredes, Joana; Sousa, Sónia; Leite, Marina; Matos, Paulo; Milanezi, Fernanda; Ribeiro, Ana Sofia; Mendes, Nuno; Licastro, Danilo; Karhu, Auli; Oliveira, Maria José; Ligtenberg, Marjolijn; Hamelin, Richard; Carneiro, Fátima; Lindblom, Annika; Peltomaki, Paivi; Castedo, Sérgio; Schwartz, Simó; Jordan, Peter; Aaltonen, Lauri A; Hofstra, Robert M W; Suriano, Gianpaolo; Stupka, Elia; Fialho, Arsenio M; Seruca, Raquel

2010-02-15

377

The original shaker-with-syndactylism mutation (sy) is a contiguous gene deletion syndrome.  

PubMed

Tests for allelism among mice with four different mutant alleles at the shaker-with-syndactylism locus on mouse Chromosome (Chr) 18 provide evidence that the original radiation-induced mutation, sy, is a deletion including at least two genes associated with distinct phenotypes. Mice homozygous for sy have syndactylous feet and other skeletal malformations, are deaf, and exhibit abnormal behavior characteristic of vestibular dysfunction. Two less severe spontaneous mutations, shown to be allelic with sy, cause syndactylism when homozygous (hence named fused phalanges, sy(fp) and sy(fp-2J)), but do not affect hearing and behavior. Here we describe a third spontaneous mutation allelic with sy that does not affect foot morphology (hence named no syndactylism, sy(ns)), but that does cause deafness and balance defects when homozygous. Complementation test results indicate that sy(fp) and sy(fp-2J) are alleles of the same gene, but that sy(ns) is an allele of a different gene. The original sy mutation, therefore, includes both of the genes defined by these three spontaneous mutations. Typing of DNA markers in sy/sy mice revealed a deletion of approximately 1 cM in the sy region of Chr 18, including D18Mit52, D18Mit124, D18Mit181, and D18Mit205. The genetic relationships described here will aid in positional cloning efforts to identify the genes responsible for the disparate phenotypes associated with the sy locus. PMID:9799839

Johnson, K R; Cook, S A; Zheng, Q Y

1998-11-01

378

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

379

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

380

A mutation in gene CNGA3 is associated with day blindness in sheep.  

PubMed

Lambs with congenital day blindness show diminished cone function, which is characteristic of achromatopsia, a congenital disorder described in humans and dogs. To identify gene(s) associated with sheep day blindness, we investigated mutations in the CNGA3, CNGB3, and GNAT2 genes which have been associated with achromatopsia. Sequencing the coding regions of those genes from four affected and eight non-affected lambs showed that all affected lambs were homozygous for a mutation in the CNGA3 gene that changes amino acid R236 to a stop codon. By PCR-RFLP-based testing, homozygosity for the stop codon mutation was detected in another 19 affected lambs. Non-affected individuals (n=386) were non-carriers or heterozygous for the mutation. While a selection program has been launched to eradicate the day blindness mutation from Improved Awassi flocks, a breeding nucleus of day-blind sheep has been established to serve as animal models for studying human achromatopsia. PMID:19874885

Reicher, Shay; Seroussi, Eyal; Gootwine, Elisha

2010-02-01

381

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.

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

2014-01-01

382

The ?uvrB mutations in the Ames strains of Salmonella span 15 to 119 genes  

Microsoft Academic Search

The ?uvrB mutations present in strains of Salmonellaenterica Typhimurium used commonly in the Salmonella (Ames) mutagenicity assay were isolated independently for at least five different his mutants. These deletions all involved the galactose operon, biotin operon, nucleotide-excision-repair uvrB gene, and chlorate-resistance genes. Beyond this, the size of the deletions and the number and type of genes deleted have remained unknown

Steffen Porwollik; Rita Mei-Yi Wong; Simon H. Sims; Roel M. Schaaper; David M. DeMarini; Michael McClelland

2001-01-01

383

Somatic Mutations of the MEN1 Tumor Suppressor Gene in Sporadic Gastrinomas and Insulinomas  

Microsoft Academic Search

Gastrinomasand insulinomasare frequent in multipleendocrineneo plasia type 1 (MEN1). The MEN1 tumor suppressor gene was recently identified. To elucidate the etiological role of the MEN1 gene in sporadic enteropancreatic endocrine tumorigenesis, we analyzed tumors (28 gas trinomas and 12 insulinomas) from 40 patIents for MEN1 gene mutations andallelicdeletions. Onecopyof theMENIgenewasfoundto be deleted in 25 of 27 (93%) sporadic gastrinomasand in

Zhengping Zhuang; Svetlana Pack; Steve Huang; Thu A. Pham; Chaoyu Wang; Sunita K. Agarwal; Larisa V. Debelenko; Siradanahalli C. Guru; Pachiappan Manickam; Shodimu-Emmanuel Olufemi; Fang Yu; Christina Heppner; Judy S. Crabtree

384

Heterozygous mutation in 5’-untranslated region of sepiapterin reductase gene (SPR) in a patient with dopa-responsive dystonia  

Microsoft Academic Search

The search for mutations in genes coding for components of the biopterin pathway other than GTPCH1 revealed a mutation in the gene coding for sepiapterin reductase ( SPR) in 1 of 95 patients with GCH1-negative dopa-responsive dystonia (DRD). The mutation detected in SPR is a G?A transition at position –13 of the untranslated region of the gene. This resulted in

Daniela Steinberger; Nenad Blau; Dimitri Goriuonov; Juliane Bitsch; Michael Zuker; Sibylla Hummel; Ulrich Müller

