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Recurrent Mutation (recurrent + mutation)
Selected AbstractsMutation screening of the androgen receptor promoter and untranslated regions in prostate cancerTHE PROSTATE, Issue 15 2006Kati K. Waltering Abstract Background Mechanisms, other than gene amplification, leading to overexpression of AR in androgen ablation-resistant prostate cancer remain unknown and could include genetic alterations in the promoter or untranslated regions (UTR) of the AR gene. Materials and Methods DNAs from five prostate cancer cell lines, 19 LuCaP xenografts, 44 clinical tumors, and 36 non-malignant controls were used for screening mutations in the upstream regulatory region, promoter and the 5,- and 3,-UTRs of the AR gene with denaturating high performance liquid chromatography (DHPLC) and sequencing. Results Ten different sequence variations were found in prostate cancer cell lines and xenografts. However, none of them were recurrent or were found in clinical prostate cancer specimens or in normal controls. Conclusions Recurrent mutations in the promoter or UTRs of AR seem to be rare, and thus not likely mechanisms for the increased expression of the gene in the androgen ablation-resistant prostate cancer. Prostate 66: 1585,1591, 2006. © 2006 Wiley-Liss, Inc. [source] ORIGINAL ARTICLE Laboratory science: Molecular analysis in two Tunisian families with combined factor V and factor VIII deficiencyHAEMOPHILIA, Issue 5 2010H. E. ABDALLAH Summary., Combined factor V (FV) and factor VIII (FVIII) deficiency (F5F8D) is a rare autosomal recessive disorder caused by mutations in LMAN1 or MCFD2 genes which encode proteins that form a complex involved in the transport of FV and FVIII from the endoplasmic reticulum to Golgi apparatus. We report two novel mutations in MCFD2 gene and one recurrent mutation in LMAN1 gene that caused combined FV and FVIII deficiency in two unrelated Tunisian Muslim families. For the first family two patients were homozygous for a new missense mutation Asp81His in exon 3 of MCFD2 and heterozygous for a second new missense mutation Val100Asp in the same exon. Replacement respectively of the hydrophilic Asp residue with hydrophobic positively charged His and of the hydrophobic neutral Val residue with the Asp residue most likely disrupts the MCFD2,LMAN1 interaction, thus leading to the disease phenotype. For the second family a reported Arg202X mutation in exon 5 in the LMAN1 gene was identified in the homozygous state. [source] m.6267G>A: a recurrent mutation in the human mitochondrial DNA that reduces cytochrome c oxidase activity and is associated with tumors,HUMAN MUTATION, Issue 6 2006M. Esther Gallardo Abstract Complete sequencing of the mitochondrial genome of 13 cell lines derived from a variety of human cancers revealed nine novel mitochondrial DNA (mtDNA) variations. One of them, m.6267G>A, is a recurrent mutation that introduces the Ala122Thr substitution in the mitochondrially encoded cytochrome c oxidase I (MT-CO1): p.MT-CO1: Ala122Thr (GenBank: NP_536845.1). Biochemical analysis of the original cell lines and the transmitochondrial cybrids generated by transferring mitochondrial DNAs to a common nuclear background, indicate that cytochrome c oxidase (COX) activity, respiration, and growth in galactose are impaired by the m.6267G>A mutation. This mutation, found twice in the cancer cell lines included in this study, has been also encountered in one out of 63 breast cancer samples, one out of 64 colon cancer samples, one out of 260 prostate cancer samples, and in one out of 15 pancreatic cancer cell lines. In all instances the m.6267G>A mutation was associated to different mtDNA haplogroups. These findings, contrast with the extremely low frequency of the m.6267G>A mutation in the normal population (1:2264) and its apparent absence in other pathologies, strongly suggesting that the m.6267G>A missense mutation is a recurrent mutation specifically associated with cancer. Hum Mutat 27(6), 575,582, 2006. © 2006 Wiley-Liss, Inc. [source] A high proportion of founder BRCA1 mutations in Polish breast cancer familiesINTERNATIONAL JOURNAL OF CANCER, Issue 5 2004Bohdan Górski Abstract Three mutations in BRCA1 (5382insC, C61G and 4153delA) are common in Poland and account for the majority of mutations identified to date in Polish breast and breast,ovarian cancer families. It is not known, however, to what extent these 3 founder mutations account for all of the BRCA mutations distributed throughout the country. This question has important