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At least 595 records · Page 33Linked to original sources
PubMed1999

Spontaneous mutation rate of measles virus: direct estimation based on mutations conferring monoclonal antibody resistance.

High mutation rates typical of RNA viruses often generate a unique viral population structure consisting of a large number of genetic microvariants. In the case of viral pathogens, this can result in rapid evolution of antiviral resistance or vaccine-escape mutants. We determined a direct estimate of the mutation rate of measles virus, the next likely target for global elimination following poliovirus. In a laboratory tissue culture system, we used the fluctuation test method of estimating mutation rate, which involves screening a large number of independent populations initiated by a small number of viruses each for the presence or absence of a particular single point mutation. The mutation we focused on, which can be screened for phenotypically, confers resistance to a monoclonal antibody (MAb 80-III-B2). The entire H gene of a subset of mutants was sequenced to verify that the resistance phenotype was associated with single point mutations. The epitope conferring MAb resistance was further characterized by Western blot analysis. Based on this approach, measles virus was estimated to have a mutation rate of 9 x 10(-5) per base per replication and a genomic mutation rate of 1.43 per replication. The mutation rates we estimated for measles virus are comparable to recent in vitro estimates for both poliovirus and vesicular stomatitis virus. In the field, however, measles virus shows marked genetic stability. We briefly discuss the evolutionary implications of these results.

Animals↗
PubMed2004

Mismatch repair gene PMS2: disease-causing germline mutations are frequent in patients whose tumors stain negative for PMS2 protein, but paralogous genes obscure mutation detection and interpretation.

The MutLalpha heterodimer formed by mismatch repair (MMR) proteins MLH1 and PMS2 is a major component of the MMR complex, yet mutations in the PMS2 gene are rare in the etiology of hereditary nonpolyposis colorectal cancer. Evidence from five published cases suggested that contrary to the Knudson principle, PMS2 mutations cause hereditary nonpolyposis colorectal cancer or Turcot syndrome only when they are biallelic in the germline or abnormally expressed. As candidates for PMS2 mutations, we selected seven patients whose colon tumors stained negative for PMS2 and positive for MLH1 by immunohistochemistry. After conversion to haploidy, truncating germline mutations of PMS2 were found in two patients (2192delTAACT and deletion of exon 8). These mutations abrogated PMS2 protein in germline cells by Western analysis. In two additional patients, PMS2 protein from one allele also was abrogated. Novel or previously described missense variants of PMS2 were detected, but their pathogenicity is undetermined. We detected and characterized a new transcript, PMS2CL, showing 98% sequence identity with exons 9 and 11-15 of PMS2 and emanating from a locus close to PMS2 in chromosome 7p. Its predicted protein product was not detected. Thus, in addition to several previously described PMS2-related genes resembling the 5' end of PMS2, at least one related gene resembles the 3' end of PMS2. In conclusion, both detectable and presently undefined germline mutations are deleterious and produce susceptibility to cancer by the two-hit mechanism. Paralogous genes interfere with mutation detection, resulting in underdiagnosis of PMS2 mutations. Mutation detection in PMS2 requires haploid DNA.

Adaptor Proteins, Signal Transducing↗
PubMed2006

Mutations in coagulation factor XIII A gene in eight unrelated Indians. Five novel mutations identified by a novel PCR-CSGE approach.

