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PubMed2001

Recurrent mutations in P- and T-proteins of the glycine cleavage complex and a novel T-protein mutation (N145I): a strategy for the molecular investigation of patients with nonketotic hyperglycinemia (NKH).

Screening a DNA bank from 50 patients with enzymatic confirmation of their diagnosis of nonketotic hyperglycinemia gave allele frequencies of 5% for R515S of P-protein (glycine decarboxylase) and 7% for R320H of T-protein (aminomethyltransferase). In a previous report we found that 3% of the same patient alleles were positive for T-protein IVS7-1G>A. In total, testing for these three mutations identified 15% of alleles and positive results (one or two mutations) were found in 11 of the 50 patients. In addition, a novel point mutation in T-protein, N145I, was found in a single case and a PCR/restriction enzyme assay was developed for its detection.

Amino Acid Oxidoreductases↗
PubMed1995

Clinical characteristics of 16 cystic fibrosis patients with the missense mutation R334W, a pancreatic insufficiency mutation with variable age of onset and interfamilial clinical differences.

We present the genotype/phenotype correlation analysis for 16 cystic fibrosis (CF) patients who carry mutation R334W. Current age and age of diagnosis was significantly higher in the R334W/any-mutation group (P < 0.05 and P < 0.01), compared with the delta F508/delta F508 group. A slightly, but not significantly, worse lung function was found in the R334W/any-mutation group, when compared with the delta F508/delta F508 patients. The proportion of patients with lung colonization with bacterial pathogens was slightly, but not significantly, higher in the R334W/any-mutation group (71.4%), compared with the delta F508/delta F508 or R334W/delta F508 groups (55.5%). None of the R334W patients had meconium ileus but 60% were pancreatic insufficient (PI), a significantly lower proportion (P << 0.001) than delta F508/delta F508 patients. Two R334W/N1303K compound heterozygous sisters of three sibs with genotype R334W/delta F508 showed interfamilial discordant clinical data for lung and pancreatic function. The data provided here for mutation R334W demonstrate that this mutation is responsible for a less severe form of CF than delta F508. Interfamilial differences for PI and lung function suggest that other factors, viz. genetic, environmental and medical, contribute to the wide spectrum of clinical differences observed in CF patients with the same CF transmembrane conductance regulator genotypes.

Age of Onset↗
PubMed1981

Mutations affecting translational fidelity in the eucaryote Podospora anserina: characterization of two ribosomal restrictive mutations.

Fifty-nine mutations that restrict suppressor efficiency were selected in the fungus Podospora anserina using four different screening methods. Previous genetic analysis has shown that these antisuppressors lie in six loci and that they could be similar to ribosomal restrictive mutations known in Escherichia coli. The present study deals with the response of two of them, AS1-1 and AS6-1, to paromomycin and low temperature both in vivo and in vitro. The data demonstrate that ribosomes of the mutant and double-mutant strains are equally resistant to the ambiguity effect of paromomycin. These data are the first demonstration of mutations that increase translational fidelity in eucaryotic organism.

Ascomycota↗
PubMed1989

Hungarian surveillance of germinal mutations. Lack of detectable increase in indicator conditions caused by germinal mutations following the Chernobyl accident.

The Hungarian surveillance of germinal mutations is based on three indicator conditions seen in offspring, i.e., 15 sentinel anomalies, Down syndrome and component anomaly pairs of unidentified multiple congenital anomalies. It is an "opportunistic program," because the necessary data are available from the Hungarian Congenital Malformation Registry. This system is described and the criteria of a good registry are summarized. The analysis of indicator conditions caused by germinal mutations did not reveal any measurable mutagenic effects in Hungary following the accident at the Chernobyl nuclear power plant. The pros and cons of germinal mutation surveillance are discussed.

Abnormalities, Multiple↗
PubMed1986

The same "TATA" box beta-thalassemia mutation in Chinese and US blacks: another example of independent origins of mutation.