implications for health policy and the design of epidemiologic studies. To establish the relative contributions of founder and nonfounder BRCA mutations, we established the entire spectrum of BRCA1 and BRCA2 mutations in a large set of breast,ovarian cancer families with origins in all regions of Poland. We sequenced the entire coding regions of the BRCA1 and BRCA2 genes in 100 Polish families with 3 or more cases of breast cancer and in 100 families with cases of both breast and ovarian cancer. A mutation in BRCA1 or BRCA2 was detected in 66% of breast cancer families and in 63% of breast,ovarian cancer families. Of 129 mutations, 122 (94.6%) were in BRCA1 and 7 (5.4%) were in BRCA2. Of the 122 families with BRCA1 mutations, 119 (97.5%) had a recurrent mutation (i.e., one that was seen in at least 2 families). In particular, 111 families (91.0%) carried one of the 3 common founder mutations. The mutation spectrum was not different between families with and without ovarian cancer. These findings suggest that a rapid and inexpensive assay directed at identifying the 3 common founder mutations will have a sensitivity of 86% compared to a much more costly and labor-intensive full-sequence analysis of both genes. This rapid test will facilitate large-scale national epidemiologic and clinical studies of hereditary breast cancer, potentially including studies of chemoprevention. © 2004 Wiley-Liss, Inc. [source] Assessing the extent of genome-wide intralocus sexual conflict via experimentally enforced gender-limited selectionJOURNAL OF EVOLUTIONARY BIOLOGY, Issue 4 2008E. H. MORROW Abstract Intralocus sexual conflict, which occurs when a trait is selected in opposite directions in the two sexes, is a taxonomically widespread phenomenon. The strongest genetic evidence for a gender load due to intralocus sexual conflict comes from the Drosophila melanogaster laboratory model system, in which a negative genetic correlation between male and female lifetime fitness has been observed. Here, using a D. melanogaster model system, we utilize a novel modification of the ,middle class neighbourhood' design to relax selection in one sex, while maintaining selection in the other. After 26 generations of asymmetrical selection, we observed the expected drop in fitness of the non-selected sex compared to that of the selected sex, consistent with previous studies of intralocus sexual conflict in this species. However, the fitness of the selected sex also dropped compared to the base population. The overall decline in fitness of both the selected and the unselected sex indicates that most new mutations are harmful to both sexes, causing recurrent mutation to build a positive genetic correlation for fitness between the sexes. However, the steeper decay in the fitness of the unselected sex indicates that a substantial number of mutations are gender-limited in expression or sexually antagonistic. Our experiment cannot definitively resolve these two possibilities, but we use recent genomic data and results from previous studies to argue that sexually antagonistic alleles are the more likely explanation. [source] Contrasting genetic structures of two parasitic nematodes, determined on the basis of neutral microsatellite markers and selected anthelmintic resistance markersMOLECULAR ECOLOGY, Issue 24 2009A. SILVESTRE Abstract For the first time, the neutral genetic relatedness of natural populations of Trichostrongylid nematodes was investigated in relation to polymorphism of the ,-tubulin gene, which is selected for anthelminthic treatments. The aim of the study was to assess the contribution of several evolutionary processes: migration and genetic drift by neutral genetic markers and selection by anthelminthic treatments on the presence of resistance alleles at ,-tubulin. We studied two nematode species (Teladorsagia circumcincta and Haemonchus contortus) common in temperate climatic zones; these species are characterized by contrasting life history traits. We studied 10 isolated populations of goat nematode parasites: no infected adult goat had been exchanged after the herds were established. Beta-tubulin polymorphism was similar in these two species. One and two ,-tubulin alleles from T. circumcincta and H. contortus respectively were shared by several populations. Most of the ,-tubulin alleles were ,private' alleles. No recombination between alleles was detected in BZ-resistant alleles from T. circumcincta and H. contortus. The T. circumcincta populations have not diverged much since their isolation (FST <0.08), whereas