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At least 19 recordsLinked to original sources
PubMed1992

Polymerase chain reaction and other methods to detect hot-spot and multiple gene mutations.

Gene mutations responsible for main genetic diseases as Duchenne/Becker muscular dystrophy or cystic fibrosis, and involved in more important diseases like cancer or cardiac diseases have been identified. Direct DNA tests can now be performed for these disorders. However, despite the knowledge of the exact alteration of the DNA sequence in these diseases, incorporating DNA analysis into large screening programs has been hindered by technical difficulties since each different mutation requires a different probe to be detected. To overcome these problems the polymerase chain reaction technique (PCR) has been proposed. Multiplex PCR procedure is possible and consists of simultaneously amplifying several separate DNA sequences (the upper limit of the number of multiplex reactions that can be executed at one time is not known; eight or nine separate DNA sequences amplified have already been described). Another approach is to directly sequence the gene mutations generally concentrated in 'hot-spot' regions. This way it is possible to identify numerous mutations using only one micro-sequencing reaction (50-100 nucleotides). New generations of very sophisticated systems like capillary electrophoresis or non-isotopic, but very sensitive, microsequencing systems should allow in a near future to withdraw the use of PCR for this purpose.

Base Sequence↗
PubMed1986

Nucleotide sequence analysis of murine 21-hydroxylase genes: mutations affecting gene expression.

Steroid 21-hydroxylase [21-OHase; steroid 21-monooxygenase; steroid, hydrogen-donor:oxygen oxidoreductase (21-hydroxylating); EC 1.14.99.10] is a cytochrome P-450 enzyme required for the adrenal synthesis of mineralocorticoids and glucocorticoids. The gene encoding this protein is present in two copies (21-OHase A and B) in the S region of the murine major histocompatibility complex. Previous studies utilizing gene-specific oligonucleotide probes and gene transfer showed that only the 21-OHase A gene is expressed in the BALB/c mouse. Here, we present the complete primary structures of both BALB/c 21-OHase encoding genes. Comparison of the nucleotide sequences defines a deletion of 215 nucleotides spanning the second exon of the 21-OHase B gene; other nucleotide changes in the 21-OHase B gene introduce frame shifts and premature termination codons. Southern blot analysis of C57BL/6 and DBA/2J mice indicates that a similar deletion is present in these strains; however the C3H/HeJ strain is a structural variant. A hybrid gene composed of the 21-OHase B promoter placed 5' of the 21-OHase A structural sequences was efficiently transcribed following transfection into Y1 adrenocortical tumor cells. These findings demonstrate that the 21-OHase B gene promoter is functional and suggest that mutations within the 21-OHase B structural gene are responsible for its lack of expression.

Amino Acid Sequence↗
PubMed1977

Induction of gene mutations and gene conversions by vinyl chloride metabolites in yeast.

Chloroethylene oxide and 2-chloroacetaldehyde, two metabolites of vinyl chloride, and 2-chloroethanol, a putative metabolic intermediate, were assayed for their genetic activity in the yeasts Schizosaccharomyces pombe and Saccharomyces cerevisiae. Chloroethylene oxide was found to be the most effective in inducing forward mutations in Sch. pombe and gene conversions in S. cerevisiae, increasing the mutation and conversion frequencies 340 and 50 times, respectively, over those of the controls. In either the presence or the absence of mouse liver microsomes, 2-chloroacetaldehyde showed only feeble genetic activity, and 2-chloroethanol was completely inactive in both yeast strains. In contrast to vinyl chloride, 2-chloroacetaldehyde did not induce forward mutations in Sch. pombe inthe host-mediated assay in mice. The results strongly support the hypothesis that chloroethylene oxide is one of the principal mutagenic agents formed from vinyl chloride in the presence of mouse liver enzymes.

Acetaldehyde↗
PubMed1979

[Comparative study of mutator-gene prv and several other mutator-genes of Escherichia coli K-12].