A Chinese beta +-thalassemia gene in a new haplotype was chosen for cloning and sequencing. The mutation identified was an A-G transition at position -29 in the TATA box of the beta-globin gene. This mutation has not been seen previously in Chinese but has been documented in American blacks on a different chromosomal background. This observation provides further evidence for independent origins of the same mutation in distinct ethnic groups.

Asian People↗
PubMed1988

The phenotypic suppression of a mutation in the gene rplX for ribosomal protein L24 by mutations affecting the lon gene product for protease LA in Escherichia coli K12.

A suppressor mutation of a temperature-sensitive mutant of ribosomal protein L24 (rplX19) was mapped close to the lon gene by genetic analysis and was shown to affect protease LA. The degradation and the synthesis rates of individual ribosomal proteins were determined. Proteins L24, L14, L15 and L27 were found to be degraded faster in the original rplX19 mutant than in the rplX19 mutant containing the suppressor mutation. Other ribosomal proteins were either weakly or not at all degraded in both mutants. Temperature-sensitive growth was also suppressed by the overproduction of mutant protein L24 from a plasmid. Our results suggest that (1) either free ribosomal proteins or proteins bound to abortive assembly precursors are highly susceptible to the lon gene product and (2) the mutationally altered protein L24 can still function at the nonpermissive growth temperature of the mutant, if it is present in sufficient amounts.

ATP-Dependent Proteases↗
PubMed1983

Frameshift mutations induced by an Escherichia coli strain carrying a mutator gene, mutD5.

We have studied eight frameshift mutations induced by the Escherichia coli mutator allele mutD5 in a derivative of the bacteriophage M13mp8, carrying an insertion of 91 base pairs derived from the tetR gene of pBR 322. All mutations were analyzed by the dideoxy sequencing method and were found to be deletions of a GC base pair which occurred in regions characterized by the presence of at least two GC base pairs. We have attempted to explain these results by the looping-out model, which was previously proposed to unify the results obtained with mutD5.

Base Sequence↗
PubMed1982

Analysis of revertants of a ribosomal mutation in Podospora anserina: evidence for new ribosomal mutations which confer hypersensitivity to paromomycin.

This paper describes the analysis of cold-resistant revertants of a cold-sensitive mutant. Pm1-1 is a ribosomal mutation screened for its paromomycin resistance. Suppression of its cold sensitivity occurs with two kinds of external mutations localized in two different loci. One of them, PmB, is assumed to be a ribosomal gene. PmB mutations confer hypersensitivity to paromomycin in vivo as well as in vitro in a cell-free protein synthesis system.

Ascomycota↗
PubMed1996

Mutations in STS1 suppress the defect in 3' mRNA processing caused by the rna15-2 mutation in Saccharomyces cerevisiae.

In a search for proteins associated with Rna15p in processing the 3' ends of messenger RNAs, we have looked for suppressors that correct, even partially, the thermosensitive growth defect of the rna15-2 mutant. Mutations in a single locus that we named SSM5, were able to suppress both the thermosensitivity of cell growth and the mRNA 3' processing defect associated with the rna15-2 mutation, but only slightly alleviated the thermosensitive growth defect of an rna14-1 mutant. The ssm5-1 mutant is sensitive to hydroxyurea at 37 degrees C, a drug that inhibits DNA synthesis. By screening for complementation of the hydroxyurea-sensitive phenotype we cloned the corresponding wild-type gene and found that it corresponds to the essential gene STS1 (also named DBF8). Sts1p has an apparent molecular weight of 30 kDa and was confirmed to be a cytosolic protein by immunofluorescence analysis. Western blot analysis indicates that the thermosensitive mutant strains rna15-2, rna14-1 and pap1-1 present a very low level of the Rna15p at 37 degrees C. The ssm5-1 mutation restores the level of Rna15p in the rna15-2 ssm5-1 double mutant. Use of the two-hybrid system suggests that Sts1p does not interact directly with Rna15p, but may be active as a homodimer. The present data suggest that Sts1p may play a role in the transport of Rna15p from the cytoplasm to the nucleus.