H. contortus displayed marked local genetic differentiation (FST ranging from 0.08 to 0.18). These findings suggest that there are severe bottlenecks in the H. contortus populations, possibly because of their reduced abundance during unfavourable periods and their high reproductive rate, which allows the species to persist even after severe population reduction. Overall, the data reported contradict the hypothesis of the origin of ,-tubulin resistance alleles in these populations from a single mutational event, but two other hypotheses (recurrent mutation generating new alleles in isolated populations and the introduction of existing alleles) emerge as equally likely. [source] Evidence for the existence of some dissociation in an otherwise strong linkage disequilibrium between mitochondrial and chloroplastic genomes in Cyclobalanopsis glaucaMOLECULAR ECOLOGY, Issue 10 2003T.-P. Lin Abstract Variations in mitochondrial DNA in Cyclobalanopsis glauca (Thunb. ex Murray) Oerst. were studied in 140 trees from 32 populations collected from within the tree's natural range. By sequencing two mitochondrial DNA intron fragments (nad4/3 -nad4/4r and nad7/2 -nad7/3r), we revealed a total of 1788 bp and five polymorphic sites which allowed us to distinguish six mitotypes. The mitochondrial DNA markers provided replicated data to support population phylogeographical scenarios suggested previously using chloroplastic DNA markers. The gene genealogical tree of mitochondrial DNA was partially congruent with the chloroplastic DNA tree owing to the slower mutation rate and different mutational direction. Significant linkage disequilibrium existed between the two organellar genomes. Further paring analyses between fragments synthesized using different primers, accompanied by exclusion of polymorphic sites, showed that the random association could be attributed specifically to one of the polymorphic sites of the petG- trnP fragment of the chloroplastic genome, and the three polymorphic sites of the nad4/3- nad4/4r fragment of the mitochondrial genome. The former was inferred to derive from paternal leakage, and the latter from recurrent mutation. These polymorphic sites were also responsible for uncoupling of the combined gene tree of mitotype and chlorotype. In conclusion, specific fragments found in this study contribute to the incomplete congruence of the two organellar lineages that otherwise associate well phylogeographically. [source] The linkage disequilibrium between chloroplast DNA and mitochondrial DNA haplotypes in Beta vulgaris ssp. maritima (L.): the usefulness of both genomes for population genetic studiesMOLECULAR ECOLOGY, Issue 2 2000B. Desplanque Abstract The structure and evolution of the plant mitochondrial genome may allow recurrent appearance of the same mitochondrial variants in different populations. Whether the same mitochondrial variant is distributed by migration or appears recurrently by mutation (creating homoplasy) in different populations is an important question with regard to the use of these markers for population genetic analyses. The genetic association observed between chloroplasts and mitochondria (i.e. two maternally inherited cytoplasmic genomes) may indicate whether or not homoplasy occurs in the mitochondrial genome. Four-hundred and fourteen individuals sampled in wild populations of beets from France and Spain were screened for their mitochondrial and chloroplast polymorphisms. Mitochondrial DNA (mtDNA) polymorphism was investigated with restriction fragment length polymorphism (RFLP) and chloroplast DNA (cpDNA) polymorphism was investigated with polymerase chain reaction PCR,RFLP, using universal primers for the amplification. Twenty and 13 variants for mtDNA and cpDNA were observed, respectively. Most exhibited a widespread geographical distribution. As a very strong linkage disequilibrium was estimated between mtDNA and cpDNA haplotypes, a high rate of recurrent mutation was excluded for the mitochondrial genome of beets. Identical mitochondrial variants found in populations of different regions probably occurred as a result of migration. We concluded from this study that mtDNA is a tool as valuable as cpDNA when a maternal marker is needed for population genetics analyses in beet on a large regional scale. [source] One novel and one recurrent mutation in the PROS1 gene cause type I protein S deficiency in patients with pulmonary embolism associated with deep vein thrombosisAMERICAN JOURNAL OF HEMATOLOGY, Issue 10 2006Kazuhiro Mizukami Abstract We investigated