Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “frameshift 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 127 records · Page 7Linked to original sources
PubMed2006

A novel frameshift mutation in the 5alpha-reductase type 2 gene in Korean sisters with male pseudohermaphroditism.

OBJECTIVE: To describe two cases of 5alpha-reductase deficiency and the identification of a novel frameshift mutation in this sibling pair. DESIGN: Case report. SETTING: An adolescent clinic at a university hospital. PATIENT(S): A 14-year-old girl and her younger sister, who presented with primary amenorrhea, deepening of the voice, and clitoromegaly. INTERVENTION(S): Deoxyribonucleic acid was extracted from peripheral blood, and 8 exons of the androgen receptor gene and 5 exons of the steroid 5alpha-reductase type 2 gene (encoded by SRD5A2 gene) were amplified by polymerase chain reaction and subjected to sequence analyses. MAIN OUTCOME MEASURE(S): Genetic diagnosis of 5alpha-reductase deficiency. RESULT(S): There was no evidence of a genetic abnormality in the 8 screened exons of the androgen receptor gene, but exon 4 of the SRD5A2 gene showed a novel homozygous deletion of the thymine at nucleotide position c.655 (c.655delT), leading to a frameshift mutation predicted to result in an abnormally long protein with an extended termination signal. CONCLUSION(S): The molecular characterization of the mutation can be a relevant tool for a correct diagnosis of 5alpha-reductase deficiency.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMedDate not supplied

A common PEX1 frameshift mutation in patients with disorders of peroxisome biogenesis correlates with the severe Zellweger syndrome phenotype.

Peroxisome biogenesis disorders are a heterogeneous group of human neurodegenerative diseases caused by peroxisomal metabolic dysfunction. At the molecular level, these disorders arise from mutations in PEX genes that encode proteins required for the import of proteins into the peroxisomal lumen. The Zellweger syndrome spectrum of diseases is a major sub-set of these disorders and represents a clinical continuum from Zellweger syndrome (the most severe) through neonatal adrenoleukodystrophy to infantile Refsum disease. The PEX1 gene, which encodes a cytoplasmic AAA ATPase, is the responsible gene in more than half of the Zellweger syndrome spectrum patients, and mutations in PEX1 can account for the full spectrum of phenotypes seen in these patients. In these studies, we have undertaken mutation analysis of PEX1 in skin fibroblast cell lines from Australasian Zellweger syndrome spectrum patients. A previously reported common PEX1 mutation that gives rise to a G843D substitution and correlates with the less severe disease phenotypes has been found to be present at high frequency in our patient cohort. We also report a novel PEX1 mutation that occurs at high frequency in Zellweger syndrome spectrum patients. This mutation produces a frameshift in exon 13, a change that leads to the premature truncation of the PEX1 protein. A Zellweger syndrome patient who was homozygous for this mutation and who survived for less than two months from birth had undetectable levels of PEX1 mRNA. This new common mutation therefore correlates with a severe disease phenotype. We have adopted procedures for the detection of this mutation for successful prenatal diagnosis.

ATPases Associated with Diverse Cellular Activitie↗
PubMed1990

Induction of -2 frameshift mutations within alternating GC sequences by carcinogens that bind to the C8 position of guanine residues: development of a specific mutation assay.

Using a forward mutation assay we have previously found that N-2-acetylaminofluorene (AAF), a strong chemical carcinogen, induces a majority of frameshift mutations located at specific sequences called mutation hot spots. Among these hot spot sequences, the NarI sequence (GGCGCC), is specific for -2 frameshifts (GGCGCC)----GGCC). Interestingly, these frameshift mutations occur independently of a functional umuDC locus. Being interested in elucidating this mutation pathway we have developed a reversion assay that is specific for this class of mutations. The assay is based on the reversion of a +2 frameshift mutant of plasmid pBR322 from tetracycline sensitivity to tetracycline resistance. It is shown that only "true" reversion events lead to tetracycline resistance. The carcinogen AAF induces this reversion event at a frequency that is increased four- to fivefold over the background frequency. A series of chemical carcinogens which, like AAF, bind covalently to the C8 position of guanine, are compared for their efficiency to induce this specific mutation event. Large variations in the mutagenic efficiency of these chemicals are observed and discussed in terms of the anti/syn conformation of the carcinogen-modified guanine residue. Based on this test, we describe a convenient spot assay that this presently used in our laboratory to isolate Escherichia coli mutants affected in this mutation pathway.