Factor XIII deficiency is a rare autosomal (1:2,000,000) recessive disorder of blood coagulation usually attributed to mutations in the coagulation factor XIII (FXIII) A gene. We have studied the molecular basis of FXIII deficiency in eight unrelated South Indian patients. Their diagnosis was based on clinical history, normal plasma clotting times and increased solubility of fibrin clot in 5 mol/l urea. Genomic DNA was screened for FXIII A gene defects by a novel PCR and CSGE strategy. Mutations were identified in all these patients. Five of these were novel mutations occurring in four patients. These included a novel c.210T > G transversion in homozygosity in exon 3 predicting a Tyr69X in the beta-sandwich domain in one patient. Another patient was compound heterozygote for a novel c.791C > T transition predicting a Ser263Phe in the core domain and a novel c.2045-1G > A transition at the acceptor splice junction of intron 14. Two novel frame shifts were also identified in two patients in a homozygous condition. One of them resulted from a single base 'G' duplication (c.892_895dupG) at codons Ser290/Ala291fs affecting the core domain and the other was due to a single base 'A' duplication (c.1642_1644dupA) and at codonTyr547fs affecting barrel-1 domain. The remaining four patients had the previously reported Arg260His, Ser413Leu, and Val414Phe (n = 2) missense mutations in the core domain. The novel mutations identified were considered to be disease causative by studying the nature of mutation, the degree of conservation of the mutated aminoacid among transglutaminases of different species and by molecular modeling. Apart from describing a significant number of novel mutations, this report is the first study from Southern India to describe FXIII A gene mutations.

Adolescent↗
PubMed1999

Splicing mutations in KCNQ1: a mutation hot spot at codon 344 that produces in frame transcripts.

BACKGROUND: Long-QT syndrome is a monogenic disorder that produces cardiac arrhythmias and can lead to sudden death. At least 5 loci and 4 known genes exist in which mutations have been shown to be responsible for the disease. The potassium channel gene KCNQ1, previously named KVLQT1, on chromosome 11p15.5 is one of these. METHODS AND RESULTS: We initially analyzed one family using microsatellite markers and found linkage to KCNQ1. Mutation detection showed a G to C change in the last base of exon 6 (1032 G-->C) that does not alter the coded alanine. Restriction digest analysis in the family showed that only affected individuals carried the mutation. A previous report suggested that a G to A substitution at the same position may act as a splice mutation in KCNQ1, but no data was given to support this hypothesis nor was the transcription product identified. We have shown by reverse-transcription polymerase chain reaction that 2 smaller bands were produced for the KCNQ1 gene transcripts in addition to the normal-sized transcripts when lymphocytes of affected individuals were analyzed. Sequencing these transcripts showed a loss of exon 7 in one and exons 6 and 7 in the other, but an in-frame transcript was left in each instance. We examined other families in whom long-QT syndrome was diagnosed and found another unreported splice-site mutation, 922-1 G-->C, in the acceptor site of intron 5, and 2 of the previously reported 1032 G-->A mutations. All these showed a loss of exons 6 and 7 in the mutant transcripts, validating the proposal that a consensus sequence is affected in the exonic mutations and that the integrity of the base at position 1032 is essential for correct processing of the transcript. CONCLUSIONS: The 6 cases already reported in the literature with the 1032 G-->A transition, the novel 1032 G-->C transversion, and a recent G-->T transversion at the same base show that codon 344 is the second most frequently mutated after codon 341, suggesting at least two hotspots for mutations in KCNQ1.

Child, Preschool↗
PubMed2000

Effects of flecainide in patients with new SCN5A mutation: mutation-specific therapy for long-QT syndrome?

BACKGROUND: Mutations in the cardiac sodium channel gene (SCN5A) can cause one variant of the congenital long-QT syndrome. The effects of some of these mutations on the alpha-subunit channel properties can be blocked by type Ib antiarrhythmic drugs. Recently, we have described a new SCN5A mutation (D1790G) that affects the channel properties in a manner suggesting that sodium blockers of the Ib type will be ineffective in carriers of this mutation. Hence, the ECG effects of flecainide-acetate, a type Ic sodium blocker, were evaluated in carriers of this mutation. METHODS AND RESULTS: Eight asymptomatic mutation carriers and 5 control subjects were studied. Intravenous lidocaine was tested first in only 2 mutation carriers and had no significant effect on any ECG parameter. Flecainide significantly shortened all heart rate-corrected repolarization duration parameters only in carriers and not in control subjects: QT(c) shortened by 9.5% (from 517+/-45 to 468+/-36 ms, P=0.011), and the S-offset to T-onset interval shortened by 64.7% (from 187+/-88 to 66+/-50 ms, P=0.0092). Flecainide also normalized the marked baseline repolarization dispersion in most mutation carriers. These effects among carriers were maintained during long-term (9 to 17 months) outpatient flecainide therapy with no adverse effects. CONCLUSIONS: This report is the first to describe SCN5A mutation carriers who significantly responded to flecainide therapy yet did not respond to lidocaine. These results have important implications for long-QT allele-specific therapeutic strategies.

