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At least 127 records · Page 7Linked to original sources
PubMed2005

[Mutation detection of mismatch repair genes in hereditary nonpolyposis colorectal cancer by denaturing high-performance liquid chromatography].

OBJECTIVES: To establish DHPLC method in detecting mutations of mismatch repair genes, hMLH1 and hMSH2, and to identify germline mutations of hMLH1 and hMSH2 in HNPCC kindreds fulfilling Chinese HNPCC criteria. METHODS: Fourteen peripheral blood DNA samples from 14 unrelated HNPCC probands fulfilling Chinese HNPCC criteria were obtained respectively. PCR amplified 35 exons of two main mismatch repair genes, hMLH1 and hMSH2. DHPLC followed by DNA sequencing was used to detect and confirm mutations. RESULTS: a total of 41 colorectal cancers and 19 extracolonic tumors were developed in 14 HNPCC kindreds, and gastric cancer was the most common extracolonic tumor type. Twelve single nucleotide changes were identified by DHPLC in 14 probands. Among them, three were missense mutations, one was a nonsense mutation. Other single nucleotide changes included five single nucleotide polymorphisms, two intron single nucleotide changes, one synonymous mutation. hMLH1 EXON19 CODON749 TAC-->TAG (Tyr-->X), hMSH2 EXON12 CODON629 CAA-->CGA (Gln-->Arg) and hMSH2 EXON15 CODON839 CAT-->CGT (His-->Arg) were new discovered mutations. CONCLUSIONS: (1) DHPLC was considered to be highly effective, convenient technique with consistent results for the mutation detection of hMLH1 and hMSH2 genes. (2) Valid mutations of hMLH1 and hMSH2 genes were identified in about one-third HNPCC kindreds fulfilling Chinese HNPCC criteria and missense mutation was the most common mutational types in this cohort of families.

Adaptor Proteins, Signal Transducing↗
PubMed1994

[Genetic heterogeneity of hypertrophic cardiomyopathy in Japanese].

Familial hypertrophic cardiomyopathy (FHCM) is thought to be caused by missense mutations in cardiac beta-myosin heavy chain (beta-MHC) gene in 30-40% of affected Caucasian individuals. On the other hand, it has been reported that Japanese FHCM is closely linked to DNA marker PALB on chromosome 18q by linkage analysis. Therefore, in order to elucidate the etiological significance of missense mutations in beta-MHC gene in Japanese HCM patients, we have investigated the sequence variation in exon 3 to 25 of beta-MHC gene from 16 multiplex FHCM kindreds and 28 sporadic patients by polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) method. In this study we demonstrated one missense mutation (codon741: GlyGGG-->ArgAGG) in only one kindred among 16 multiplex Japanese kindreds with FHCM. Two synonymous mutations (codon715: TryTAC-->TryTAT, codon 989: IleATT-->IleATC) are demonstrated in another kindred. The same mutation in codon 989 is also detected in one sporadic patient. Furthermore, we performed linkage study with two DNA markers (F13B on chromosome 1q, D11S916: AMF185yal on chromosome 11p-q) which are recently reported to be linked with FHCM. Three and four families showed statistically negative linkage with F13B and D11S916 (AMF185yal), respectively. These results suggest that several responsible genes for HCM may exist in Japanese and principal responsible gene for Japanese HCM is different from it for Caucasian HCM.

Asian People↗
PubMedDate not supplied

[The genetic variability of the protease-encoding region in HIV-1 A isolates and in CRF03_AB recombinants as observed in the CIS territory].

Protease-encoding nucleotide sequences of 27 HIV-1 variants isolated in Russia and other CIS countries from seropositive intravenous drug-users were analyzed. None of the above persons did ever take antiretroviral drugs. The nucleotide sequences were shown to belong to subtypes A and to be have a high degree of genetic homogeneity (0.00-3.23; mean--1.38 +/- 0.79). No isolates contained any primary mutations of resistance to protease inhibitors. At the same time, above one half of the isolates bore the V771 substitution, which, according to published data, is the secondary mutation of resistance that conditions a higher resistance to Nelfinavir. Moreover, the substitution was associated with 2 synonymous mutations in triplets 31 and 78, which denotes a single origin for all V771 variants.

Adolescent↗
PubMed1997

Novel alleles of the chemokine-receptor gene CCR5.

