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Results for “Point Mutation”

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At least 1,135 records · Page 63Linked to original sources
PubMed1998

Simple detection of a point mutation in LDL receptor gene causing familial hypercholesterolemia in southern Italy by allele-specific polymerase chain reaction.

Polymerase chain reaction (PCR) amplification of specific alleles allowed the rapid detection of a point mutation (missense Gly528 --> Asp) in exon 11 of the low density lipoprotein receptor gene which was otherwise not detectable by exon amplification and enzymatic digestion as it does not modify the normal restriction pattern. The mutant allele, designated as FH-Palermo-1 from the origin of the first carrier family identified, gave a specific PCR product of 109 bp clearly distinct from the product of 168 bp obtained from other alleles with a nonspecific couple of primers. This method allowed us to distinguish one positive sample mixed with up to 11 parts of normal DNA. Furthermore, the specific amplification product was characterized by a Bsm I restriction site not present in nonspecific products.

Alleles↗
PubMedDate not supplied

Non-Alzheimer dementia with status spongiosus and neuronal cell loss showing unusual perineuronal structures and point mutation at 129 codon of prion protein.

The subject presented with intellectual decline followed by progressive muscle weakness of the bilateral upper limbs when he was 60 years old. He had a point mutation (methionin-valine) at 129 prion protein codon. He died at the age of 63 and necropsy revealed bilateral frontal lobe atrophy. The frontal cortex showed neuronal cell loss in layers II and III with spongiform change. Reusche silver impregnation technique for beta-peptide combined with ubiquitin immunostaining revealed perineuronal structures encircling degenerated neurons and ubiquitin-immunoreactive (IR) dot-like deposits. They were distributed particularly in the temporal neocortex and entorhinal cortex. They differed from either classic senile or diffuse plaque by the absence of amyloid core in the center and of amyloid fibrils. Ubiquitin-IR materials were also found as neuronal inclusions in the hippocampal granular cells. Nigral degeneration and neuronal loss in the hypoglossal nerve nucleus and in the anterior horn of the spinal cord were also found and spinal cord motoneurons had Bunina body inclusions. The clinical features and pathological findings were consistent with non-Alzheimer dementia with status spongiosus and neuronal cell loss. The unusual perineuronal structures found in our case might be a specific cellular pathology of dementia of the frontal lobe type.

Cell Death↗
PubMed2002

Replication failure, genome instability, and increased cancer susceptibility in mice with a point mutation in the DNA ligase I gene.

DNA ligase I has a key role in DNA replication in the joining together of short replication intermediates. We used gene targeting to introduce a point mutation into the mouse DNA ligase I gene that was present in a human cancer patient with immunodeficiency and a cellular accumulation of DNA replication intermediates. Mutant mice grew more slowly and showed hematopoietic defects at critical stages at which the demands for DNA replication were highest. In the spleen and thymus of mutant mice, the accumulation of a sub-G1, but nonapoptotic, population was observed that we believe may represent cells with single-strand DNA breaks. In mutant bone marrow, occasional DNA replication failure was observed. The level of genome instability was significantly elevated in the spleens of DNA ligase I mutant mice and, because we have found no evidence for any DNA repair defect associated with DNA ligase I deficiency, we believe that this may result directly from the accumulation of replication intermediates. Mutant mice showed an increased incidence of spontaneous cancers with a diverse range of epithelial tumors, particularly cutaneous adnexal tumors that are rare in mice. The origin of the tumors from generalized genome instability, rather than the inactivation of one key control gene, should make DNA ligase I mutant mice a useful model to investigate the relationship between genome instability and cancer in humans.

Animals↗
PubMed1998

HMG CoA lyase deficiency: identification of five causal point mutations in codons 41 and 42, including a frequent Saudi Arabian mutation, R41Q.

The hereditary deficiency of 3-hydroxy-3-methylglutaryl (HMG) CoA lyase (HL; OMIM 246450 [http://www3.ncbi.nlm.nih. gov:80/htbin-post/Omim/dispmim?246450]) results in episodes of hypoketotic hypoglycemia and coma and is reported to be frequent and clinically severe in Saudi Arabia. We found genetic diversity among nine Saudi HL-deficient probands: six were homozygous for the missense mutation R41Q, and two were homozygous for the frameshift mutation F305fs(-2). In 32 non-Saudi HL-deficient probands, we found three R41Q alleles and also discovered four other deleterious point mutations in codons 41 and 42: R41X, D42E, D42G, and D42H. In purified mutant recombinant HL, all four missense mutations in codons 41 and 42 cause a marked decrease in HL activity. We developed a screening procedure for HL missense mutations that yields residual activity at levels comparable to those obtained using purified HL peptides. Codons 41 and 42 are important for normal HL catalysis and account for a disproportionate 21 (26%) of 82 of mutant alleles in our group of HL-deficient probands.