2004-01-01

385

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

386

Imperfect Genes, Fisherian Mutation and the Evolution of Sex  

PubMed Central

In this paper we present a mathematical model of mutation and selection that allows for the coexistence of multiple alleles at a locus with very small selective differences between alleles. The model also allows for the determination of fitness by multiple loci. Models of this sort are biologically plausible. However, some previous attempts to construct similar models have assumed that all mutations produce a decrease in fitness, and this has led to a tendency for the average fitness of population members to decline when population numbers are finite. In our model we incorporate some of the ideas of R. A. FISHER, so that both deleterious and beneficial mutations are possible. As a result, average fitness tends to approach a stationary distribution. We have used computer simulation methods to apply the Fisherian mutation model to the problem of the evolution of sex and recombination. The results suggest that sex and recombination can provide very large benefits in terms of average fitness. The results also suggest that obligately sexual species will win ecological competitions with species that produce a substantial fraction of their offspring asexually, so long as the number of sites under selection within the genomes of the competing species is not too small and the population sizes are not too large. Our model focuses on fertility selection in an hermaphroditic plant. However, the results are likely to generalize to a wide variety of other situations as well.

Peck, J. R.; Barreau, G.; Heath, S. C.

1997-01-01

387

A Nonsense Mutation in the Acid ?-Glucosidase Gene Causes Pompe Disease in Finnish and Swedish Lapphunds  

PubMed Central

Pompe disease is a recessively inherited and often fatal disorder caused by the deficiency of acid ?-glucosidase, an enzyme encoded by the GAA gene and needed to break down glycogen in lysosomes. This glycogen storage disease type II has been reported also in Swedish Lapphund dogs. Here we describe the genetic defect in canine Pompe disease and show that three related breeds from Scandinavia carry the same mutation. The affected dogs are homozygous for the GAA c.2237G>A mutation leading to a premature stop codon at amino acid position 746. The corresponding mutation has previously been reported in humans and causes infantile Pompe disease in combination with a second fully deleterious mutation. The affected dogs from both the Finnish as well as the Swedish breed mimic infantile-onset Pompe disease genetically, but also clinico-pathologically. Therefore this canine model provides a valuable tool for preclinical studies aimed at the development of gene therapy in Pompe disease.

Seppala, Eija H.; Reuser, Arnold J. J.; Lohi, Hannes

2013-01-01

388

Novel Mutations in the CLCN1 Gene of Myotonia Congenita: 2 Case Reports  

PubMed Central

Introduction: Myotonia Congenita is an inherited myotonia that is due to a mutation in the skeletal muscle chloride channel CLCN1. These mutations lead to reduced sarcolemmal chloride conductance, causing delayed muscle relaxation that is evident as clinical and electrical myotonia. Methods: We report the clinical presentations of two individuals with Myotonia Congenita (MC). Results: Patient 1 has been diagnosed with the recessive form of MC, known as the Becker variant, and Patient 2 has been diagnosed with the dominant form of MC, known as the Thomsen variant. In both patients, the diagnosis was made based on the clinical presentation, EMG and CLCN1 gene sequencing. Patient 1 also had a muscle biopsy. Conclusions: Genetic testing in both patients reveals previously unidentified mutations in the CLCN1 gene specific to Myotonia Congenita. We report the salient clinical features of each patient and discuss the effects and common types of CLCN1 mutations and review the literature.

Lakraj, Amanda Amrita; Miller, Geoffrey; Vortmeyer, Alexander O.; Khokhar, Babar; Nowak, Richard J.; DiCapua, Daniel B.

2013-01-01

389

Mutations in TRPS1 gene in trichorhinophalangeal syndrome type I in Asian patients.  

PubMed

The trichorhinophalangeal syndromes (TRPSs) are rare hereditary diseases with mainly autosomal dominant inheritance. Three different forms sharing similar clinical features with heterogeneous mutations have been identified: type I (TRPS I), type II (TRPS II) and type III (TRPS III). These syndromes have characteristic facial abnormalities such as sparse and slow-growing scalp hair, laterally sparse eyebrows, bulbous pear-shaped nose, elongated and flat philtrum, thin upper lip, and protruding ears. Various skeletal abnormalities are also frequently noted: short stature, shortening of the phalanges and metacarpals, cone-shaped epiphyses and Perthes-like change of the hips.(1-4) The TRPS1 gene was first identified in 2000 and mapped to 8q24.1.(1) More than 50 mutations have been found in the gene to date. We here report mutation analysis of eight patients with the typical phenotype of TRPS I, revealing five novel mutations. PMID:20394624

Chen, L-H; Ning, C-C; Chao, S-C

2010-08-01

390

Mutations in the gene encoding PDGF-B cause brain calcifications in humans and mice.  

PubMed

Calcifications in the basal ganglia are a common incidental finding and are sometimes inherited as an autosomal dominant trait (idiopathic basal ganglia calcification (IBGC)). Recently, mutations in the PDGFRB gene coding for the platelet-derived growth factor receptor ? (PDGF-R?) were linked to IBGC. Here we identify six families of different ancestry with nonsense and missense mutations in the gene encoding PDGF-B, the main ligand for PDGF-R?. We also show that mice carrying hypomorphic Pdgfb alleles develop brain calcifications that show age-related expansion. The occurrence of these calcium depositions depends on the loss of endothelial PDGF-B and correlates with the degree of pericyte and blood-brain barrier deficiency. Thus, our data present a clear link between Pdgfb mutations and brain calcifications in mice, as well as between PDGFB mutations and IBGC in humans. PMID:23913003

Keller, Annika; We