The CCR5 gene encodes a cell-surface chemokine-receptor molecule that serves as a coreceptor for macrophage-tropic strains of HIV-1. Mutations in this gene may alter expression or function of the protein product, thereby altering chemokine binding/signaling or HIV-1 infection of cells that normally express CCR5 protein. Indeed, homozygotes for a 32-bp deletion allele of CCR5 (CCR5-delta 32), which causes a frameshift at amino acid 185, are relatively resistant to HIV-1 infection. Here we report the identification of 16 additional mutations in the coding region of the CCR5 gene, all but 3 of which are codon altering or "nonsynonymous." Most mutations were rare (found only once or twice in the sample); five were detected exclusively among African Americans, whereas eight were observed only in Caucasians. The mutations included 11 codon-altering nonsynonymous variants, one trinucleotide deletion, one chain-termination mutant, and three synonymous mutations. The high predominance of codon-altering alleles among CCR5 mutants (14/17 [81%], including CCR5-delta 32) is consistent with an adaptive accumulation of function-altering alleles for this gene, perhaps as a consequence of historic selective pressures.

Alleles↗
PubMed2005

A novel missense mutation, F826Y, in the mineralocorticoid receptor gene in Japanese hypertensives: its implications for clinical phenotypes.

A gain-of-function mutation resulting in the S810L amino acid substitution in the hormone-binding domain of the mineralocorticoid receptor (MR, locus symbol NR3C2) is responsible for early-onset hypertension that is exacerbated in pregnancy. The objective of this study was to test whether other types of missense mutations in the hormone-binding domain could be implicated in hypertension in Japanese. Here, we screened 942 Japanese patients with hypertension for the S810L mutation in exon 6 in the MR. We did not identify the S810L mutation in our hypertensive population, indicating that S810L does not play a major role in the etiology of essential hypertension in Japanese. However, we identified a novel missense mutation, F826Y, in three patients in a heterozygous state, in addition to four single nucleotide polymorphisms, including one synonymous mutation (L809L). The F826Y mutation is present in the MR hormone-binding domain and might affect the ligand affinity. The F826Y mutation was also identified in 13 individuals (5 hypertensives and 8 normotensives) in a Japanese general population (n=3,655). The allele frequency was 0.00178. The frequencies of the F826Y mutation in the hypertensive population (3/942) and in the hypertensive group (5/ 1,480) and the normotensive group (8/2,175) in the general population were not significantly different, suggesting that this mutation does not greatly affect hypertension. Although it is unclear at present whether or not the F826Y mutation makes a substantial contribution to the mineralocorticoid receptor activity, this missense mutation may contribute, to some extent, to clinical phenotypes through its effects on MR.

Aged↗
PubMed2006

Mutations in the tyrosine kinase domain of the EGFR gene are rare in synovial sarcoma.

The prognosis of patients with synovial sarcomas is poor. New therapeutic strategies, such as target inhibition of the tyrosine kinase activity of the epidermal growth factor receptor (EGFR) with erlotinib and gefinitib, could be effective, because most synovial sarcomas overexpress this protein. In lung cancer, the responsiveness to gefinitib is strongly related to the presence of mutations in the tyrosine kinase domain of the EGFR gene, while erlotinib sensitivity seems to be partly linked to chromosome 7 polysomy or gene amplification. To clarify the role of EGFR in synovial sarcoma and to explore the potential for a targeted therapy approach, we have examined 13 of these soft tissue tumors. We have analyzed the EGFR expression by immunohistochemistry, searched for polysomy and gene amplification with fluorescence in situ hybridization (FISH) and screened for EGFR mutations in exons 18-21 using PCR and direct sequencing. All 13 tumors showed strong diffuse or focal EGFR expression. No amplifications of the EGFR gene were found. In contrast, several point mutations were identified in exons 18-21 of two synovial sarcomas. Whereas one of these tumors carried only a synonymous mutation, two missense mutations in exons 19 and 21 of the EGFR gene (P733S and A840 T, respectively) could be demonstrated in the second sample. In conclusion, strong EGFR expression in synovial sarcomas is not related to gene amplification. The existence of mutations in the tyrosine kinase domain of the EGFR gene in a small subset of synovial sarcomas suggests that only few patients may profit from the tyrosine kinase inhibitor therapy.