Mutations prv1, prv2 and mutR34, increasing frequencies of intragenic recombinations, are found not to complement and therefore to be alleles of one gene. Checking for the influence of mutator genes mutS3, mutT1 and uvrE502 on the intragenic recombination in conjugational crossings has shown that mutators mutS3 and uvrE502 increase the frequency of intragenic recombinations while mutT1 does not change it. None of the examined mutator genes influence the conjugational frequencies of recombination. A supplementary analysis for the mutability of the mutant prv1 has been carried out. The prv1 mutation can induce mutations of the frameshift type. Mutations uvrA6, recB21, recC22 and lexA produce no influence on the display of a mutator effect of the prv1 mutation.

Conjugation, Genetic↗
PubMed1990

Transformation of chicken embryo fibroblast cells by avian retroviruses containing the human Fyn gene and its mutated genes.

The transforming activity of the human fyn protein, p59fyn, which is a kinase of the src family, was investigated by testing the effect of recombinant avian retrovirus (Fyn virus) expressing p59fyn on chickens or cultured chicken embryo fibroblast (CEF) cells. The Fyn virus did not induce transformed foci. After several passages of the virus stock on CEF cells, however, a few foci were detected in the presence of dimethyl sulfoxide. Chickens inoculated with Fyn virus at the stage of 12-day-old embryos developed fibrosarcomas 3 to 6 weeks after hatching. The viruses obtained from these foci and from one of the tumor tissues showed high transforming activity in the presence of dimethyl sulfoxide, suggesting that these viruses carry spontaneous mutations of the fyn gene. Four fyn genes from CEF DNAs infected with transforming viruses were molecularly cloned, and their products were confirmed to possess transforming activity. DNA sequence analysis of the fyn genes showed that two of the four mutants have Thr instead of Ile at position 338 in the kinase domain. The other two mutants carry deletions of 78 and 108 base pairs, respectively, which result in complete loss of region C of SH2. The overall level of proteins containing phosphotyrosine was significantly higher in transformed cells than in normal CEF cells. Our data indicate that when expressed at high levels in a retrovirus, normal p59fyn cannot cause cellular transformation, but that mutant p59fyn with either a single amino acid substitution in the kinase domain or a deletion including region C produces a transforming protein, perhaps due to enhanced tyrosine kinase activity. This is the first observation that deletion of region C can unmask the potential transforming activity of a src family kinase.

Amino Acid Sequence↗
PubMed1990

Sequence analysis of three tRNA(Phe) nuclear genes and a mutated gene, and one gene for tRNA(Ala) from Arabidopsis thaliana.

Three genes and one mutant gene for tRNA(Phe) (GAA) and one gene for tRNA(Ala) (UGC) were isolated from a whole-cell DNA library of Arabidopsis thaliana. All three tRNA(Phe) genes are identical in their nucleotide sequence, but differ in their 5' and 3' flanking regions. The mutant tRNA(Phe) (GAA) gene differs from the other three genes by one nucleotide change from highly conserved G to C at the 57th nucleotide position. The primary structure of the first tRNA(Ala) gene was also determined in this experiment.

Base Sequence↗
PubMed2024

Predictive modeling of gene mutations for the survival outcomes of epithelial ovarian cancer patients.

Epithelial ovarian cancer (EOC) has a low overall survival rate, largely due to frequent recurrence and acquiring resistance to platinum-based chemotherapy. EOC with homologous recombination (HR) deficiency has increased sensitivity to platinum-based chemotherapy because platinum-induced DNA damage cannot be repaired. Mutations in genes involved in the HR pathway are thought to be strongly correlated with favorable response to treatment. Patients with these mutations have better prognosis and an improved survival rate. On the other hand, mutations in non-HR genes in EOC are associated with increased chemoresistance and poorer prognosis. For this reason, accurate predictions in response to treatment and overall survival remain challenging. Thus, analyses of 360 EOC cases on NCI's The Cancer Genome Atlas (TCGA) program were conducted to identify novel gene mutation signatures that were strongly correlated with overall survival. We found that a considerable portion of EOC cases exhibited multiple and overlapping mutations in a panel of 31 genes. Using logistical regression modeling on mutational profiles and patient survival data from TCGA, we determined whether specific sets of deleterious gene mutations in EOC patients had impacts on patient survival. Our results showed that six genes that were strongly correlated with an increased survival time are BRCA1, NBN, BRIP1, RAD50, PTEN, and PMS2. In addition, our analysis shows that six genes that were strongly correlated with a decreased survival time are FANCE, FOXM1, KRAS, FANCD2, TTN, and CSMD3. Furthermore, Kaplan-Meier survival analysis of 360 patients stratified by these positive and negative gene mutation signatures corroborated that our regression model outperformed the conventional HR genes-based classification and prediction of survival outcomes. Collectively, our findings suggest that EOC exhibits unique mutation signatures beyond HR gene mutations. Our approach can identify a novel panel of gene mutations that helps improve the prediction of treatment outcomes and overall survival for EOC patients.