Anti-Arrhythmia Agents↗
PubMed2004

Ramifications of four concurrent thrombophilic mutations and one hypofibrinolytic mutation.

A kindred was examined in which the 48-year-old white female proband with three deep venous thrombosis-pulmonary emboli events had four thrombophilic and one hypofibrinolytic mutations, and in which her 14-year-old asymptomatic daughter had four thrombophilic mutations. The proband was heterozygous for the G1691A factor V Leiden, G20210A prothrombin, and platelet glycoprotein IIIa PL A1/A2 mutations, had high factor VIII (221%), and was homozygous for the 4G4G plasminogen activator inhibitor-1 gene mutation, with high plasminogen activator inhibitor activity (23.7 U/mL). Her 14-year-old daughter was homozygous for the G1691A factor V Leiden and platelet glycoprotein IIb-IIIa PL A2/A2 mutations, compound heterozygous for the C677T and A1298C methylenetetrahydrofolate reductase (MTHFR) mutations, and heterozygous for the G20210A prothrombin mutation, a combination with an estimated likelihood of 1.6 x 10(-7). In 247 white healthy controls, there was no V Leiden homozygosity and no V Leiden-prothrombin gene compound heterozygosity. Heterozygosity for the V Leiden and prothrombin gene mutations was 3.2% and 4.1%, respectively. Homozygosity for the platelet glycoprotein IIb-IIIa PL A2A2, PAI-1 gene 4G4G, and C677T MTHFR mutations was 3.2%, 22.7%, and 12%, respectively. The proband will receive anticoagulation therapy for life. Beyond aspirin, avoidance of exogenous estrogens, and enoxaparin prophylaxis during pregnancy, it is not known whether the proband's daughter should have lifelong anticoagulation therapy, or only after her first thrombotic event.

Blood Coagulation Disorders↗
PubMed2006

Does tumorigenesis select for or against mutations of the DNA repair-associated genes BRCA2 and MRE11?: considerations from somatic mutations in microsatellite unstable (MSI) gastrointestinal cancers.

BACKGROUND: The BRCA2 and MRE11 proteins participate in the repair of double-strand DNA breaks by homologous recombination. Germline BRCA2 mutations predispose to ovarian, breast and pancreatic cancer, while a germline MRE11 mutation is associated with an ataxia telangiectasia-like disorder. Somatic mutations of BRCA2 are rare in typical sporadic cancers. In tumors having microsatellite instability (MSI), somatic truncating mutations in a poly [A] tract of BRCA2 are reported on occasion. RESULTS: We analyzed gastrointestinal MSI cancers by whole gene BRCA2 sequencing, finding heterozygous truncating mutations in seven (47%) of 15 patients. There was no cellular functional defect in RAD51 focus-formation in three heterozygously mutated lines studied, although other potential functions of the BRCA2 protein could still be affected. A prior report of mutations in primary MSI tumors affecting the IVS5-(5-15) poly [T] tract of the MRE11 gene was confirmed and extended by analysis of the genomic sequence and protein expression in MSI cancer cell lines. Statistical analysis of the published MRE11 mutation rate in MSI tumors did not provide evidence for a selective pressure favoring biallelic mutations at this repeat. CONCLUSION: Perhaps conflicting with common suspicions, the data are not compatible with selective pressures during tumorigenesis promoting the functional loss of BRCA2 and MRE11 in MSI tumors. Instead, these data fit closely with an absence of selective pressures acting on BRCA2 and MRE11 gene status during tumorigenesis.