Adolescent↗
PubMed1986

The rate with which spontaneous mutation alters the electrophoretic mobility of polypeptides.

Studies of a Japanese population, involving a total of 539,170 locus tests distributed over 36 polypeptides, yielded three presumptive spontaneous mutations altering the electrophoretic mobility of the polypeptide. This corresponds to a mutation rate of 0.6 X 10(-5) per locus per generation. The a priori probability that undetected discrepancies between legal and biological parentage might in our test system result in an apparent electrophoretic mutation in this population is calculated to be only 0.3 X 10(-7) per locus per generation. Since electrophoresis only detects about half of the amino acid substitutions due to mutations of nucleotides, the corrected rate for mutations causing amino acid substitutions in polypeptides is 1.2 X 10(-5) per locus per generation. With allowance for synonymous mutations and those resulting in stop codons, the total mutation rate for nucleotide changes in the exons encoding a polypeptide becomes approximately equal to 1.8 X 10(-5) per locus per generation. When the present observations are combined with all of the other available data concerning mutation resulting in electrophoretic variants, the electrophoretic rate drops to 0.3 X 10(-5) per locus per generation, the total locus rate drops to roughly 1.0 X 10(-5), and the nucleotide rate drops to 1 X 10(-8). Even with this lower estimate, given approximately equal to 2 X 10(9) nucleotides in the haploid genome and an average of 10(3) exon nucleotides per polypeptide encoded, the implication, if these exon rates can be generalized, is of approximately equal to 20 nucleotide mutations per gamete per generation. This estimate of the frequency of "point" mutations does not include small duplications, rearrangements, or deletions resulting from unequal crossing-over, transcription errors, etc.

Child↗
PubMed1999

A simple method for estimating the intensity of purifying selection in protein-coding genes.

We propose a method by which the intensity of purifying selection on a functional protein-coding gene is estimated by using three aligned homologous sequences: a processed pseudogene (psi), a functional paralog from the same species (g), and a functional ortholog from a different species (o). For each such trio, we calculate the numbers of nucleotide substitutions along the branches leading to psi and g, i.e., K psi and K(g). If we assume that the mutation rates are the same in the genes and the pseudogenes and that mutations occurring in a pseudogene do not affect the fitness of the organism, we can show that the fraction of mutations that are selectively neutral, fg, is equal to the ratio K(g)/K psi. Since advantageous mutations occur only very rarely, such that they do not contribute significantly to the rate of molecular evolution, the fraction of deleterious mutations that are subject to purifying selection is 1-fg. Therefore, the K(g)/K psi ratio can be used directly to estimate the intensity of purifying selection, thereby isolating its effects on the rate of evolution from those of mutation. We compared the selection intensities of 12 orthologous protein-coding pairs from humans and murids. As expected, the fraction of mutations that are subject to purifying selection is strongest in the second codon position and weakest in the third. Interestingly, the mean fractions of effectively neutral mutations in the third codon position were only 41% and 42% for murids and humans, respectively, indicating that many synonymous mutations are subject to selective constraint. In several orthologous genes, we found that the intensity of purifying selection is very different between murid and human orthologous genes. There was no statistically significant difference in overall intensity of purifying selection between humans and murids. Thus, purifying selection does not seem to be an important factor contributing to the observed differences in the rates of evolution between these two taxa.

Animals↗
PubMed1994

Sequence variation in the outer-surface-protein genes of Borrelia burgdorferi.

Borrelia burgdorferi is a spirochete pathogen transmitted among warm-blooded hosts by ixodid ticks. Frequency-dependent selection for variant outer-surface proteins might be expected to arise in this species, since rare variants are more likely to avoid immune surveillance in previously infected hosts. We sequenced the OspA and OspB genes of nine North American strains and compared them with nine strains previously described. For each gene, the mean number of synonymous substitutions per synonymous site and the mean number of nonsynonymous substitutions per nonsynonymous site show only a twofold excess of silent mutations. Synonymous rates vary widely along the OspB protein. Some regions show a significant excess of silent substitutions, while divergence in other regions is constrained by biased base composition or selection. The presence, in antigenically important regions of the protein, of significant variation among strains, as well as evidence for recombination among strains, should be considered in attempts to develop vaccines against this disease.