Humans↗
PubMed1990

Detection of ras gene mutations in human lung cancers by single-strand conformation polymorphism analysis of polymerase chain reaction products.

A simple, sensitive method of DNA analysis of nucleotide substitutions, namely, single-strand conformation polymorphism analysis of polymerase chain reaction products (PCR-SSCP analysis), was used for detection of mutated ras genes in surgical specimens of human lung cancer. Of a total of 129 tumors analysed, 22 contained a mutated ras gene. Of the 66 adenocarcinomas analysed, 14 contained an activated c-Ki-ras2 gene (the mutations in codon 12 in 6, in codon 13 in 4, in codon 18 in one, and in codon 61 in 3), one contained a c-Ha-ras1 gene with a mutation in codon 61 and 3 contained N-ras genes with mutations (in codon 12 in one and in codon 61 in 2). Mutated rats genes were also found in 2 of 36 squamous cell carcinomas (c-Ha-ras1 genes with mutations in codon 61) and 2 of 14 large cell carcinomas (c-Ki-ras2 genes with mutations in codon 12). No mutation of the ras gene was detected in 8 small cell carcinomas and 5 adenosquamous cell carcinomas. These results indicate that activation of the ras gene was not frequent (17%) in human lung cancers, that among these lung cancers mutation of the ras gene was most frequent in adenocarcinomas (27%) and 73% of the point mutations were in the c-Ki-ras2 gene in codon 12, 13, 18 or 61.

Base Sequence↗
PubMed1989

The liver/erythrocyte pyruvate kinase gene complex [Pk-1] in the mouse: structural gene mutations.

Nine enzyme activity variants of liver/erythrocyte pyruvate kinase have been found amongst laboratory and wild mice. Four of these variants have been shown by biochemical and immunological criteria to be mutations of the structural gene, Pk-1s. These four structural gene mutations, and two regulatory gene mutations, define the gene complex, [Pk-1]. One allele of the structural gene, Pk-1sl, found in the inbred strain C57BL, has an unusual phenotype and affects the expression of pyruvate kinase in the liver but not erythrocyte. A possible mechanism for this tissue-specific structural gene mutation is suggested.

Animals↗
PubMed1991

Overview: industrial perspectives on existing in vivo gene mutation assays.

In vivo gene mutation assays are considered the most definitive for the evaluation of human health risks. Suggestions are provided here for the critical evaluation of the application of established in vivo gene mutation assays and alternative approaches in the evaluation of industrial chemicals. Objective evaluation of the assays and approaches based on sound science and practical issues will allow better application of the existing assays. Such an evaluation may also help illuminate areas of improvement, as well as help guide the development of future assays.

Animals↗
PubMed1975

Mutator genes and selection for the mutation rate in bacteria.

Gene frequencies in populations of haploid, asexual organisms are described by linear recurrence equations. Several models in which the mutation rate is controlled by one locus and the fitness is controlled at one or more other loci are developed. It is shown that good approximations can be introduced to give explicit solutions for the course of selection in these models. It is shown that a strong non-equilibrium selection for mutator genes is possible even when the presence of such a gene decreases the fitness of an individual. Experiments that corroborate these conclusions are discussed along with the effects of population size that determine the applicability of these results to natural populations.

Alleles↗
PubMed1992

Frequent association of p53 gene mutation in invasive bladder cancer.