ATP-Binding Cassette Transporters↗
PubMed1994

Spectrum of spontaneous missense mutations causing cyclic AMP-resistance phenotypes in cultured S49 mouse lymphoma cells differs markedly from those of mutations induced by alkylating mutagens.

Mutants of S49 mouse lymphoma cells resistant to cytolysis by analogs of cyclic AMP (cAMP) generally have missense mutations in the gene encoding the regulatory subunit of cAMP-dependent protein kinase. We have compared the mutations in 95 spontaneous isolates with those in 60 mutagen-induced isolates by sequence analysis of amplified cDNAs. Twenty-nine single basepair substitutions in 19 codons produced selectable phenotypes. The spontaneous mutant spectrum was dominated by a CpG transition hotspot in the codon for Arg334. This and other nearby CpG sites were found to be methylated in genomic S49 cell DNA by restriction enzyme analyses. Most of the remaining spontaneous mutants had either G-C-->C-G or T-A-->G-C transversions, which have been associated with damage caused by oxygen radicals. In contrast, the majority of mutants induced with the alkylating mutagens ethyl methanesulfonate (EMS) and N-methyl-N'-nitro-N-nitrosoguanidine had G-C-->A-T mutations at non-CpG sites; in addition, EMS induced several A-T-->G-C, A-T-->T-A, and G-C-->T-A substitutions. A single ICR191-induced mutant analyzed had a unique A-T-->G-C lesion. A number of spontaneous and mutagen-induced isolates had closely linked double or triple substitutions, and two isolates had tandem triple substitutions.

Alkylating Agents↗
PubMed1987

Inhibition of mutation induction and unchanged mutational specificity in Escherichia coli K12 overproducing the RecA protein.

Induced mutagenesis was studied in Escherichia coli K12 cells in relation to the level of RecA-protein (P-RecA). In experiments strains AB2497, AB2497(pBR322) and AB2497(pX02) were used. The multicopy plasmid pX02 is a recombinant of pBR322 and recA+ gene of E. coli K12. Cells carrying this plasmid overproduce the P-RecA constitutively. Mutagenesis was induced by the decay of incorporated 6-3H-thymidine. Mutations of the argE3 (ochre) to Arg+ prototrophy were followed. Besides the frequency of mutations, mutagenic specificity was determined. In cells AB2497(pX02) which overproduce the P-RecA the yield of Arg+ revertants was markedly reduced compared with that in strains AB2497 or AB2497(pBR322), whereas the mutagenic specificity was not changed. In all the strains studied the predominant type of mutation produced was the base substitution in the A:T base pair.

Escherichia coli↗
PubMed2026

Co-mutation Based Genetic Networks to Infer Temporal Mutation Dynamics in Ancient Human Mitochondrial Genomes.

The evolutionary history of Homo sapiens is marked by complex interactions between environmental, cultural, and genetic factors. To investigate the molecular signatures of these processes, we analyzed ancient mitochondrial DNA (mtDNA) across temporal and geographic contexts using principles of co-occurrence of minor alleles defined as co-mutation, through spatiotemporal co-mutation networks of variable sites. Haplogroup-based assessments of variable sites revealed a major transition from foraging to agrarian lifestyles during the Copper-Bronze Age. Genetic network analyses demonstrated that COX and CYB loci exhibited distinct temporal dynamics, with their interactions modulated by NADH dehydrogenase genes in a geological age-dependent manner. To complement the network approach, we constructed phylogeny-based gene interaction networks and assessed polymorphism-to-divergence from chimpanzee ratios. The tree-based networks displayed topologies consistent with co-mutation analyses but showed reduced gene-gene connectivity. Polymorphism/divergence analysis further indicated that the CYB gene has been under long-term purifying selection, whereas ATP6, COX, and NADH dehydrogenase genes experienced episodic purifying selection aligned with distinct historical phases. Collectively, our findings demonstrate that network-based analysis of ancient mtDNA provides insights into early human lifestyle transitions and haplogroup diversification, contributing to the evolutionary foundations of modern human populations.