Base Sequence↗
PubMed1994

Suppression of a mitochondrial point mutation in a tRNA gene can cast light on the mechanisms of 3' end-processing.

We used a genetic approach to study the nuclear factors involved in the biogenesis of mitochondrial tRNAs. A point mutation in the mitochondrial tRNA(Asp) gene of Saccharomyces cerevisiae had previously been shown to result in a temperature-sensitive respiratory-deficient phenotype as a result of the absence of 3' end-processing of the tRNA(Asp). Analysis of mitochondrial revertants has shown that all revertants sequenced have a G-A compensatory change at position 53, which restores the hydrogen-bond with the mutated nucleotide. We then searched for nuclear suppressors to identify the nuclear gene(s) involved in mitochondrial tRNA 3' end-processing. One such suppressor mutation was further characterized: it restores tRNA(Asp) maturation and growth at 36 degrees C on glycerol medium in heterozygous diploids, but leads to a defective growth phenotype in haploids.

Base Sequence↗
PubMed1996

Did de novo MELAS common mitochondrial DNA point mutation (mtDNA 3243, A-->G transition) occur in the mother of a proband of a Japanese MELAS pedigree?

MELAS is a major maternally inherited mitochondrial (mt) encephalomyopathy of which 80% of cases are associated with mtDNA point mutation (mtDNA 3243, A-->G transition) which exists under heteroplasmic conditions with wild-type mtDNA. The origin of this mutation remains obscure in the reported pedigrees. I analyzed this mutation in a Japanese MELAS pedigree by PCR. The proband had typical MELAS features. The proband's mother was oligosymptomatic (fatigability, nerve deafness and diabetes mellitus). The proband's maternal grandmother was diagnosed as having senile dementia of the Alzheimer type clinically. The brother of the proband's mother was healthy. The ratios of this mutation in muscle and leukocytes of the proband and his mother were 89%, 36%, 79% and 10%, respectively. There were no mutations in muscle and leukocytes of the proband's maternal grandmother and his mother's brother. These results showed the possibility that this mutation occurred in the proband's mother.

Adenine↗
PubMed1993

Ras gene point mutation is a rare event in premalignant tissues and malignant cells and tissues from oral mucosal lesions.

Three series of biopsy specimens of premalignant and malignant oral lesions, together with seven human keratinocyte cultures, previously established from oral squamous cell carcinomas, were analysed for point mutation in exons 1 and 2 of the c-Ha-ras, c-Ki-ras and N-ras genes by direct nucleotide sequencing of DNAs amplified in the polymerase chain reaction (PCR). Only one out of 12 biopsy samples (8.3%), a well-differentiated carcinoma which was the latest in a series of floor of mouth lesions from 1 of the 3 patients studied, harboured a mutant c-Ha-ras gene, being heterozygous at codon 12 for a GGA-GTA change. One cell line (H357) showed heterozygosity in both exons 1 and 2 of c-Ha-ras, harbouring a GGT to AGT mutation over codon 13 and a CAG to CAA mutation over codon 61. The remaining six oral carcinoma cell lines (85.7%) were homozygous normal at both exons 1 and 2 of c-Ha-ras. All cell lines showed normal c-Ki-ras and N-ras loci. We conclude that ras gene mutation is an infrequent occurrence in the malignant progression of oral epithelial cells, despite the probable importance of chemical carcinogens in the aetiology of the disease. We emphasise the need to search for other cellular sequences which may be targets for chemical or viral carcinogens.

Base Sequence↗
PubMed1996

A new point mutation in the luteinising hormone receptor gene in familial and sporadic male limited precocious puberty: genotype does not always correlate with phenotype.