Apoptosis Regulatory Proteins↗
PubMed2000

Phenotype of AD-HSP due to mutations in the SPAST gene: comparison with AD-HSP without mutations.

BACKGROUND: "Pure" autosomal dominant hereditary spastic paraparesis (AD-HSP) is clinically and genetically heterogeneous. There are at least seven genetic loci with varying ages at onset and disability. The SPAST gene at the SPG4 locus on chromosome 2p is the major disease gene for AD-HSP. OBJECTIVES: To investigate whether there are distinct clinical features among families with AD-HSP due to SPAST mutations compared with families excluded from SPG4. METHODS: Nineteen families with "pure" AD-HSP were identified, and the clinical features of family members were compared using a standard protocol. With use of genetic studies, the families were divided into two groups for comparison: those with mutations in SPAST, the "mutation-positive" group, and those excluded from SPG4 on the basis of linkage studies, the "SPG4-excluded" group. RESULTS: Twenty-nine individuals from four families had mutations in SPAST, whereas 22 individuals from three families comprised the SPG4-excluded group; in 11 families, the pattern of linkage was unknown. In the one remaining family, no mutations were found despite strong linkage to SPG4. Different mutations were identified in the four SPAST pedigrees, but the clinical picture was similar in each. Comparison of the mutation-positive group with the SPG4-excluded group revealed an older age at onset (p = 0.03), more disability (p = 0.001), more rapidly progressive paraparesis (p = 0.044), and more cognitive impairment (p = 0.024) among affected individuals with SPAST mutations, not confounded by disease duration. CONCLUSION: Despite different mutations, SPAST families have a similar phenotype that can be distinguished from other genetic groups.

Adenosine Triphosphatases↗
PubMed2006

Multiplex tetra-primer amplification refractory mutation system PCR to detect 6 common germline mutations of the MUTYH gene associated with polyposis and colorectal cancer.

BACKGROUND: We describe a simple tetra-primer amplification refractory mutation system PCR (T-ARMS-PCR) for detecting MUTYH mutations, which are associated with colorectal adenomas and colorectal cancer. METHODS: We designed specific T-ARMS-PCR assays for 6 mutations (Y165C, G382D, 1395_7delGGA, Y90X, 1103delC, and R231H) selected on the basis of the frequency of their occurrence. We also designed a set of 3 multiplex T-ARMS PCR assays, each for detection of 2 mutations. We tested DNA samples from patients with attenuated or classic adenomatous polyposis coli and no detectable APC germline mutations. RESULTS: All mutations were easily detected with both the specific and multiplex T-ARMS-PCR assays. Results were confirmed by DNA HPLC analysis in all 54 patients, and each mutation was confirmed by direct DNA sequencing. CONCLUSIONS: T-ARMS-PCR does not require any special equipment, and it provides rapid, reproducible, and cost-effective detection of common MUTYH mutations. Multiplex T-ARMS-PCR allows the detection of 6 common MUTYH mutations with use of as few as 3 single tube PCR reactions. It could be useful to carry out large population-based epidemiologic studies.

Adenomatous Polyposis Coli↗
PubMed2002

uvsZ1 mutation shows epistatic relations with uvsD153 and uvsJ1 mutations without any involvement with checkpoint control in Aspergillus nidulans.

The participation of the recently described uvsZ1 mutation in checkpoint control and the identification of epistatic relations between uvsZ1 mutation and uvsD153 and uvsJ1 mutations are provided. The effect of mutation uvsZ1 in mitotic exchanges into paba-bi (chromosome I) and cho-nic (chromosome VII) genetic intervals has also been evaluated. The mutation uvsZ1 was epistatic with regard to uvsD153 and uvsJ1 mutations, with no involvement with checkpoint control. In contrast to mutations in UvsB and UvsF groups, the uvsZ1 mutation failed to cause any changes in the frequencies of mitotic crossing-over. The distinct phenotypic traits given by mutation uvsZ1 suggest the presence of complex interactions among the different DNA repair pathways. Interaction may be an additional cell strategy of DNA damage response.

