Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “MUTATION”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 1,603 records · Page 89Linked to original sources
PubMed1980

[Mapping of mutations in genes of Flexner shigellae controlling the synthesis of certain ribosomal proteins and study of the effect of these mutations on bacterial virulence].

The study, carried out to localize the mutations which determine resistance to spectinomycin and neamin, has revealed that in Sh. Flexneri the genes of the str -- s area and located in the order similar to the order of their location in E. coli K12: spc A -- nea A -- str A -- nea B. Mutation in spc A gene was shown to have no influence on the capacity of the shigellae for causing keratoconjunctivitis, whereas nea A mutation resulted in the complete loss of virulence; in str A and nea B mutations the complete or partial loss of pathogenic properties was also observed.

Chromosome Mapping↗
PubMed1994

First de novo mutations in the protein C gene of two patients with type I deficiency: a missense mutation and a splice site deletion.

In a series of 40 patients with symptomatic protein C deficiency, we identified two sporadic cases with novel mutations that probably affect gene expression. The mutations, a 5-bp deletion of the donor splice site of intron f (nucleotides 3455 to 3459) and a mutation of nucleotide 8523 in exon IX leading to the substitution of Ser 270 by Pro, were not found in the protein C gene of the patients' parents. Transmission of the paternal and maternal protein C alleles was apparently normal on the basis of frequent polymorphisms in exons I, VI, and VIII. We also checked the transmission of the chromosomal material by analyzing the beta-globin gene frameworks and three variable number of tandem repeats (VNTRs). By combining the results of intragenic polymorphism, VNTR and beta-globin gene framework analyses, we were able to exclude nonpaternity and confirm the de novo origin of the mutation.

Adult↗
PubMed1993

p53 mutations in mouse mammary epithelial cells: instability in culture and discordant selection of mutations in vitro versus in vivo.

The phenotypes of p53 mutations found in human and murine tumors often are analyzed using a variety of transformation assays in vitro, but data have not been available to correlate in vitro effects with in vivo activities. We have assessed the effects of p53 mutations using mouse mammary epithelial cell lines which can be analyzed both in vitro and in vivo. Parental mammary epithelial cell lines (FSK series) injected into cleared mammary fat pads of syngeneic mice frequently give rise to preneoplastic lesions (HAN) which can be reestablished in culture (TM lines) to permit analysis of genetic changes important in the development of preneoplasia. Characterization of the FSK3 cell line revealed a cell population mixed with respect to p53 genotypes. One subpopulation of mutant (Ser233-234) p53-expressing cells was selected in a preneoplastic mammary outgrowth in vivo (TM3), whereas another minor population of mutant (Pro135) p53-expressing cells was selected during culturing of FSK3 cells in vitro. When FSK3 cells were subdivided and passaged in parallel in vitro, p53 genotypes continued to evolve and diverge. These findings reveal that selective pressures exerted on mammary epithelial cell populations in vivo are different from pressures present in vitro. Selective forces may vary from one cell culture environment to another. The growth advantage conferred by a specific p53 mutation appears to differ in vivo versus in vitro. We propose that caution should be exercised when attempting to correlate the effects of p53 mutations assayed in cell culture systems with the in situ phenotypes of mutant p53 in cancer.

Amino Acid Sequence↗
PubMed1996

The age of human mutation: genealogical and linkage disequilibrium analysis of the CLN5 mutation in the Finnish population.

Variant late infantile neuronal ceroid lipofuscinosis (vLINCL) is an autosomal recessive progressive encephalopathy of childhood enriched in the western part of Finland, with a local incidence of 1 in 1500. We recently assigned the locus for vLINCL, CLN5, to 13q21.1-q32. In the present study, the haplotype analysis of Finnish CLN5 chromosomes provides evidence that one single mutation causes vLINCL in the Finnish population. Eight microsatellite markers closely linked to the CLN5 gene on chromosome 13q were analyzed, to study identity by descent by shared haplotype analysis. One single haplotype formed by flanking markers D13S160 and D13S162 in strong linkage disequilibrium (P < .0001) was present in 81% of disease-bearing chromosomes. Allele 4 at the marker locus D13S162 was detected in 94% of disease-bearing chromosomes. To evaluate the age of the CLN5 mutation by virtue of its restricted geographical distribution, church records were used to identify the common ancestors for 18 vLINCL families diagnosed in Finland. The pedigrees of the vLINCL ancestors merged on many occasions, which also supports a single founder mutation that obviously happened 20 to 30 generations ago (i.e., approximately 500 years ago) in this isolated population. Linkage disequilibrium was detected with seven markers covering an extended genetic distance of 11 cM, which further supports the young age of the CLN5 mutation. When the results of genealogical and linkage disequilibrium studies were combined, the CLN5 gene was predicted to lie approximately 200 - 400 kb (total range 30 - 1360 kb) from the closest marker D13S162.