Genomic DNA from two families with male limited precocious puberty was examined for mutations of the LH receptor gene. In family 1, several members of the pedigree have FMPP, whereas in family 2 there is only one affected subject. A point mutation (T --> C at nucleotide 1192) resulting in substitution of threonine for methionine 398 in the second transmembrane domain of the LH receptor protein was found in both families. In addition, one member of family 1 has the mutation, but no evidence of precocious puberty. All obligate carriers within this family were shown to have the mutation, and it was not detected in 94 chromosomes from unaffected and unrelated white subjects. In family 2, the index case was the only one to have the mutation. A previously unreported neutral dimorphism (C --> T at nucleotide 1065) is also described.

Base Sequence↗
PubMed2003

First Streptococcus agalactiae isolates highly resistant to quinolones, with point mutations in gyrA and parC.

Three isolates of Streptococcus agalactiae highly resistant to multiple fluoroquinolones were isolated in Japan. Compared with susceptible strains of S. agalactiae, these quinolone-resistant strains had double point mutations within the quinolone resistance-determining regions of gyrA and parC; Ser-81 was changed to Leu (TCA --> TTA) in the amino acid sequence deduced from gyrA, and Ser-79 was changed to Phe (TCC --> TTC) in the amino acid sequence deduced from parC. Comparative sequence analysis revealed the possibility of gene transfer between S. agalactiae and another beta-hemolytic streptococcus, Streptococcus difficile.

Aged↗
PubMed1994

Point mutation of glycine receptor alpha 1 subunit in the spasmodic mouse affects agonist responses.

Homozygotic spasmodic (spd/spd) mice suffer from a motor disorder resembling poisoning by the glycine receptor antagonist strychnine. Here, a point mutation was identified in the glycine receptor alpha 1 subunit gene of the spasmodic mouse which predicts an alanine-to-serine exchange at position 52 of the mature polypeptide. Upon expression in Xenopus laevis oocytes, alpha 1A52S receptor channels displayed reduced responses to glycine, beta-alanine and taurine when compared to recombinant alpha 1 glycine receptors. As glycine receptor content in spinal cord and native molecular weight appeared unaltered, this suggests that the spasmodic phenotype results from an altered neurotransmitter sensitivity of the mutant alpha 1A52S subunit.

Alanine↗
PubMed2000

Severe cognitive impairment in DMD: obvious clinical indication for Dp71 isoform point mutation screening.

Duchenne muscular dystrophy is associated with variable degrees of selective cognitive defect with lower scores for verbal intelligence and reading abilities. A number of findings have shown that rearrangements located in the second part of the gene seem to be preferentially associated with cognitive impairment. Several dystrophin transcripts are expressed in the brain. The more distal of them, Dp71, is predominant. We have carried out a mutational analysis of Dp71 transcript in 12 DMD patients severely, mildly or not retarded, all without detectable deletion or duplication. We have detected five point mutations causing Dp71 premature translation termination. All were found among the more severely mentally retarded patients of this group (VIQ < 50 and/or no reading acquisition).

Adolescent↗
PubMed1982

An in vitro RNA polymerase III system from S. cerevisiae: effects of deletions and point mutations upon SUP4 gene transcription.

A soluble cell-free extract containing RNA polymerase III and factors essential for selective transcription of the yeast SUP4-o tRNATyr gene was prepared from Saccharomyces cerevisiae cells. An intragenic promoter for yeast RNA polymerase III was identified within the yeast tRNATyr coding sequence by testing several sup4 genes with 5'- and 3'-terminal deletions in the homologous transcription system. Thirty-four different sup4 genes with spontaneous mutations were also tested in the in vitro system. Two point mutations drastically reduced transcription initiation and two other mutations caused premature termination. These mutations have nearly identical effects on SUP4 gene transcription by Xenopus RNA polymerase III (1), which demonstrates that the essential features of RNA polymerase III transcription initiation and termination signals have been conserved throughout the course of eukaryotic evolution.

Base Sequence↗
PubMed1999

Structural and mutagenesis studies of leishmania triosephosphate isomerase: a point mutation can convert a mesophilic enzyme into a superstable enzyme without losing catalytic power.