the molecular basis of type I protein S (PS) deficiency in two unrelated Japanese families, in which both probands developed pulmonary embolism associated with deep vein thrombosis. Nucleotide sequencing of amplified DNA revealed distinct point mutations in the PROS1 gene of the probands, which were designated protein S Sapporo 1 and protein S Sapporo 2. Additional mutations in the PROS1 gene were excluded by DNA sequencing of all exons and intron/exon boundaries. In the 25-year-old Japanese male patient who carried protein S Sapporo 1, we identified a heterozygous A-to-T change in the invariant ag dinucleotide of the acceptor splice site of intron f of the PROS1 gene. This mutation is a novel splice site mutation that impairs normal mRNA splicing, leading to exon 7 skipping, which was confirmed by platelet mRNA analysis. Translation of this mutant transcript would result in a truncated protein that lacks the entire epidermal growth factor-like domain 3 of the PS molecule. In a 31-year-old Japanese male and his younger brother who each carried protein S Sapporo 2, we detected a previously described heterozygous T-to-C transition at nucleotide position 1147 in exon 10 of the PROS1 gene, which predicts an amino acid substitution of tryptophan by arginine at residue 342 in the laminin G1 domain of the PS molecule. Both mutations would cause misfolding of the PS protein, resulting in the impairment of secretion, which is consistent with the type I PS deficiency phenotype. Am. J. Hematol., 2006. © 2006 Wiley-Liss, Inc. [source] Founder Effects for ATM Gene Mutations in Italian Ataxia Telangiectasia FamiliesANNALS OF HUMAN GENETICS, Issue 5 2009Luciana Chessa Summary We screened ATM gene mutations in 104 Italian Ataxia-Telangiectasia patients from 91 unrelated families (detection rate 90%) and found 21 recurrent mutations in 63 families. The majority (67%) of patients were compound heterozygotes, while 33% were homozygotes. To determine the existence of common haplotypes and potential founder effects, we analyzed five microsatellite markers within and flanking the ATM gene. Haplotype analysis was carried out in 48/63 families harbouring 16 of the 21 recurrent mutations. Forty different haplotypes were detected in the 48 A-T families studied. We found that the majority of patients with the same recurrent mutation originated from the same geographical area. All but one recurrent mutation analyzed displayed a common haplotype suggesting a single origin that then spread to different geographical areas. The high number of different haplotypes does not allow the screening of ATM mutations by haplotype analysis alone in the Italian population. The finding of recurrent public mutations without founder effect suggests the existence of ,mild' hot spots of mutation located along the sequence of the ATM gene. [source] Multiple cutaneous and uterine leiomyomata resulting from missense mutations in the fumarate hydratase geneCLINICAL & EXPERIMENTAL DERMATOLOGY, Issue 1 2006G. S. Chuang Summary Multiple cutaneous and uterine leiomyomata (MCL) is an autosomal dominant disorder characterized by the development of benign smooth muscle tumours (leiomyomas) in the skin and uterus of affected women, and in the skin of affected men. In rare cases, MCL has been associated with a predisposition to the rare type II papillary renal cell cancer, also known as hereditary leiomyomatosis and renal cell cancer. The genetic locus for MCL has been mapped to chromosome 1q42.3,43 and subsequently, germline mutations in the fumarate hydratase (FH) gene have been identified. In addition, analysis of FH in some tumours of MCL patients revealed a second mutation inactivating the wild-type allele, suggesting that FH may function as a tumour suppressor gene. Here, we report two cases of MCL patients with FH mutations, designated as T287P and R190L. T287P represents a novel mutation of a highly conserved amino acid of the FH protein. In addition, a patient with an unusual clinical presentation of MCL was found to have the recurrent mutation, R190L, raising the possibility of incorporating FH sequencing as a diagnostic tool. Our findings extend the allelic series of mutations in FH and support its status as the underlying cause of MCL. [source] Identification of a recurrent mutation in the human hairless gene underlying atrichia with papular lesionsCLINICAL & EXPERIMENTAL DERMATOLOGY, Issue 4 2005M. Massé Summary Identification of mutations in the hairless (HR) gene in patients with atrichia with papular lesions (APL) has proven of