2-Acetylaminofluorene↗
PubMed2001

A mutation in the GTPase domain of the large subunit rRNA is involved in the suppression of a -1T frameshift mutation affecting a mitochondrial gene in Chlamydomonas reinhardtii.

The dum19 mutation isolated in Chlamydomonas reinhardtii is due to the deletion of one T at codon 152 of the mitochondrial cox1 gene sequence. Phenotypically, the dum19 mutant is characterized by a lack of cytochrome c oxidase activity and is unable to grow under heterotrophic conditions. A spontaneous pseudo-revertant that grows slowly in the dark was isolated from the dum19 mutant strain. A genetic and molecular analysis allowed us to demonstrate that the revertant phenotype is the consequence of two additional mutations that together act as a frameshift suppressor: an m mutation affecting a mitochondrial gene other than cox1 and an n mutation affecting a nuclear gene. On its own the n mutation does not act as a suppressor, whereas the m mutation very slightly compensates for the effect of the -1T mutation. Sequencing analysis showed that the m mutation affects the GTPase-associated domain of the large subunit (LSU) ofmitochondrial rRNA. Surprisingly, two substitutions, A1090 to G and A1098 to C, were found in the LSU rRNA of the revertant, the latter one being already present in the dum19 mutant strain itself. The A1090 to G substitution is thus involved in the suppression of the frameshift mutation, but it is not clear whether the change at position 1098 is also required for the expression of the suppressed phenotype. To our knowledge, this is the first example of a mutation in the GTPase-associated domain acting as a suppressor of a frameshift mutation.

Animals↗
PubMed2005

Identification of a novel frameshift mutation in the DFNB31/WHRN gene in a Tunisian consanguineous family with hereditary non-syndromic recessive hearing loss.

Approximately 80% of hereditary hearing loss is non-syndromic. Non-syndromic deafness is the most genetically heterogeneous trait. The most common and severe form of hereditary hearing impairment is autosomal recessive non-syndromic hearing loss (ARNSHL), accounting for approximately 80% of cases of genetic deafness. To date, 22 genes implicated in ARNSHL have been identified. Recently a gene, DFNB31/WHRN, which encodes a putative PDZ scaffold protein called whirlin, was found to be responsible for the ARNSHL DFNB31. We found evidence for linkage to the DFNB31locus in a consanguineous Tunisian family segregating congenital profound ARNSHL. Mutation screening of DFNB31/WHRNrevealed four nonpathogenic sequence variants and a novel frameshift mutation [c.2423delG] + [c.2423delG] that changed the reading frame and induced a novel stop codon at amino acid 818 ([p.Gly808AspfsX11] + [p.Gly808AspfsX11]). To determine the contribution of the DFNB31locus in the childhood deafness, we performed linkage analysis in 62 unrelated informative families affected with ARNSHL. No linkage was found to this locus. From this study, we concluded that DFNB31/WHRN is most likely to be a rare cause of ARNSHL in the Tunisian population.

Consanguinity↗
PubMed1981

Frameshift mutations: relative roles of simple intercalation and of adduct formation.

The contribution of "simple" intercalation and of adduct formation on the expression of frameshift mutations in Salmonella typhimurium was investigated using 9-aminoacridine and derivatives capable of either only intercalating between DNA base pairs or of forming adducts with DNA as well. For a chemical capable of intercalating as well as of forming an adduct, only a small portion of the frameshift mutagenicity is due to "simple" intercalation. Analogs only able to induce frameshift mutations as a result of intercalation generally display only a fraction (approx. 1%) of the frameshift activity of the analog capable of forming DNA adducts.