The dimeric enzyme triosephosphate isomerase (TIM) has a very tight and rigid dimer interface. At this interface a critical hydrogen bond is formed between the main chain oxygen atom of the catalytic residue Lys13 and the completely buried side chain of Gln65 (of the same subunit). The sequence of Leishmania mexicana TIM, closely related to Trypanosoma brucei TIM (68% sequence identity), shows that this highly conserved glutamine has been replaced by a glutamate. Therefore, the 1.8 A crystal structure of leishmania TIM (at pH 5.9) was determined. The comparison with the structure of trypanosomal TIM shows no rearrangements in the vicinity of Glu65, suggesting that its side chain is protonated and is hydrogen bonded to the main chain oxygen of Lys13. Ionization of this glutamic acid side chain causes a pH-dependent decrease in the thermal stability of leishmania TIM. The presence of this glutamate, also in its protonated state, disrupts to some extent the conserved hydrogen bond network, as seen in all other TIMs. Restoration of the hydrogen bonding network by its mutation to glutamine in the E65Q variant of leishmania TIM results in much higher stability; for example, at pH 7, the apparent melting temperature increases by 26 degrees C (57 degrees C for leishmania TIM to 83 degrees C for the E65Q variant). This mutation does not affect the kinetic properties, showing that even point mutations can convert a mesophilic enzyme into a superstable enzyme without losing catalytic power at the mesophilic temperature.

Animals↗
PubMed1998

Point mutations of ornithine decarboxylase gene are an infrequent event in colorectal cancer but a missense mutation was found in a replication error positive patient with hMSH2 germline mutation.

BACKGROUND: Ornithine decarboxylase (ODC; EC 4.1.1.17) is the first rate-limiting enzyme in the biosynthesis of polyamines. ODC protein has a characteristic amino acid sequence, the PEST sequence, which is related to the enzyme's rapid degradation. ODC cDNA prepared from human hepatoma tissues has been reported to show nonsense or missense mutations. METHODS: We examined somatic mutations of ODC cDNA by RT-PCR-SSCP analysis and mRNA expressions by RT-PCR in 50 colorectal cancer tissues to investigate the involvement of ODC gene alterations in colorectal cancers. RESULTS: Increased expression of the ODC gene was observed in 36 cases (86%) out of the 42 examined by RT-PCR. In one case, a missense mutation was found in the cancer tissue but not in normal mucosa. The missense mutation from Asp to Asn at codon 424, in the PEST region, possibly stabilizes the ODC protein. In colorectal cancer, replication error and a germline mutation in hMSH2 gene were observed. CONCLUSIONS: The missense mutation at codon 424 is speculated to be a cause of stabilization and a passenger mutation owing to the mutator phenotype. Since only one of 50 colorectal cancers exhibited a missense mutation of the ODC gene, mutations in ODC gene are not frequent in colorectal cancer. The increased expression of the ODC gene was noted in 86% of colorectal cancer tissues by RT-PCR, however, it was not due to point mutations in ODC coding exons.

Colonic Neoplasms↗
PubMed1996

Recessively inherited L-DOPA-responsive parkinsonism in infancy caused by a point mutation (L205P) in the tyrosine hydroxylase gene.

Tyrosine hydroxylase (TH) catalyzes the conversion of L-tyrosine to L-dihydroxyphenylalanine (L-DOPA), the rate-limiting step in the biosynthesis of dopamine. This report describes a missense point mutation in the human TH (hTH) gene in a girl presenting parkinsonian symptoms in early infancy and a very low level of the dopamine metabolite homovanillic acid in the CSF. DNA sequencing revealed a T614-to-C transition in exon 5 (L205P). Both parents and the patient's brother are heterozygous for the mutation. Site-directed mutagenesis and expression in different systems revealed that the recombinant mutant enzyme had a low homospecific activity, i.e. approximately 1.5% of wt-hTH in E. coli and approximately 16% in a cell-free in vitro transcription-translation system. When transiently expressed in human embryonic kidney (A293) cells a very low specific activity (approximately 0.3% of wt-hTH) and immunoreactive hTH (< 2%) was obtained. The expression studies are compatible with the severe clinical phenotype of the L205P homozygous patient carrying this recessively inherited mutation. Treatment with L-DOPA resulted in normalisation of the CSF homovanillic acid concentration and a sustained improvement in parkinsonian symptoms.

Cell Line↗
PubMed2005

Loss of zolpidem efficacy in the hippocampus of mice with the GABAA receptor gamma2 F77I point mutation.