Ancient humans↗
PubMed2006

DPYD*2A mutation: the most common mutation associated with DPD deficiency.

BACKGROUND: Dihydropyrimidine dehydrogenase (DPD) enzyme is responsible for the elimination of approximately 80% of administered dose of 5-FU. DPD deficiency has been associated with severe 5-FU toxicity. Syndrome of DPD deficiency manifests as diarrhea, stomatitis, mucositis, and neurotoxicity and in some cases death. This is a true pharmacogenetic syndrome, with symptoms being unrecognizable until exposure to the drug. PATIENTS AND METHODS: A 75-year-old patient with metastatic pancreatic adenocarcinoma developed grade 4 thrombocytopenia, grade 3 coagulopathy, and grade 3 neurologic toxicity with a fatal outcome following administration of 5-FU. Due to pancytopenia, DPD activity could not be determined in peripheral blood mononuclear cells (PBMC) using a previously described radioassay. Therefore, screening and genotypic analysis of homozygous and heterozygous, known and unknown sequence variants, in the DPYD gene were performed using DHPLC as previously described. All DPYD sequence variants identified by DHPLC were confirmed by DNA sequencing using a dideoxynucleotide chain termination method and capillary electrophoresis on an ABI 310 Automated DNA Sequencer. RESULTS: Genotyping analysis of the DPYD gene revealed the presence of the heterozygous mutation, IVS14 + 1 G > A, DPYD*2A. CONCLUSION: Genotypic analysis using DHPLC can be employed to screen DPD deficiency in a patient with severe neutropenia. The mutation IVS14 + 1 G > A, DPYD*2A, is the most common mutation associated with DPD deficiency. A G > A base change at the splice recognition sequence of intron 14, leads to exon skipping and results in a 165-bp deletion in the DPD mRNA. We have previously demonstrated that a homozygote DPYD*2A genotype results in complete deficiency while the heterozygous DPYD*2A genotype results in partial deficiency of DPD.

Adenocarcinoma↗
PubMed1998

Early-onset Alzheimer's disease due to mutations of the presenilin-1 gene on chromosome 14: a 7-year follow-up of a patient with a mutation at codon 139.

Mutations in the presenilin-1 gene (PS-1 gene) on chromosome 14 have recently been identified as a cause of familial early-onset Alzheimer's disease (EOAD). To our knowledge, only two German EOAD patients with mutations in the PS-1 gene have been identified thus far. Herein we report the case of a German EOAD patient with a family history of dementia and a missense mutation at codon 139 (M139V) of the PS-1 gene. The patient came to our clinic for the first time when he was 44 years old. During the following 7 years, his Mini-Mental State Examination (MMSE) score dropped from 24 to 0. Myocloni were an early neurological symptom that was already present during the first consultation. We could demonstrate that myoclonic activity was of cortical origin using a back-averaging method. Magnetic resonance imaging (MRI) revealed only slight changes in the early stage of the disease. Follow-up MRI studies showed progression of bitemporal ventricular enlargement and progressive frontal and temporal cortical atrophy. Although the majority of EOAD patients belong to the sporadic (non-genetic) type of AD, early-onset dementia, early myocloni and a familial history of AD should direct attention to the possibility of a genetic form of AD.

Adult↗
PubMed2003

Leigh syndrome due to compound heterozygosity of dihydrolipoamide dehydrogenase gene mutations. Description of the first E3 splice site mutation.