Aminoacridines↗
PubMed2000

Fanconi anemia A due to a novel frameshift mutation in hotspot motifs: lack of FANCA protein.

Homozygosity for a frameshift mutation at codon 1213 of FANCA gene was identified in a Turkish patient. Immunoprecipitation-western blot analysis showed the complete absence of the FANCA protein band. This novel mutation, a deletion of T at position 3639 in exon 37 (3639delT), is responsible for the disease and causes premature termination of translation 32 aa downstream. The deletion is (i) the T residue of 2 overlapping TGAGGC and CCTG hot spot motifs, (ii) flanked by several direct repeats, (iii) surrounded by the highly GC rich region that have frequently been identified at the site of human DNA deletions. The patient is the third living child of a first degree cousin marriage. The major abnormalities of the patient at the age of 6 months were growth retardation, microcephaly, hypoplastic right thumb, distal displacements of both thumbs and pelvic displacement of left kidney. Hematological presentation of the disease started before the age of 4 years.

Cell Cycle Proteins↗
PubMed1997

Localized reversible frameshift mutation in an adhesin gene confers a phase-variable adherence phenotype in mycoplasma.

The variable adherence-associated (Vaa) antigen of Mycoplasma hominis is an abundant surface lipoprotein adhesin that may mediate important interactions of this wall-less prokaryotic pathogen with the human host. Extensive mutational variation of Vaa size, as well as sequence and antigenic divergence, has been described previously. Using a series of clonal isolates representing an isogenic lineage of variants oscillating in Vaa expression, Vaa is further shown in this study to undergo high-frequency phase variation in expression, which correlated precisely with the ability of M. hominis to adhere to cultured human cells. Although no DNA rearrangements or sequence differences in the 5' regions flanking vaa alleles were detected between Vaa+ and Vaa variants, intragenic vaa sequences from this lineage revealed an oscillating mutation involving a single nucleotide deletion/insertion in a short tract of adenine residues near the 5' end of the mature Vaa coding sequence, which created a translational frameshift resulting in either a complete Vaa ORF or an in-frame UAG stop codon immediately downstream of the poly-A tract. Evidence for the occurrence of this high-frequency frameshift mutation in vivo was obtained from analysis of PCR-generated vaa sequences amplified from the joint synovial fluid of a patient with M. hominis-associated arthritis, which indicated that Vaa phase variation occurs during M. hominis infection in the natural host. These results identify a distinctive frameshift mutator element in the vaa gene that governs M. hominis adherence and highlight the importance of mutational alteration of primary gene products on the mycoplasma surface as a means of generating and maintaining functional diversity in the host.

Adhesins, Bacterial↗
PubMed2000

Clinical, cellular, and molecular features of an Israeli xeroderma pigmentosum family with a frameshift mutation in the XPC gene: sun protection prolongs life.

An Ashkenazi Jewish Israeli family with two children affected with severe xeroderma pigmentosum was investigated. A son, XP12TA, developed skin cancer at 2 y and died at 10 y. A daughter, XP25TA, now 24 y old, was sun protected and began developing skin cancers at 10 y. Their cultured skin fibroblasts showed reductions in post-ultraviolet survival (11% of normal), unscheduled DNA synthesis (10% of normal), global genome DNA repair (15% of normal), and plasmid host cell reactivation (5% of normal). Transcription-coupled DNA repair was normal, however. Northern blot analysis revealed greatly reduced xeroderma pigmentosum complementation group C mRNA. A plasmid host cell reactivation assay assigned the cells to xeroderma pigmentosum complementation group C. Cells from both parents and an unaffected child exhibited normal post-ultraviolet-C survival and normal DNA repair. Sequencing the xeroderma pigmentosum complementation group C cDNA of XP12TA and XP25TA revealed a homozygous deletion of two bases (del AT 669-670) in exon 5 with a new termination site 10 codons downstream that is expected to encode a truncated xeroderma pigmentosum complementation group C protein. Sequence analysis of the xeroderma pigmentosum complementation group C cDNA in cells from the parents found identical heterozygous mutations: one allele carries both the exon 5 frameshift and an exon 15 polymorphism and the other allele carries neither alteration. Cells from the unaffected brother had two normal xeroderma pigmentosum complementation group C alleles. This frameshift mutation in the xeroderma pigmentosum complementation group C gene led to reduced DNA repair with multiple skin cancers and early death. Sun protection delayed the onset of skin cancer and prolonged life in a sibling with the same mutation.