Chromosomes, Human, Pair 13↗
PubMed1996

Mutation in the gene coding for coagulation factor V and resistance to activated protein C: detection of the genetic mutation by oligonucleotide ligation assay using a semi-automated system.

Resistance of coagulation factor Va to inactivation by activated protein C (APCR) is associated with a point mutation in which adenine is substituted for guanine at nucleotide 1691 in the gene coding for factor V (FV Leiden). To date, this mutation of factor V is the most frequent genetic risk factor for venous thrombophilia. In this report, we describe the adaptation of an automatable oligonucleotide ligation assay (OLA) to detect the mutation in polymerase chain reaction-amplified DNA samples from 40 normal, 20 affected heterozygous, and 3 affected homozygous individuals. The genotypes determined by conventional allele-specific restriction enzyme site analysis were in complete concordance with the results obtained by ELISA-based oligonucleotide-ligation assay. The automated oligonucleotide ligation assay provides a rapid, reliable, nonisotopic method to detect the mutation responsible for APCR that can rapidly be applied to large population screening.

Enzyme-Linked Immunosorbent Assay↗
PubMed1997

Affected members of melanoma-prone families with linkage to 9p21 but lacking mutations in CDKN2A do not harbor mutations in the coding regions of either CDKN2B or p19ARF.

Mutations in the gene encoding the cell cycle inhibitor CDKN2A have been identified in some melanoma kindreds linked to 9p21. However, many such families show no evidence of mutations in the coding regions of CDKN2A. In this study, we examined whether two other potential tumor suppressors, CDKN2B and p19ARF, which also map within the 9p21 region, play a role in the development of familial melanoma. We found no mutations in the coding regions of either gene in melanoma-prone families with evidence of linkage to 9p21. We conclude either that another melanoma susceptibility gene exists within this chromosomal area or that mutations in noncoding regions of CDKN2A, CDKN2B, or p19ARF predispose to melanoma.

Carrier Proteins↗
PubMed1997

Ehlers-Danlos syndrome type VI results from a nonsense mutation and a splice site-mediated exon-skipping mutation in the lysyl hydroxylase gene.

We have characterized a patient with Ehlers-Danlos syndrome type VI as a compound heterozygote for the lysyl hydroxylase (LH) gene, with a pathogenetic mutation in each allele contributing to the very low levels of mRNA and LH activity in his fibroblasts. Amplification of full-length LH cDNAs resulted in normal-sized (2.9-kb) and shortened (2.8-kb) transcripts indicative of two populations of alleles. One allele contained a paternally inherited C1557 to G transition that coded for a premature stop codon (Y511X) and introduced an Nhe I restriction site in exon 14 of the LH gene. The mutation in the other allele was an exon 5 deletion that produced the shortened polymerase chain reaction transcript and generated a premature stop codon at the beginning of exon 7. Sequencing of genomic DNAs spanning exon 5 showed a mutation in the consensus donor splice site at the beginning of intron 5 (gt-->at) in both the proband and his mother. Via reverse transcriptase-polymerase chain reaction, the parents' fibroblasts showed a disproportionately lower level of each mutant allele compared to their normal alleles. This study suggests that the decreased transcription of the LH gene, which may be attributed to the presence of the nonsense mutations, accounts for the LH deficiency, and consequently, this patient's clinical phenotype of Ehlers-Danlos syndrome type VI.

Alleles↗
PubMedDate not supplied

Mutations in Hirschsprung disease: when does a mutation contribute to the phenotype.

Hirschsprung disease is a congenital disorder clinically characterized by the absence of colonic ganglia and genetically by extensive heterogeneity. Genes involved include RET, GDNF, EDNRB and EDN3. Mutations of these genes may give dominant, recessive, or polygenic patterns of inheritance. In particular in the case of missense mutations, it is therefore far from easy to assess whether a given mutation will contribute to the phenotype. We discuss criteria for such an assessment and pay special attention to functional assays. The interpretation of mutations as contributing to a disease phenotype or as merely representing a rare polymorphism has direct clinical consequences. Hirschsprung disease with major and modifying sequence variants in a variety of genes might well serve as a model for the many complex disorders for which the search for genes involved has only just been initiated.