UNLABELLED: A boy with recurrent episodes of hypoglycaemia and ataxia, microcephaly, mental retardation, permanent lactic acidaemia, intermittent 2-oxoglutaric aciduria as well as elevation of serum branched chain amino acids was diagnosed with dihydrolipoamide dehydrogenase (E3) deficiency. Analysis of genomic DNA revealed compound heterozygosity for two novel mutations: I393T in exon 11, located at the interface domain of the protein and possibly interfering with its dimerisation, and IVS9+1G>A located at a consensus splice site. A heterozygous polymorphism was also detected. In the patient's cDNA the I393T mutation and the polymorphism appeared to be homozygous, indicating that the mRNA coming from the IVS9+1G>A mutant allele is not stable. CONCLUSION: as opposed to the non-neurological phenotype of patients with a homozygous G229C mutation, this patient developed Leigh syndrome. Dihydrolipoamide dehydrogenase and pyruvate dehydrogenase complex activities in muscle were 29% and 14% of the lowest control values, respectively. Pyruvate dehydrogenase complex activity in fibroblasts was normal, however, indicating that the biochemical examination of defects in energy metabolism should be performed in a more energy demanding tissue.

Child, Preschool↗
PubMed1999

A mitochondrial cytochrome b mutation but no mutations of nuclearly encoded subunits in ubiquinol cytochrome c reductase (complex III) deficiency.

Ubiquinol cytochrome c reductase (complex III) deficiency represents a clinically heterogeneous group of mitochondrial respiratory chain disorders that can theoretically be subject to either a nuclear or a mitochondrial mode of inheritance. In an attempt to elucidate the molecular bases of the disease, we first determined the nucleotide sequence of three unknown subunits (9.5 kDa, 7.2 kDa, 6.4 kDa) by cyberscreening of human expressed sequence tag data bases and sequenced the 11 cDNA subunits encoding complex III in five patients with isolated complex III deficiency. No mutation in the nuclearly encoded complex III subunits was observed, but a mutation in the cd2 helix of the mitochondrial (mt) cytochrome b gene was found to alter the conformation of the bc1 complex in one patient with severe hypertrophic cardiomyopathy. The present study is highly relevant to genetic counseling as the absence of mtDNA mutations in all but one patient in our series strongly supports autosomal rather than maternal inheritance in the majority of patients with complex III deficiency.

Amino Acid Sequence↗
PubMed1977

Mutation in continuous cultures of Schizosaccharomyces pombe. I. Dependence of the kinetics of mutation accumulation upon the growth-limiting nutrilite.

The rate of spontaneous mutation to resistance to the 12,13-epoxytrichothecene trichodermin has been determined under different growth limiting conditions in continuous cultures of the microbial eukaryote Schizosaccharomyces pombe. In agreement with data obtained in bacterial systems by previous workers the kinetics observed for the accumulation of mutations is found to be dependent upon the nutrient used to limit the growth of the population. Under conditions of glucose-limitation mutation accumulation is directly proportional to the rate of cell division, while under histidine-limitation it is proportional to chronological time. Various possible explanations for these observations are discussed.

Ascomycota↗
PubMed1978

Mutation in continuous cultures of Schizosaccharomyces pombe II. Effect of amino acid starvation on mutational response and DNA concentration.

In agreement with the results obtained in Escherichia coli by other workers and our own previous data, the kinetics with which spontaneous mutations to resistance to the 12,13-epoxytrichothecene trichodermin accumulate in a lysine auxotroph of Schizosaccharomyces pombe are dependent upon the nutrilite used to limit the growth of the population. Under conditions of glucose-limitation mutation accumulation is proportional to generation time, while under lysine-limitation it becomes proportional to chronological time. In contrast to observations made in bacterial system, however, no significant change in the DNA content per cell is noted in slow growing cultures grown under amino acid starvation. These findings help to eliminate some of the theories put forward to explain the differential mutational responses observed under different growth limiting regimes.

Ascomycota↗