Adult↗
PubMed2001

Frameshift mutation in PRKDC, the gene for DNA-PKcs, in the DNA repair-defective, human, glioma-derived cell line M059J.

Anderson, C. W., Dunn, J. J., Freimuth, P. I., Galloway, A. M. and Allalunis-Turner, M. J. Frameshift Mutation in PRKDC, the Gene for DNA-PKcs, in the DNA Repair-Defective, Human, Glioma-Derived Cell Line M059J. Radiat. Res. 156, 2-9 (2001). The glioma-derived cell line M059J is hypersensitive to ionizing radiation, lacks DNA-PK activity, and fails to express protein for the catalytic subunit, DNA-PKcs, while a sister cell line, M059K, derived from the same tumor, has normal DNA-PK activity. Both cell lines are near pentaploid and have multiple copies of chromosome 8, the chromosome on which the DNA-PKcs gene, PRKDC, is located. Sequence analysis of PCR-amplified exons revealed the loss in M059J cells of a single "A" nucleotide in exon 32, corresponding to the first nucleotide of codon 1351 (ACC, Thr) of PRKDC. Loss of the "A" nucleotide would terminate the DNA-PKcs reading frame early in exon 33. DNA from M059K cells had only the wild-type sequence. An analysis of sequences surrounding PRKDC exon 32 from 87 unrelated individuals revealed no polymorphic nucleotides except for a triplet repeat near the 3' end of this exon; no individual had a frameshift mutation in exon 32. No other sequence differences in PRKDC between M059J and M059K cells were observed in approximately 15,000 bp of genomic sequence including the sequences of exons 5 through 38 and surrounding intron sequence, suggesting a possible reduction to homozygosity at this locus prior to acquisition of the mutation leading to the M059J cell line.

Catalytic Domain↗
PubMed2002

beta-Spectrin São PauloII, a novel frameshift mutation of the beta-spectrin gene associated with hereditary spherocytosis and instability of the mutant mRNA.

Hereditary spherocytosis (HS) is a common inherited anemia characterized by the presence of spherocytic red cells. Defects in several membrane protein genes have been involved in the pathogenesis of HS. beta-Spectrin-related HS seems to be common. We report here a new mutation in the beta-spectrin gene coding region in a patient with hereditary spherocytosis. The patient presented acanthocytosis and spectrin deficiency and, at the DNA level, a novel frameshift mutation leading to HS, i.e., a C deletion at codon 1392 (beta-spectrin São PauloII), exon 20. The mRNA encoding beta-spectrin São PauloII was very unstable and the mutant protein was not detected in the membrane or in other cellular compartments. It is interesting to note that frameshift mutations of the beta-spectrin gene at the 3' end allow the insertion of the mutant protein in the red cell membrane, leading to a defect in the auto-association of the spectrin dimers and consequent elliptocytosis. On the other hand, beta-spectrin São PauloII protein was absent in the red cell membrane, leading to spectrin deficiency, HS and the presence of acanthocytes.

Acanthocytes↗
PubMed1997

A direct role for DNA polymerase III in adaptive reversion of a frameshift mutation in Escherichia coli.