Endothelin-3↗
PubMed2000

Compound heterozygous patient with glycogen storage disease type III: identification of two novel AGL mutations, a donor splice site mutation of Chinese origin and a 1-bp deletion of Japanese origin.

Glycogen storage disease type III (GSD III) is an autosomal recessive disorder caused by deficiency of glycogen-debranching enzyme (AGL). We studied a 2-year-old GSD III patient whose parents were from different ethnic groups. Nucleotide sequence analysis of the patient showed two novel mutations: a single cytosine deletion at nucleotide 2399 (2399delC) in exon 16, and a G-to-A transition at the +5 position at the donor splice site of intron 33 (IVS33+5G>A). Analysis of the mRNA produced by IVS33+5G>A showed aberrant splicing: skipping of exon 33 and activation of a cryptic splice site in exon 34. Mutational analysis of the family revealed that the 2399delC was inherited from her father, who is of Japanese origin, and the IVS33+5G>A from her mother, who is of Chinese descent, establishing that the patient was a compound heterozygote. To our knowledge, this is the first report of a mutation identified in a GSD III patient from the Chinese population.

Child, Preschool↗
PubMed2005

Autosomal dominant hereditary spastic paraplegia: DHPLC-based mutation analysis of SPG4 reveals eleven novel mutations.

We set up a new denaturing high-performance liquid chromatography (DHPLC)-based protocol to screen patients with autosomal dominant hereditary spastic paraplegia (AD-HSP) for mutations in SPG4. Six patients had a complicated form and 49 a pure HSP phenotype. We also analyzed 19 unrelated patients presenting with an HSP phenotype (pure in 17 and complicated in two subjects) but no clear family history, as such patients may be cases of dominant inheritance with low penetrance. The overall frequency of SPG4 mutations in our study of HSP (in which prior linkage data were unavailable) was 32.4%, rising to 46.9% when only pure AD-HSP patients were considered. This figure falls well within the range reported in different populations. Rather as expected, the clinical data available for the patients did not support an easy genotype-phenotype correlation. Moreover, the clinical picture was not influenced by the length of the predicted residual gene product. As well as identifying novel variants in SPG4, this study constitutes the molecular characterization of the largest cohort of Italian AD-HSP patients studied to date. In addition, it provided an efficient, cost-effective, and reliable detection protocol for mutational screening of SPG4, which might facilitate medical genetic counseling.

Adenosine Triphosphatases↗
PubMedDate not supplied

X-linked adrenomyeloneuropathy associated with 14 novel ALD-gene mutations: no correlation between type of mutation and age of onset.

Adrenomyeloneuropathy (AMN) represents a milder form of X-linked adrenoleukodystrophy (ALD), the most frequent peroxisomal disorder. The disease is characterised by an abnormal accumulation of saturated, very long chain, fatty acids, because of altered peroxisomal beta-oxidation that concomitantly leads to demyelination in the central and peripheral nervous systems. ALD shows a highly variable phenotypic expression and extensive mutation analysis in ALD patients has failed to establish a genotype-phenotype correlation, even in the presence of the same ALD-gene defect. Therefore, we have looked for a relationship between the molecular lesion and the age of onset in 19 patients with a well-classified clinical course of AMN. The nearly complete novel spectrum of ALD gene mutations identified has revealed no obvious correlation between the type of mutation and age of AMN onset in this small series. However, intrafamiliar concordance could be observed with respect to the occurrence of adrenocortical insufficiency. This supports the idea of one (or more) additional gene(s) contributing to the phenotypic expression of ALD.

ATP Binding Cassette Transporter, Subfamily D, Mem↗
PubMed2001

Antithrombin deficiency in Brazilian patients with venous thrombosis: molecular characterization of a single splice site mutation, an insertion and a de novo point mutation.