Aspergillus nidulans↗
PubMed1999

[p53 tumor suppressor gene mutation and prognosis in 105 cases of bladder cancer--the relationship between mutation of the p53 gene with clinicopathological features and smoking].

PURPOSE: Alterations of the p53 tumor suppressor gene are the most common genetic change detected in human cancers. The incidence of p53 gene mutation in bladder tumor patients were studied and were compared with clinicopathological findings, smoking history and prognosis. MATERIALS AND METHODS: Polymerase chain reaction single-strand conformation polymorphism (PCR-SSCP) was used for analysis from exon 4 to 9 of p53 gene in 105 cases of primary bladder tumors. RESULT: p53 matations were detected in 38 or 105 patients (36.2%). Kaplan-Meier Survival curves fo groups wit or without p53 gene mutation show a statistically significant difference (p = 0.0098). The mutation of p53 gene in stages pT 1 pT 1. pT 2, pT 3, pT 4 was found in 2 of 12 (16.7%), 8 of 32 (25.0%), 10 of 25 (40.0%), 12 of 20 (60.0%), 6 of 16 (37.5%) and in grades I, II, III, was noted in 1 of 17 (5.9%), 16 of 49 (32.7%), 21 of 39 (53.8%) cases, respectively. Significant differences were found for groups with grade I and grade II-III (p = 0.0045) cancers and in cases of superficial (stage pTa-1) and muscle-invasive (pT 2-4) tumors (p = 0.0148). However, mutation of p53 was not related to either age or sex in 105 patients. Recurrence rates in stage pTa-1 superficial tumor group with or without p53 mutation showed a statistically significant difference (p = 0.0419). No statistically significant difference was noted between p53 mutation and habitual smoking as well as durations of smoking. CONCLUSIONS: p53 mutations occur more commonly in higher grades and later stages of bladder tumors. Our results suggest that the prognostic factor is linked to not only histological findings but also to the presence of p53 mutation. The mutations of the p53 gene may be involved in the late events of tumorigenesis and might be used as good molecular markers for prognosis in bladder tumor.

Aged↗
PubMed1999

Detection of mutations in the enhancer 2/core promoter region of hepatitis B virus in patients with chronic hepatitis B virus infection: comparison with mutations in precore and core regions in relation to clinical status.

To investigate the meaning of the mutations in the enhancer 2/core promoter (Enh2/CP) region of hepatitis B virus (HBV) during the chronic HBV infection, mutations were examined in the Enh2/ CP region (carboxyl half of X region) and their correlation with mutations in the precore and core regions in relation to the presence of chronic liver disease. The entire nucleotide sequences of the Enh2/CP region were determined by direct sequencing of the amplified products derived from 30 cases with chronic HBV infection. The results were compared to the mutations in the precore and core regions. In the Enh2/CP region, 91 generally scattered nucleotide substitutions were detected. There were 11 substitutions in the 10 asymptomatic healthy carriers (mean, 1.1/case) and 80 in the 20 chronic liver disease patients (4.0/case). The most frequent substitutions from A to T at nucleotide 1764 and from G to A at nucleotide 1766 were seen in none of the 10 asymptomatic carriers and in 14 (70%) of the 20 chronic liver disease patients. Comparisons of mutations in the precore and core regions revealed that 14 of 16 patients with mutations in the core region had the mutations in the Enh2/CP region and/or a precore stop codon mutation. These data suggest that mutations in the Enh2/CP and precore regions may affect the expression of the core and HBeAg peptides and might be involved in the pathogenesis of chronic liver disease.

Adolescent↗
PubMed1999

Detection of mutations of p53 tumor suppressor gene in pancreatic juice and its application to diagnosis of patients with pancreatic cancer: comparison with K-ras mutation.