Animals↗
PubMed2002

Identification and in vitro expression of novel CDH23 mutations of patients with Usher syndrome type 1D.

Usher syndrome (USH) is a group of autosomal recessive sensory disorders characterized by progressive retinitis pigmentosa (RP) and sensorineural hearing impairment. Usher syndrome type 1 (USH1), with additional vestibular dysfunction, represents the most severe form and shows extensive allelic and non-allelic heterogeneity. At least six USH1 loci exist (USH1A-F), and four of the underlying genes have been identified. Recently, a novel gene, cadherin 23 (CDH23), was shown to be mutated in USH1D. We performed mutation screening by single strand conformation polymorphism (SSCP) analysis and direct sequencing on 33 USH1 patients previously excluded for USH1B and USH1C. On eight disease alleles of four patients, four different mutations were identified, three of them novel (c.6933delT, c.5712G-->A, and IVS45-9G-->A). Exon trapping experiments were performed with two mutations. In the case of a c.5712G-->A transition of the last base of exon 42, that is an apparently synonymous mutation, skipping of exon 42 was observed. By the mutation IVS45-9G-->A, a novel splice acceptor site was created and the insertion of 7 intronic bp was observed. Two mutations, IVS45-9G-->A and the previously described IVS51+5G-->A, were each found in more than one patient. Haplotype analysis by SNPs within CDH23 suggests common ancestors for each of the mutations. Among the total of 52 USH1 cases studied by us, CDH23 mutations account for about 10% of all disease alleles. Our results further suggest that in patients with a typical USH1D phenotype, a significant portion of CDH23 mutations leads to premature termination of translation or loss of numerous amino acid residues, with a high frequency of changes causing aberrant splicing of CDH23 mRNA.

Adolescent↗
PubMed2005

A novel maternal lineage revealed in sheep (Ovis aries).

It is generally believed that domestic sheep have two maternal lineages (haplotypes A and B), based on mitochondrial DNA analysis. In the present study, we provide evidence that a novel maternal lineage (haplotype C) is exhibited in Chinese native sheep. To verify this finding, 231 samples were collected from six Chinese local breeds, which cover the vast geographical region of sheep inhabitation in China. For comparison, 50 samples were collected from two Western breeds collected in China. Mitochondrial DNA was screened by PCR single-strand conformational polymorphism (SSCP), leading to the identification of novel band patterns in ND2 and ND4 genes in the Chinese breeds. Interestingly, mutations at the two loci were in strong linkage disequilibrium. Direct sequencing of the DNA fragments revealed a non-synonymous substitution in ND2. Furthermore, two synonymous mutations were identified by comparisons of the novel type (haplotype C) and the established types (haplotypes A and B). The entire mitochondrial control region for 55 samples was then sequenced to construct a phylogenetic tree and median joining network. Both the tree and network demonstrated a topology of three groups, which is in consistent with the SSCP analysis. Unlike Western breeds, Chinese breeds are composed mainly of haplotypes A and B, but with a small fraction of haplotype C. According to Fu's test and mismatch distribution, haplotype C has not been subject to a recent population expansion. Based on these results, we propose a novel origin for Chinese sheep.

Animals↗
PubMed2026

The distribution of fitness effects of nonsynonymous mutations varies phylogenetically across animals.

The distribution of fitness effects (DFE) describes the selection coefficients of newly arising mutations and fundamentally influences population genetic processes. However, the extent and mechanisms of differences in the DFE for non-synonymous mutations have not been systematically investigated across species with divergent phylogenetic histories and ecologies. Here, we inferred the DFE in natural populations of 11 animal (sub)species, including humans, mice, fin whales, vaquitas, wolves, collared flycatchers, pied flycatchers, halictid bees, Drosophila, and mosquitoes. We found that mammals have a higher proportion of strongly deleterious mutations (defined as s≤-0.01; 22% to 47% in mammals; 0.0% to 5.4% in insects and birds) and a lower proportion of weakly deleterious mutations than insects and birds. Further, the DFE co-varies with phylogeny, such that the mean mutation effects are more similar in closely related species (Pagel's λ = 0.84, P = 0.01). Next, we investigated whether various summary statistics of the DFE were related to variation in life-history traits across these organisms. We found some support for genome size, body mass, and long-term effective population size being correlated with the DFE. Overall, our findings are consistent with predictions derived independently from the Fisher's Geometric Model (FGM), which defines organismal complexity as the number of phenotypes under selection. FGM predicts that mutations are more deleterious in complex organisms, while strongly deleterious mutations occur more frequently in smaller populations. Our study demonstrates strong phylogenetic signal in the evolution of a fundamental population genetics parameter, and proposes that, through mechanisms of epistasis, long-term population size and organismal complexity could be underlying variation in the DFE across animals.