critical importance, as it provides a basis for the differentiation between APL and alopecia universalis. The establishment of the diagnostic criteria for APL has triggered the identification of a large number of APL patients among those suspected to suffer from alopecia universalis. This advancement has resulted in the discovery of an increasing number of hairless mutations in both consanguineous and nonconsanguineous APL families. Here, we report the identification of a homozygous mutation, 3434delC, in an APL patient of Arab--Palestinian descent. The proband is a 23-year-old female with generalized scalp and body alopecia. To confirm the diagnosis of APL and to identify the specific mutation, we sequenced the hairless gene. Sequencing of all exons of the hairless gene revealed a homozygous frameshift mutation, 3434delC, in exon 18. Interestingly, the same mutation was previously identified in an Arab--Israeli family. Our data suggest that the 3434delC mutation most likely represents a founder mutation in this geographical region. [source] Syndrome-causing mutations of the BLM gene in persons in the Bloom's Syndrome Registry,,HUMAN MUTATION, Issue 8 2007James German Abstract Bloom syndrome (BS) is caused by homozygous or compound heterozygous mutations in the RecQ DNA helicase gene BLM. Since the molecular isolation of BLM, characterization of BS-causing mutations has been carried out systematically using samples stored in the Bloom's Syndrome Registry. In a survey of 134 persons with BS from the Registry, 64 different mutations were identified in 125 of them, 54 that cause premature protein-translation termination and 10 missense mutations. In 102 of the 125 persons in whom at least one BLM mutation was identified, the mutation was recurrent, that is, it was shared by two or more persons with BS; 19 of the 64 different mutations were recurrent. Ethnic affiliations of the persons who carry recurrent mutations indicate that the majority of such persons inherit their BLM mutation identical-by-descent from a recent common ancestor, a founder. The presence of widespread founder mutations in persons with BS points to population genetic processes that repeatedly and pervasively generate mutations that recur in unrelated persons. Hum Mutat 28(8), 743,753, 2007. Published 2007 Wiley-Liss, Inc. [source] Mutations in the holocarboxylase synthetase gene HLCS,HUMAN MUTATION, Issue 4 2005Yoichi Suzuki Abstract Holocarboxylase synthetase (HLCS) deficiency is an autosomal recessive disorder. HLCS is an enzyme that catalyzes biotin incorporation into carboxylases and histones. Since the first report of the cDNA sequence, 30 mutations in the HLCS gene have been reported. Mutations occur throughout the entire coding region except exons 6 and 10. The types of mutations are one single amino acid deletion, five single nucleotide insertions/deletions, 22 missense mutations, and two nonsense mutations. The only intronic mutation identified thus far is c.1519+5G>A (also designated IVS10+5G>A), which causes a splice error. Several lines of evidence suggest that c.1519+5G>A is a founder mutation in Scandinavian patients. Prevalence of this mutation is about 10 times higher in the Faroe Islands than in the rest of the world. The mutations p.L237P and c.780delG are predominant only in Japanese patients. These are probably founder mutations in this population. Mutations p.R508W and p.V550M are identified in several ethic groups and accompanied with various haplotypes, suggesting that these are recurrent mutations. There is a good relationship between clinical biotin responsiveness and the residual activity of HLCS. A combination of a null mutation and a point mutation that shows less than a few percent of the normal activity results in neonatal onset. Patients who have mutant HLCS with higher residual activity develop symptom after the neonatal period and show a good clinical response to biotin therapy. Hum Mutat 26(4), 285,290, 2005. © 2005 Wiley-Liss, Inc. [source] Erratum: mutational screening of the RB1 gene in Indian patients with retinoblastoma reveals eight novel and several recurrent mutations ,,HUMAN MUTATION, Issue 6 2003Velamakanni Saroj Kiran The original article to which this Erratum refers was published in Human Mutation 22:339 Human Mutation (2003) 22(4) 339 The authors have noted several errors in their manuscript that they were unable to correct prior to publication. They regret the errors and list corrections below: 1.Abstract line 9,10: "Eight novel mutations were identified, including 4 single base changes," This should read: "Eight novel mutations were identified, including 5 single base changes," 2.Page 3 2nd line from bottom: ",(g.76940del12; IVS15del+20-33) extending from +18 to +32 of the intron (RB72)." This should be ",(g.76940del14; IVS15del+20-33) extending from +20 to +33 of the intron (RB72)." 