Zolpidem is a hypnotic benzodiazepine site agonist with some gamma-aminobutyric acid (GABA)(A) receptor subtype selectivity. Here, we have tested the effects of zolpidem on the hippocampus of gamma2 subunit (gamma2F77I) point mutant mice. Analysis of forebrain GABA(A) receptor expression with immunocytochemistry, quantitative [(3)H]muscimol and [(35)S] t-butylbicyclophosphorothionate (TBPS) autoradiography, membrane binding with [(3)H]flunitrazepam and [(3)H]muscimol, and comparison of miniature inhibitory postsynaptic current (mIPSC) parameters did not reveal any differences between homozygous gamma2I77/I77 and gamma2F77/F77 mice. However, quantitative immunoblot analysis of gamma2I77/I77 hippocampi showed some increased levels of gamma2, alpha1, alpha4 and delta subunits, suggesting that differences between strains may exist in unassembled subunit levels, but not in assembled receptors. Zolpidem (1 microm) enhanced the decay of mIPSCs in CA1 pyramidal cells of control (C57BL/6J, gamma2F77/F77) mice by approximately 60%, and peak amplitude by approximately 20% at 33-34 degrees C in vitro. The actions of zolpidem (100 nm or 1 microm) were substantially reduced in gamma2I77/I77 mice, although residual effects included a 9% increase in decay and 5% decrease in peak amplitude. Similar results were observed in CA1 stratum oriens/alveus interneurons. At network level, the effect of zolpidem (10 microm) on carbachol-induced oscillations in the CA3 area of gamma2I77/I77 mice was significantly different compared with controls. Thus, the gamma2F77I point mutation virtually abolished the actions of zolpidem on GABA(A) receptors in the hippocampus. However, some residual effects of zolpidem may involve receptors that do not contain the gamma2 subunit.

Action Potentials↗
PubMed1995

Point mutations of ras and Gs alpha subunit genes in thyroid tumors.

We studied 43 thyroid tumors including 5 adenomatous goiters, 7 follicular adenomas, 22 papillary carcinomas, and 9 medullary carcinomas with regard to the presence of point mutations in the genes of Gs alpha subunit (Gs alpha), Gi2 alpha subunit (Gi2 alpha), H-ras, K-ras, and N-ras by a polymerase chain reaction-direct sequencing method. An adenomatous goiter and a follicular adenoma showed double mutations at codon 227 and 231, and 4 papillary carcinomas showed mutation at codon 231 of the Gs alpha gene. An adenomatous goiter, a follicular adenoma, and a papillary carcinoma showed a missense mutation in codon 13 of the K-ras gene. There were no such missense mutations of these G-protein or ras genes in medullary carcinomas. These data indicate that the genetic events involved in the oncogenesis of parafollicular C-cells are different from those of thyroid follicular cells, in which missense mutations of Gs alpha and ras genes seem to play important roles in tumorigenesis.

Base Sequence↗
PubMed1998

The frequency of an inactivating point mutation (566C-->T) of the human follicle-stimulating hormone receptor gene in four populations using allele-specific hybridization and time-resolved fluorometry.

We have described previously in the Finnish population an inactivating point mutation (566C-->T) in the human FSH receptor (FSHR) gene. In women, this mutation causes hypergonadotropic ovarian failure with arrest of follicular maturation and infertility, whereas in men, there is variable suppression of spermatogenesis, but no absolute infertility. To determine whether the same FSHR mutation occurs in other populations, its frequency was determined in Finland, Switzerland, Denmark, and the Chinese population of Singapore. The mutation was screened for using genomic DNA extracted from whole blood or dried blood spots. Exon 7 of the FSHR gene was first amplified using a pair of biotinylated primers. The PCR products were then immobilized on streptavidin-coated microtitration wells and hybridized using short allele-specific oligonucleotide probes labeled with europium. Time-resolved fluorometry was used for europium signal detection. To test the reliability of this method, 40 isolated DNA samples and 35 dried blood spot samples were blindly tested for the 566C-->T FSHR mutation. The analyses yielded identical results with denaturing gradient gel electrophoresis and allele-specific restriction enzyme digestion of the same samples, thus demonstrating the reliability of the tested method. Automation of this procedure allows the screening of large numbers of samples, which was subsequently carried out to investigate the frequency of the 566C-->T mutation in the study populations. A total of 4981 samples from the above-mentioned 4 countries were analyzed. The frequency of the 566C-->T mutation was 0.96% for all Finnish samples (n=1976), with a strong enrichment of the mutant allele in the northeastern part of the country. Only 1 mutation carrier was identified in the samples from Switzerland (n=1162), whereas none was found in samples from Denmark (n=1094) and the Singapore Chinese (n=540). These results suggest that the 566C-->T mutation of the FSHR gene is enriched in Finland, but is uncommon in other populations.

Alleles↗