Structural alterations of the p53 gene were investigated to elucidate the molecular biological difference between superficial and invasive bladder cancer by polymerase chain reaction single-strand conformation polymorphism analysis. In 25 bladder cancers obtained from 23 patients, p53 gene mutations were investigated in exon regions 4 to 11. Twenty-four were transitional cell carcinomas, and the remaining one was a squamous cell carcinoma. Only one of 13 superficial bladder cancers, including pTis, pTa, and pT1, was found to have p53 gene mutation. However, of 12 invasive bladder cancers with pT2, pT3, and pT4, six primary carcinomas, including a squamous cell carcinoma and one metastatic carcinoma, were found to have p53 gene mutations. The number of cancers examined in Grades 1, 2, and 3 was three, seven, and 15, respectively. p53 gene mutation was not found in any of the ten cancers with Grades 1 and 2, while eight of 15 bladder cancers with Grade 3 were found to have p53 gene mutation. The results indicated that the incidence of p53 gene mutations appeared to be much higher in invasive-type and high-grade bladder cancers than in superficial and low-grade ones. Our results are compatible with the recently published results by Sidransky et al. [Science (Washington DC), 252: 706-709, 1991] showing that p53 gene mutations were frequently found in invasive bladder cancers by sequence analysis on polymerase chain reaction amplified products corresponding to exons 5 to 9. Our results are also compatible with previously reported results by Olumi et al. (Cancer Res., 50: 7081-7083, 1990) showing that the loss of chromosome 17p, revealed by analysis with restriction fragment length polymorphism, was frequent in high-grade bladder cancers. In this study, p53 gene mutations were often found in exon 4 as well as in other exons. Therefore, this region should also be examined for screening of mutations of this gene in bladder cancer. There appeared to be no consistent mutation sites in exons 4 to 11 of the p53 gene and no specific patterns of the mutation in bladder cancer.

Base Sequence↗
PubMedDate not supplied

Oligotriche and quaking gene mutations. Phenotypic effects on mouse spermatogenesis and testicular steroidogenesis.

The phenotypic actions of the oligotriche gene mutation on testicular function have not been elucidated, although it is known that male mice homozygous for the mutation are infertile. In the present study, the effect of the oligotriche gene mutation on mouse testicular function was analyzed by comparing normal and mutant mice. Spermatogenesis was analyzed by enumerating germ cells in seminiferous tubules at specific stages of spermatogenesis and by electron microscopy. Steroidogenic potential was estimated by radioimmunometric determination of testosterone secreted by testes perfused in vitro. Parallel studies were completed for male mice homozygous for the quaking gene mutation, a mutation known to cause male mouse sterility by disrupting sperm tail development. The experimental results suggest that the oligotriche and quaking gene mutations interfere with sperm tail formation by different mechanisms. Testicular steroidogenesis was not affected by either gene mutation. The results provide the first evidence that the oligotriche gene mutation induces male mouse sterility by effecting the complete absence of a sperm tail. This phenotypic action is different from that of the quaking gene mutation.

Animals↗
PubMed2026

Metagenomic Deep Sequencing Identifies Gene Mutations Associated with Chemotherapeutic Resistance in Vitreoretinal Lymphoma.

PURPOSE: To identify gene mutations associated with chemotherapeutic resistance in patients with vitreoretinal lymphoma (VRL) using metagenomic deep sequencing (MDS) of intraocular specimens. METHODS: Patients with VRL confirmed by cytopathology and immunohistochemistry, flow cytometry, and/or polymerase chain reaction for MYD88, were included. Intraocular specimens underwent MDS of the host genome. Gene mutations were identified and cross-referenced with the Catalogue of Somatic Mutations in Cancer database to determine associations with chemotherapeutic resistance. RESULTS: Forty-nine patients with VRL underwent MDS, with six specimens from four patients revealing eight gene mutations associated with chemotherapeutic resistance. Four specimens from three patients harbored mutations associated with methotrexate resistance, the mainstay of VRL treatment. In one patient, serial sampling from the initial vitrectomy and two subsequent recurrences revealed distinct resistance-associated mutations at each time point. Despite multi-agent therapy including rituximab, consolidation regimens, and lenalidomide, this patient ultimately succumbed to the disease, whereas the other three patients remained in long-term remission. CONCLUSIONS: Our findings demonstrated that specific gene mutations associated with chemotherapeutic resistance may be harbored by VRL. The detection of different resistance mutations at sequential time points in one patient may reflect clonal selection, treatment pressure, or variable detection sensitivity. The ability to easily sample ocular fluid and detect different mutations associated with tumor recurrence or persistence may provide insights into tumor pathogenesis and could inform prognosis and influence treatment decisions. These findings establish a foundation for developing targeted PCR assays for identified resistance genes, which could transform clinical practice in VRL.