3.Page 4 line 7: ",were also to recur," This should read ",were also found to recur," [source] Founder Effects for ATM Gene Mutations in Italian Ataxia Telangiectasia FamiliesANNALS OF HUMAN GENETICS, Issue 5 2009Luciana Chessa Summary We screened ATM gene mutations in 104 Italian Ataxia-Telangiectasia patients from 91 unrelated families (detection rate 90%) and found 21 recurrent mutations in 63 families. The majority (67%) of patients were compound heterozygotes, while 33% were homozygotes. To determine the existence of common haplotypes and potential founder effects, we analyzed five microsatellite markers within and flanking the ATM gene. Haplotype analysis was carried out in 48/63 families harbouring 16 of the 21 recurrent mutations. Forty different haplotypes were detected in the 48 A-T families studied. We found that the majority of patients with the same recurrent mutation originated from the same geographical area. All but one recurrent mutation analyzed displayed a common haplotype suggesting a single origin that then spread to different geographical areas. The high number of different haplotypes does not allow the screening of ATM mutations by haplotype analysis alone in the Italian population. The finding of recurrent public mutations without founder effect suggests the existence of ,mild' hot spots of mutation located along the sequence of the ATM gene. [source] New Mutations of EXT1 and EXT2 Genes in German Patients with Multiple OsteochondromasANNALS OF HUMAN GENETICS, Issue 3 2009Wolfram Heinritz Summary 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. [source] H syndrome: novel and recurrent mutations in SLC29A3BRITISH JOURNAL OF DERMATOLOGY, Issue 5 2010T.P. Priya The H syndrome (OMIM 612391) is a recently described autosomal recessive disorder characterized by cutaneous hyperpigmentation, hypertrichosis, hepatosplenomegaly, heart anomalies, hearing loss, hypogonadism, short stature (low height), hyperglycaemia/diabetes mellitus, hallux valgus, and fixed flexion contractures of the toe and finger joints.1,2 Histologically, there is an inflammatory infiltrate consisting mainly of histiocytes, later replaced by fibrosis of the deep dermis and subcutis.3 In total, 31 patients have been reported in the literature with the clinical phenotype characteristic of this syndrome.1,7 [source] 2161: Development of a next-generation sequencing platform for retinal dystrophies, with LCA and RP as proof of conceptACTA OPHTHALMOLOGICA, Issue 2010F COPPIETERS Purpose Retinal dystrophies represent an emerging group of hereditary disorders that lead to degeneration of the photoreceptors and/or the retinal pigment epithelium, resulting in irreversible blindness. They are genetically complex, with over 200 disease loci identified so far. Current genetic screening consists of microarray analysis (Asper Ophthalmics) for the most recurrent mutations, and subsequent Sanger sequencing. However, the high cost and low throughput of the latter technology limits testing to only the most recurrent genes. This project aims to develop a high throughput and cost-effective platform for screening of all known disease genes for Leber Congenital Amaurosis (LCA) and retinitis pigmentosa (RP), using the next-generation sequencing (NGS) technology. Methods A NGS panel will be developed for all 16 and 47 known LCA and RP genes, respectively, including coding and untranslated regions, regulatory regions and microRNA binding sites. The protocol will consist of the following steps: 1) high throughput primerdesign and qPCR, 2) ligation, 3) shearing and 4) sequencing on the Illumina Genome Analyser IIx (GAIIx). This innovative protocol overcomes the need for short amplicons in order to render short-read sequences by the GAIIx. This sequencing instrument was chosen because of its high capacity, low cost per base and the absence of interpretation problems at homopolymeric regions. Analysis of the variants will be performed using in-house developed and commercial software, which ranks all variants according to their pathogenic potential. Conclusion Using the proposed protocol, comprehensive screening for all known disease genes for LCA and RP will be available for the first time. [source] | |||||||||||||