The sequences of adaptive reversions of a lac frameshift mutation in Escherichia coli resemble DNA polymerase errors, and the adaptive reversions decrease in strains with an antimutator DNA polymerase III (PolIII) allele. The latter finding could imply that DNA PolIII itself makes adaptive mutations. Alternatively, normal DNA PolIII errors could saturate post-synthesis mismatch repair during adaptive mutation. If so, the antimutator strain would produce fewer adaptive mutations because it possesses greater capacity for mismatch repair which could correct errors made by a polymerase other than DNA PolIII. Mismatch repair capacity is limited specifically during adaptive mutation, necessitating a test of this indirect model. This indirect model is ruled out here by the observation that the antimutator PolIII allele decreases adaptive mutation even in mismatch repair-defective cells. This supports a direct role for DNA PolIII in recombination-dependent adaptive mutation.

Adaptation, Physiological↗
PubMed2002

Suppression of a nuclear frameshift mutation by a mitochondrial tRNA in the yeast Kluyveromyces lactis.

A fragment of mitochondrial DNA containing the Kluyveromyces lactis gene for valine-tRNA (tRNAVAL) was isolated as a multicopy suppressor of a respiratory-deficient mutant of this yeast. The mutant produced a truncated Cox14p because of a +1 frameshift mutation in COX14, a nuclear gene encoding a protein imported into mitochondria which is necessary for respiration (Fiori et al. 2000 Yeast 16: 307-314). We report here that the mitochondrial tRNAVAL gene, when transformed into K. lactis cells, is transcribed outside mitochondria and suppresses the frameshift mutation in COX14 restoring the correct reading frame during translation of its mRNA. In fact, using histidine tagging, the existence of a suppressed Cox14p of normal length was demonstrated in mutants expressing the mt-tRNAVAL from the nucleus. Suppression could occur through a non-canonical four base pairing between the tRNAVAL and the mutated mRNA or through slippage of ribosomes during translation. This is a new case of informational suppression in that the suppression of a chromosomal mutation is not caused by a second mutation but to a mislocalization/expression of a mt-tRNA.

Amino Acid Sequence↗
PubMed2005

A recurrent duodenal gastrointestinal stromal tumor with a frameshift mutation resulting in a stop codon in KIT exon 13.

Gastrointestinal stromal tumors (GISTs) are a specific and rare subset of human gastrointestinal tract tumors. Most GISTs show gain-of-function mutations of KIT, mainly in exon 11, that always maintain the reading frame. We report on data from a 43-year-old Japanese man with recurrent duodenal GIST and a frameshift mutation in KIT exon 13 together with an in-frame deletion in KIT exon 11 detected by genomic DNA sequencing. Deletion of 48 base pairs of KIT exon 11, which preserved the reading frame, was identified in both primary and recurrent tumors, whereas deletion of one nucleotide of codon 642 of KIT exon 13, which changed the reading frame and induced a novel stop codon at amino acid 644, was found only in the recurrent tumor. The predicted protein resulting from the latter would lack part of the kinase domain. To the best of our knowledge, this is the first documentation of a GIST with a frameshift mutation of KIT.

Adult↗
PubMed2001

Novel frameshift mutations near short simple repeats.

In patients with Alzheimer's disease or Down's syndrome, the cerebellar cortex exhibits protein deposits in neurofibrillary tangles and neuritic plaques. Recently, the deposits have been shown to contain protein fragments of ubiquitin-B and amyloid precursor protein (APP) with an aberrant carboxyl terminus resulting from frameshift mutations (dinucleotide deletions; DeltaGU or DeltaGA) in or adjacent to GAGAG motifs in their mRNAs, a process referred to as molecular misreading. We have now used a bacterial expression system with the green fluorescent protein as a reporter to screen gene transcripts from aged controls, Alzheimer's disease, and Down's syndrome for molecular misreading. Novel frameshift mutations at a number of locations in the transcripts of the ubiquitin-B and APP genes were discovered (DeltaGA, DeltaG, DeltaGU, DeltaGG, DeltaCA, DeltaAU, DeltaA, DeltaAA, DeltaC, DeltaU, and insertion of an A). Interestingly, most mutations were in close proximity of short simple repeats (GAGAG, GGUGGU, GAGACACACA, UCAUCAUCA, CAAACAAA, and GAAGAAGAA), demonstrating that the GAGAG motif does not constitute the only hot spot for transcriptional errors. Unlike the previously detected aberrant APP fragments, some of the novel ones have the potential to generate the neurotoxic peptide beta-amyloid. We conclude that during aging molecular misreading is a widespread phenomenon.