Chemotherapeutic resistance-associated mutations↗
PubMed1992

p53 gene mutation spectrum in hepatocellular carcinoma.

In order to clarify the significance of mutation of the p53 tumor suppressor gene in the genesis and development of human hepatocellular carcinoma (HCC) in an aflatoxin B1 low-exposure area, the spectrum, i.e., incidence, type, and site, of p53 gene mutations was examined in 169 tissue samples resected mainly from Japanese patients using single-strand conformation polymorphism analysis and direct sequencing. Forty-nine tumors (29%) showed a p53 mutation (39 point mutations and 10 frameshifts). The point mutations comprised 18 transitions, only 4 of which occurred at CpG sites, and 21 transversions. Two evolutionarily conserved domains, IV and V, contained 65% of all mutations and codon 249 was the most frequent mutation site (7/49). The spectrum of p53 mutation did not differ among HCCs in relation to the type of hepatitis virus infection, sex, age, and background liver disease of patients, tumor size, or presence of metastasis, but incidence and site were significantly associated with the degree of differentiation of cancer cells. In poorly differentiated HCC, p53 mutation was frequent (54%) and clustered on domains IV and V, whereas in well or moderately differentiated HCC, the mutation was less frequent (21%) and equally distributed on domains II to V. Restriction fragment length polymorphism analysis revealed loss of heterozygosity on chromosome 17p in 55 (69%) of 80 informative cases and in 34 (95%) of 36 cases with p53 mutation. Therefore, p53 gene mutation is suggested to occur independently of the type of viral infection or status of preexisting liver disease and to occur preferentially in moderately and poorly differentiated HCCs in association with or after loss of another p53 allele as a late event of HCC progression.

Adult↗
PubMed1992

[Tumor suppressor genes: mutations in RB and p53 genes are significant carcinogenic factors].

The RB and p53 tumour suppressor genes encode nuclear proteins that exert an inhibitive effect on cell growth. A large variety of human tumour types manifest loss or mutation of the RB or p53 genes, and p53 mutation is the commonest genetic alteration found in tumour cells. In addition, the RB and p53 proteins may be inactivated by complex formation with viral oncoproteins--for instance, in the case of cervical carcinoma carrying human papilloma virus. In vivo introduction of an intact RB or p53 gene into malignant cells lacking the respective gene results in suppression of the neoplastic phenotype and thus of tumourigenicity, p53 being the more potent of the two in this respect. Further elucidation of tumour suppressor genes may well result in future improvement in the diagnosis and treatment of cancer.

Genes, Retinoblastoma↗
PubMed1992

Detection of p53 gene mutations in human ovarian and endometrial cancers by polymerase chain reaction-single strand conformation polymorphism analysis.

The presence of mutations in the p53 gene was examined in ovarian cancers by a polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) analysis. The primers were designed to amplify exons 5 through 9 that contain phylogenetically conserved domains of the p53 gene. Mutations were detected in 5 out of 10 cases, one of which contained a deletion in the second allele. A single base substitution was detected in 4 cases at codons 162, 175, 205 and 273 and a single base insertion in one case within codon 315. A high frequency of p53 mutations in ovarian cancers and lack of mutation in 6 benign ovarian tumors and 2 normal ovaries suggested that the mutation of the p53 gene was associated with the genesis and/or progression of ovarian cancer. In 1 of 7 endometrial cancers, two mutations at codons 239 and 254 were detected.

Alleles↗