The prevalence of antithrombin (AT) deficiency in 342 unselected Brazilian patients with venous thrombosis was 1.16%, which increased to 3% when only patients under the age of 50 or with a familial history of thrombosis were considered. In two patients, a clinical (contraceptive use) or genetic risk factor (factor V Leiden and C677T in the methylene tetrahydrofolate reductase gene [MTHFR]) was identified and corroborated the hypothesis that an interaction of factors accounted for the appearance of thrombosis. However, no risk factor other than AT deficiency was identified in one patient with an important clinical and family history of spontaneous thrombosis. Three mutations were identified in these patients: a G-->A transition in intron 5 at position +1 (5'-->3'), three base insertions corresponding to arginine at position 5383 in exon 3A, and a G-->A transition at 13328, corresponding to an Ala404Thr de novo mutation. The polymorphisms in the genes coding for coagulation factors XII and XIII and fibrinogen normally associated with an increased risk for venous thrombosis were not related to thrombosis in these patients. This is the first study in South America to assess the prevalence of AT deficiency and to report the molecular characterization of the mutations involved.

Adult↗
PubMed2001

The arginine-552-cysteine (R1315C) mutation within the A1 loop of von Willebrand factor induces an abnormal folding with a loss of function resulting in type 2A-like phenotype of von Willebrand disease: study of 10 patients and mutated recombinant von Willebrand factor.

The study identified 10 patients from 6 families with prolonged bleeding time, decreased von Willebrand factor (vWF) ristocetin cofactor activity (RCoF) to vWF:Ag (antigen) ratio, and reduced ristocetin-induced platelet agglutination as well as ristocetin- or botrocetin-induced binding of plasma vWF to platelet glycoprotein Ib (GpIb). In addition, all patients showed a decrease of intermediate-molecular-weight (intermediate-MW) and high-molecular-weight (HMW) multimers of vWF. In the heterozygous state, a cysteine-to-threonine (C --> T) transversion was detected at nucleotide 4193 of the VWF gene of all patients and lead to the arginine (R)522C substitution in the A1 loop of vWF mature subunit (R1315C in the preprovWF). By in vitro mutagenesis of full-length complementary DNA (cDNA) of vWF and transient expression in COS-7 cells, the mutated C552 recombinant vWF (C552rvWF) was found to exhibit decreased expression, abnormal folding, and lack of intermediate-MW and HMW multimers. In addition, direct binding of botrocetin to C552rvWF, as well as ristocetin- and botrocetin-induced binding of C552rvWF to GpIb, was markedly decreased. Although being localized in an area of the A1 loop of vWF where most of the type 2B mutations that induce a gain-of-function have been identified, the R552C mutation induces a 2A-like phenotype with a decrease of intermediate-MW and HMW multimers as well as a loss-of-function of vWF in the presence of either ristocetin or botrocetin. (Blood. 2001;97:952-959)

Adult↗
PubMed1999

Mutation identification DNA analysis system (MIDAS) for detection of known mutations.

We introduce a novel experimental strategy for DNA mutation detection named the Mismatch Identification DNA Analysis System (MIDAS) [1, 2], which has an associated isothermal probe amplification step to increase target DNA detection sensitivity to attomole levels. MIDAS exploits DNA glycosylases to remove the sugar moiety on one strand (the probe strand) at a DNA base pair mismatch. The resulting apyrimidinic/ apurinic (AP) site is cleaved by AP endonucleases/lyases either associated with the DNA glycosylase or externally added to the reaction mixture. MIDAS utilizes 32p- or FITC-labeled oligonucleotides as mutation probes. Generally between 20-50 nucleotides in length, the probe hybridizes to the target sequence at the reaction temperature. Mismatch repair enzymes (MREs) then cut the probe at the point of mismatch. Once the probe is cleaved, the fragments become thermally unstable and fall off the target, thereby allowing another full-length probe to hybridize. This oscillating process amplifies the signal (cleaved probe). Cleavage products can be detected by electrophoretic separation followed by autoradiography, or by laser-induced fluorescence-capillary electrophoresis (LIF-CE) of fluorophore-labeled probes in two minutes using a novel CE matrix. In the present experiments, we employed the mesophilic Escherichia coli enzyme deoxyinosine 3'-endonuclease (Endo V), and a novel thermostable T/G DNA glycosylase, TDG mismatch repair enzyme (TDG-MRE). MIDAS differentiated between a clinical sample BRCA 1 wild-type sequence and a BRCA1 185delAG mutation without the need for polymerase chain reaction (PCR). The combination of MIDAS with LIF-CE should make detection of known point mutations, deletions, and insertions a rapid and cost-effective technique well suited for automation.

BRCA1 Protein↗
PubMed1997

Mutations occurring at the human minisatellite MS1 integrated in haploid yeast are similar to MS1 mutations in humans.