Because of the difficulty in obtaining biopsy specimens from pancreatic cancer patients, K-ras mutation analysis in pancreatic juice has been used for specific diagnosis. But recently, false positives have been obtained with this method. To improve the genetic diagnosis of pancreatic cancer, detection of p53 gene mutation in pancreatic juice was studied. Pancreatic juice was sampled endoscopically. Single-strand conformation polymorphism analysis was used for p53 mutation analysis. Furthermore, K-ras mutations at codon 12 were also studied in the same pancreatic cancer patients. Of 26 cases of pancreatic cancer, p53 mutations were detected in 11 (42.3%). No mutations were seen in the cases with mucin-producing adenoma nor with chronic pancreatitis. K-ras mutations were detected in 84.0% of cases by RFLP analysis, which has high sensitivity, and in 65.3% by hybridization protection assay, which has high specificity. Using a combination assay with both genes, genetic abnormalities were detected in 92.0% by RFLP and 73.1% by hybridization protection assay including two cases in which p53 alone was positive by both methods. The specificity of p53 mutation for pancreatic cancer is very high. Therefore, simultaneous analysis of p53 and K-ras mutation is suggested to enhance the genetic diagnosis of pancreatic cancer.

Aged↗
PubMed1999

Detection of five rare cystic fibrosis mutations peculiar to Southern Italy: implications in screening for the disease and phenotype characterization for patients with homozygote mutations.

BACKGROUND: The search for the eight most frequent mutations (i.e., DeltaF508, G542X, W1282X, N1303K, 1717-1G-->A, R553X, 2183AA-->G, and I148T) by allele-specific oligonucleotide dot-blot analysis revealed 78% of 396 cystic fibrosis alleles in Southern Italy. The observation of frequent haplotypes on the unidentified cystic fibrosis alleles suggested that a few mutations could account for a large number of unidentified alleles. METHODS: We screened most of the coding sequence of the cystic fibrosis transmembrane regulator gene by denaturing gradient gel electrophoresis to determine the spectrum of these mutations in 68 unrelated cystic fibrosis patients bearing one or both unidentified mutations. RESULTS: The screening revealed five mutations, R1158X, 711+1G-->T, 4016insT, L1065P, and G1244E, each of which had a frequency of 1.3-1.8% (7% collectively). The 7% increase in the detection rate (85% vs 78%) reduces by >50% the residual risk of being cystic fibrosis carriers for couples who had tested negative by molecular analysis. We therefore designed a second allele-specific oligonucleotide set to analyze the five mutations. Among the patients analyzed, one patient homozygous for the L1065P mutation expressed a mild pulmonary and intestinal form of the disease with pancreatic insufficiency. Two other patients, homozygous for mutations R1158X and 4016insT, both expressed a severe cystic fibrosis phenotype. CONCLUSIONS: Five cystic fibrosis mutations are peculiar to patients from Southern Italy. The method described for their analysis is efficient, inexpensive, and can be semi-automated by use of a robotic workstation. The results obtained in patients from Southern Italy may have an impact on laboratories in other countries, given the large migrations of populations from Southern Italy to other countries in the last two centuries.

Adult↗
PubMed1998

Truncating somatic mutation in exon 15 of the APC gene is a rare event in human breast carcinomas. Mutations in brief no. 179. Online.

Inactivation of the adenomatous polyposis coli (APC) gene is an early event in sporadic colorectal cancer. Somatic mutations have also been detected in cancers of the stomach, pancreas, thyroid, ovary and breast. Over 95% of the mutations reported in the APC gene are frameshift and nonsense mutations. The large exon 15 accounts for 77% of the coding sequence. The APC gene product interacts with cytoplasmic beta-catenin, mediates its degradation and thereby downregulates transcription exerted by the beta-catenin-Tcf complex. In the absence of a functional APC protein, beta-catenin is stabilized and accumulates in the cytoplasm. This results in uncontrolled transcriptional activation of Tcf responsive genes which may contribute to cancer progression. In order to investigate whether this pathway is disrupted by APC mutations in breast carcinoma cells, we screened 227 breast tumors for truncating mutations in exon 15 using the protein truncation test (PTT). Only one mutation, 4678delA, which was shown to be somatic, was detected by this approach. The mutation resided just outside the mutation cluster region (MCR) and resulted in a premature stop in codon 1564. Our findings do not indicate that the suppressive function of APC is commonly abrogated by truncating mutations in human breast carcinomas.