Journal Article↗
PubMed2006

[Melanin traits of Yunnan black bone sheep and TYR gene polymorphism].

The "black bone and muscle" is cardinal melanin trait of black bone sheep. The black bone sheep and the native sheep in Lanping and Luomuni sheep were chosen as materials for the measurement of TYR activity of blood and melanin content of tissues and organs. Moreover, we compared characteristic structure of melanin of black bone sheep with silky fowls. The results showed as follows: TYR activity was significantly different between black and non-black bone sheep (P<0.05); the total character of infrared spectrum (IR) of melanin of black bone sheep resembled silky fowls; and melanin was eumelanin. We firstly cloned exon1 667bp sequence of TYR gene and determined TYR gene polymorphism of black and non-black bone sheep by PCR-RFLP. Compared with sequence of TYR gene of non-black bone sheep, there were two nucleotide mutation sites in exon1 of black bone sheep, located in No.64 and No.154 amino acid codons, respectively; but they were synonymics mutation. We designed restriction site in codon 64 and check up TYR gene polymorphism. The result showed the mutation site together with the close linked gene influenced melanin trait deposition. It suggests there should be functional mutation related with melanin trait. Furthermore, there was significant correlation between TYR gene polymorphism and coat color of sheep (P<0.01), indicating TYR could influence synthesis of coat color of sheep.

Animals↗
PubMed2004

[X-linked adrenoleukodystrophy ABCD1 gene mutation analysis in China].

OBJECTIVE: To investigate mutations of ABCD1 gene in X- linked adrenoleukodystrophy (ALD) patients in China. METHODS: Polymerase chain reaction and DNA direct sequencing were employed to analyze the 10 exons of ABCD1 gene in 25 ALD patients. RESULTS: Seventeen mutations in different exons (except exons 4, 9 and 10) were identified in 18 of 25 patients. Most of the mutations were missense mutations, including R182P, G266R, H283D, S404P, N509I, R518G, L520Q, Q556R, S606L and R617C, four (H283D, S40 4P, N509I, R518G) of 10 missense mutations were novel. Also identified were 3 nonsense mutations (W132X, W242X, W595X), 1 dinucleotides deletion mutation (1414 del AG) resulting in frameshift, and 1 base pair deletion at splice acceptor site (IVS5-6 del C). Two synonymous mutations (L516L and V349V) appeared simultaneously in 2 unrelated patients, and no other mutations could be found with them in all 10 exons screened. CONCLUSION: There were no hot spot mutations in ABCD1 gene in China. Mutations in gene were found over 70% of patients with ALD in China. The ABCD1 gene mutations identified revealed no obvious correlation between the type of mutation and phenotype.

ATP Binding Cassette Transporter, Subfamily D, Mem↗
PubMed2004

Variation of the McKusick-Kaufman gene and studies of relationships with common forms of obesity.

Obesity is a prominent feature of the Bardet-Biedl syndrome (BBS), one subset of which, BBS6, is due to mutations in the chaperonin-like gene termed the McKusick-Kaufman syndrome (MKKS) gene. We tested whether variation in MKKS contributes to common and probably polygenic forms of obesity by performing mutation analysis of the coding region in 60 Danish white men with juvenile-onset obesity. Five variants were identified, including two synonymous mutations (Pro(39)Pro and Ile(178)Ile) and three nonsynonymous variants (Ala(242)Ser, Arg(517)Cys, and Gly(532)Val). Furthermore, the rare Ala(242)Ser was identified in two families and showed partial cosegregation with obesity. The Pro(39)Pro, Ile(178)Ile, and Arg(517)Cys variants are in complete linkage disequilibrium and defined a prevalent haplotype. In a case-control study, the Arg(517)Cys polymorphism allele prevalence was 11.4% [95% confidence interval (CI), 9.7-13.0] among 744 men with juvenile-onset obesity and 9.3% (CI, 7.9-10.7) among 867 control subjects (P = 0.048). However, among middle-aged men the allelic prevalence was 9.7% (CI, 7.9-11.4) among 523 obese men and 12.2% (CI, 10.8-13.6) among 1051 lean men (P = 0.037). In conclusion, it is unlikely that MKKS variants play a major role in the pathogenesis of nonsyndromic obesity, although in rare cases the A242S allele may contribute to obesity.