MS1 is one of the most variable minisatellites so far isolated from the human genome. We have previously reported an MS1 length-mutant frequency of 29.6% in overnight cultures of haploid yeast cells carrying a 1.35 kb MS1 allele. Here we present data on the instability of alleles with lengths ranging from 0.15 kb to 2.05 kb, which revealed a threshold of 0.75 kb, at and below which MS1 alleles were entirely stable. Larger alleles exhibited a length-related increase in mutation frequency. Chromosomal integration of various MS1 alleles, isolated from bacterial transformants, in haploid yeast cells also revealed a threshold for the onset of instability and a higher degree of mutability for longer alleles. DNA sequencing of alleles showed that the length changes were due to mutational events involving repeat units in the central region of MS1 which is composed of two variant repeat units only. The similarity between MS1 mutations in yeast and humans argues that yeast represents a suitable model organism for mechanistic studies on mutations occurring in human minisatellites.

Alleles↗
PubMed1992

Functional analysis of the intramolecular chaperone. Mutational hot spots in the subtilisin pro-peptide and a second-site suppressor mutation within the subtilisin molecule.

The N-terminal pro-peptide of 77 amino acid residues is essential for the folding of subtilisin, an alkaline serine protease from Bacillus subtilis. The synthetic pro-peptide has been shown to be capable of guiding the proper folding of denatured subtilisin to enzymatically active enzyme. Thus the pro-peptide serves as an intramolecular chaperone, which is removed by an autoprocessing reaction after the completion of the folding. With use of localized polymerase chain reaction random mutagenesis a total of 25 amino acid substitution mutations that affected subtilisin activities were isolated. These mutations occurred in a high frequency at the hydrophobic regions of the pro-peptide. For one of the mutations, M(-60)T, a second-site suppressor mutation, S(188)L, was isolated within the mature region. These results suggest that the pro-peptide consists of a few functional regions which interact with specific regions of the mature region of subtilisin during the folding process.

Amino Acid Sequence↗
PubMed1994

Starvation-associated mutation in Escherichia coli: a spontaneous lesion hypothesis for "directed" mutation.

When stationary phase E. coli WU3610, carrying an ochre mutation in the tyrA gene, were incubated on plates lacking tyrosine, tyrosine-independent (Tyr+) mutants appeared from day 7 onwards in a time-dependent manner. These starvation-associated mutants did not contain either identifiable tRNA suppressors or reversions at the ochre site and are thus quite distinct from the mutants commonly found to arise during active growth. When an appropriate fluctuation assay protocol was employed slow growing Tyr+ mutants were also found to arise in growing cells, and their distribution was more characteristic of a replication-dependent than a time-dependent process. The rate of appearance of starvation-associated mutants at 37 degrees C was somewhat less than at 27 degrees C and this was attributed to a reduction in viability at the higher temperature. There was no evidence for the accumulation on the plates of mutations in other genes. Tyr+ mutants were, however, shown to arise during incubation of stationary phase cells under conditions where there was no selection for tyrosine independence, provided outgrowth was subsequently permitted on plates lacking tyrosine. This distinguishes the present system from those systems exhibiting genuine "directed" or "adaptive" mutation, should they exist. To explain the specificity which occurs, it is proposed that the appearance of stationary mutants in ochre strains reflects the time-dependent accumulation in the transcribed strand of a DNA lesion that has a high probability of miscoding during transcription and replication. A mutant RNA transcript permits protein synthesis which in turn triggers DNA replication. The mutation is then fixed in the DNA as a permanent heritable change. The apparent "directedness" of the process is, on this model, determined solely by the particular miscoding DNA lesion occurring in a transcribed strand at a site where a change in phenotype permits DNA replication to occur.

Culture Media↗
PubMed1994

Analysis of benzo[a]pyrene induced mutations by the use of Restriction-Site Mutation assays in aquatic species.

Larval and toadlet stages of the clawed toad Xenopus laevis were exposed to benzo[a]pyrene in aquatic media. Mutations were analysed in a variety of restriction enzyme recognition sequences of the adult alpha 1-globin gene. Mutations were detected in the BsiLi recognition site (CCTGG) at early sampling times (6 h) in larval stages and at 8-days sampling time in post-metamorphosis toadlets. The predominant mutation detected was a G-->T base transversion at the 5th base of the CCTGG sequence. The data presented indicates that the Restriction-Site Mutation methodology has considerable potential for development as a technique for monitoring the genotoxic potential of water-borne toxins.

Animals↗