Alternative Splicing↗
PubMed1992

Association of a nonsense mutation (W1282X), the most common mutation in the Ashkenazi Jewish cystic fibrosis patients in Israel, with presentation of severe disease.

Only about 30% of the cystic fibrosis chromosomes in the Israeli cystic fibrosis patient populations carry the major CF mutation (delta F508). Since different Jewish ethnic groups tended to live as closed isolates until recent times, high frequencies of specific mutations are expected among the remainder cystic fibrosis chromosomes of these ethnic groups. Genetic factors appear to influence the severity of the disease. It is therefore expected that different mutations will be associated with either severe or mild phenotype. Direct genomic sequencing of exons included in the two nucleotide-binding folds of the putative CFTR protein was performed on 119 Israeli cystic fibrosis patients from 97 families. One sequence alteration which is expected to create a termination at residue 1282 (W1282X) was found in 63 chromosomes. Of 95 chromosomes, 57 (60%) are of Ashkenazi origin. Together with the delta F508 (23% in this group), G542X, N1303K, and 1717-1G----A mutations, the identification of 92% of cystic fibrosis chromosomes of Ashkenazi origin becomes possible. Patients homozygous for the W1282X mutation (n = 16) and patients heterozygous for the delta F508 and W1282X mutations (n = 22) had similarly severe disease, reflected by pancreatic insufficiency, high incidence of meconium ileus (37% and 27%, respectively), early age at diagnosis, poor nutritional status, and variable pulmonary function. In conclusion, the W1282X mutation is the most common cystic fibrosis mutation in the Ashkenazi Jewish patient population in Israel. This nonsense mutation is associated with presentation of severe disease.

Cystic Fibrosis↗
PubMed1990

Multiple mutations of the human cytochrome P450IID6 gene (CYP2D6) in poor metabolizers of debrisoquine. Study of the functional significance of individual mutations by expression of chimeric genes.

The debrisoquine/sparteine-type polymorphism is a clinically important inherited variation of drug metabolism characterized by two phenotypes, the extensive metabolizer and the poor metabolizer (PM). Five to 10 percent of individuals in Caucasian populations are of the PM phenotype and have deficient metabolism of debrisoquine and over 25 other drugs. Our previous studies have revealed absence of cytochrome P450IID6 protein and aberrant splicing of IID6 premRNA in livers of PMs. Moreover, two mutant alleles of the P450IID6 gene locus (CYP2D6) were identified by restriction fragment length analysis to be associated with the PM phenotype. However, the mutations of the CYP2D6 gene causing absent P450IID6 protein have not been defined. Here we report the cloning and sequencing of two types of mutant alleles of CYP2D6 isolated from genomic libraries of three PM individuals. One allele (29-A) was characterized by a single nucleotide deletion in the 5th exon with consequent frameshift and was observed in one individual only. The other type of mutant allele (29-B) was present in all three PM individuals and its sequence contained multiple mutations, notably four base changes causing amino acid changes in exons 1, 2 and 9, and a point mutation at the consensus sequence of the splice site of the 3rd intron. To understand the significance of the individual mutations, chimeric genes were constructed between the wild-type IID6 gene and the mutant 29-B allele or site-specific mutations were introduced into the IID6-cDNA and these DNA constructs were transiently expressed in COS-1 cells. The mutations in exon 1 resulted in a functionally deficient IID6 protein and the mutation at the splice site in absent IID6 protein, whereas the mutations in exons 2 and 9 were of no consequence for IID6 function. Only the mutation at the splice site thus explains the absence of P450IID6 protein in livers of PM individuals and appears to be a common cause of polymorphic drug oxidation.

Alleles↗
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↗