Adolescent↗
PubMed2006

MECP2 and CDKL5 gene mutation analysis in Chinese patients with Rett syndrome.

Rett syndrome (RTT) is a progressive neurodevelopmental disorder that is caused by mutations in the X-linked methyl-CpG-binding protein2 (MECP2) gene. In this study, the MECP2 sequences in 121 unrelated Chinese patients with classical or atypical RTT were screened for deletions and mutations. In all, we identified 45 different MECP2 mutations in 102 of these RTT patients. The p. T158M mutation (15.7%) was the most common, followed in order of frequency by p. R168X (11.8%), p. R133C (6.9%), p. R270X (6.9%), p. G269fs (6.9%), p. R255X (4.9%), and p. R306C (3.9%). In addition, we identified five novel MECP2 mutations: three missense (p. K305E, p. V122M, p. A358T), one insertion (c.45-46insGGAGGA), and one 22 bp deletion (c.881-902del22). Large deletions represented 10.5% of all identified MECP2 mutations. Conversely, mutations in exon 1 appeared to be rare (0.9%). The remaining cases without MECP2 mutations were screened for the cyclin-dependent kinase-like 5 (CDKL5) gene using denaturing high-performance liquid chromatography (DHPLC). One synonymous mutation (p. I72I) was found in exon 5, suggesting that CDKL5 is a rare cause of RTT. The overall MECP2 mutation detection rate for this patient series was 84.3:87.9% in 107 classical RTT cases and 57.1% in 14 atypical RTT cases. Moreover, there were two patients with homozygous mutations and normal female karyotypes. However, we did not pinpoint a significant relationship between genotype and phenotype in these cases.

Adolescent↗
PubMed2003

Mutation analysis of the leucine-rich, glioma inactivated 1 gene (LGI1) in Japanese febrile seizure patients.

Mutations in the leucine-rich, glioma inactivated 1 gene (LGI1) were recently identified in some families with autosomal dominant lateral temporal epilepsy (ADLTE). To investigate whether the LGI1 gene is a susceptibility gene for febrile seizures (FS), we performed a systematic search for mutations in 94 unrelated Japanese patients with FS. We detected two intronic polymorphisms (IVS2 + 19 A/G and IVS6 - 18 T/C). No non-synonymous mutation was detected. We genotyped these polymorphisms and performed a case-control study and transmission disequilibrium testing (TDT) of 62 FS families (n = 230) and 105 control subjects. None of the polymorphisms was significantly associated with FS. Our results indicate that genomic variations in the LGI1 gene are not likely to be substantially involved in the etiology of FS in the Japanese population.

Alleles↗
PubMed2003

A compositional segmentation of the human mitochondrial genome is related to heterogeneities in the guanine mutation rate.

We applied a hidden Markov model segmentation method to the human mitochondrial genome to identify patterns in the sequence, to compare these patterns to the gene structure of mtDNA and to see whether these patterns reveal additional characteristics important for our understanding of genome evolution, structure and function. Our analysis identified three segmentation categories based upon the sequence transition probabilities. Category 2 segments corresponded to the tRNA and rRNA genes, with a greater strand-symmetry in these segments. Category 1 and 3 segments covered the protein- coding genes and almost all of the non-coding D-loop. Compared to category 1, the mtDNA segments assigned to category 3 had much lower guanine abundance. A comparison to two independent databases of mitochondrial mutations and polymorphisms showed that the high substitution rate of guanine in human mtDNA is largest in the category 3 segments. Analysis of synonymous mutations showed the same pattern. This suggests that this heterogeneity in the mutation rate is partly independent of respiratory chain function and is a direct property of the genome sequence itself. This has important implications for our understanding of mtDNA evolution and its use as a 'molecular clock' to determine the rate of population and species divergence.

Algorithms↗