Amino Acid Sequence↗
PubMed2005

Identification of nine human-specific frameshift mutations by comparative analysis of the human and the chimpanzee genome sequences.

MOTIVATION: The recent release of the draft sequence of the chimpanzee genome is an invaluable resource for finding genome-wide genetic differences that might explain phenotypic differences between humans and chimpanzees. AVAILABILITY: In this paper, we describe a simple procedure to identify potential human-specific frameshift mutations that occurred after the divergence of human and chimpanzee. The procedure involves collecting human coding exons bearing insertions or deletions compared with the chimpanzee genome and identification of homologs from other species, in support of the mutations being human-specific. Using this procedure, we identified nine genes, BASE, DNAJB3, FLJ33674, HEJ1, NTSR2, RPL13AP, SCGB1D4, WBSCR27 and ZCCHC13, that show human-specific alterations including truncations of the C-terminus. In some cases, the frameshift mutation results in gene inactivation or decay. In other cases, the altered protein seems to be functional. This study demonstrates that even the unfinished chimpanzee genome sequence can be useful in identifying modification of genes that are specific to the human lineage and, therefore, could potentially be relevant to the study of the acquisition of human-specific traits.

Amino Acid Sequence↗
PubMed1984

Spontaneous mutation frequencies in Salmonella: enhancement of G/C to A/T transitions and depression of deletion and frameshift mutation frequencies afforded by anoxic incubation.

Incubation of Salmonella typhimurium under anoxic conditions (0.1% oxygen or less) results in a substantial decrease in small (3-and 6-basepair) deletions in an A/T-rich region of the hisG gene in the hisG428 ochre mutant and also decreases the frequency of minus frameshift mutations in G/C-rich sequences in the his-D3052 and hisC3076 mutants. In contrast, the frequency of G/C-----A/T transition mutations increases substantially during anoxic growth of hisG46. Growth of revertants of strains carrying accessory deletions in the uvrB region of the Salmonella chromosome is drastically impaired on glucose minimal medium when oxygen partial pressures are below 0.1% oxygen.

Aerobiosis↗
PubMed1997

GLI3 frameshift mutations cause autosomal dominant Pallister-Hall syndrome.

Pallister-Hall syndrome (PHS, M146510) was first described in 1980 in six newborns. It is a pleiotropic disorder of human development that comprises hypothalamic hamartoma, central polydactyly, and other malformations. This disorder is inherited as an autosomal dominant trait and has been mapped to 7p13 (S. Kang et al. Autosomal dominant Pallister-Hall syndrome maps to 7p13. Am. J. Hum. Genet. 59, A81 (1996)), co-localizing the PHS locus and the GLI3 zinc finger transcription factor gene. Large deletions or translocations resulting in haploinsufficiency of the GLI3 gene have been associated with Greig cephalopolysyndactyly syndrome (GCPS; M175700) although no mutations have been identified in GCPS patients with normal karyotypes. Both PHS and GCPS have polysyndactyly, abnormal craniofacial features and are inherited in an autosomal dominant pattern, but they are clinically distinct. The polydactyly of GCPS is commonly preaxial and that of PHS is typically central or postaxial. No reported cases of GCPS have hypothalamic hamartoma and PHS does not cause hypertelorism or broadening of the nasal root or forehead. The co-localization of the loci for PHS and GCPS led us to investigate GLI3 as a candidate gene for PHS. Herein we report two PHS families with frameshift mutations in GLI3 that are 3' of the zinc finger-encoding domains, including one family with a de novo mutation. These data implicate mutations in GLI3 as the cause of autosomal dominant PHS, and suggest that frameshift mutations of the GLI3 transcription factor gene can alter the development of multiple organ systems in vertebrates.

Abnormalities, Multiple↗