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 433 records · Page 24Linked to original sources
PubMed1994

McArdle's disease: a rare frameshift mutation in exon 1 of the muscle glycogen phosphorylase gene.

We have previously discovered a common nonsense mutation in exon 1 of the myophosphosphorylase gene in patients with McArdle's disease, but this failed to explain all cases. We now report a second mutation (G-->TT) in one patient, also in exon 1. This mutation causes a shift in the reading frame which results in the replacement of Val15 by Phe. A further 10 amino acids of mis-sense protein are synthesised before a stop codon is reached.

Amino Acid Sequence↗
PubMed2006

Molecular basis of Kindler syndrome in Italy: novel and recurrent Alu/Alu recombination, splice site, nonsense, and frameshift mutations in the KIND1 gene.

Kindler syndrome (KS) is a rare autosomal recessive disorder characterized by skin blistering in childhood followed by photosensitivity and progressive poikiloderma. Most cases of KS result from mutations in the KIND1 gene encoding kindlin-1, a component of focal adhesions in keratinocytes. Here, we report novel and recurrent KIND1 gene mutations in nine unrelated Italian KS individuals. A novel genomic deletion of approximately 3.9 kb was identified in four patients originating from the same Italian region. This mutation deletes exons 10 and 11 from the KIND1 mRNA leading to a truncated kindlin-1. The deletion breakpoint was embedded in AluSx repeats, specifically in identical 30-bp sequences, suggesting Alu-mediated homologous recombination as the pathogenic mechanism. KIND1 haplotype analysis demonstrated that patients with this large deletion were ancestrally related. Five additional mutations were disclosed, two of which were novel. To date, four recurrent mutations have been identified in Italian patients accounting for approximately approximately 75% of KS alleles in this population. The abundance of repetitive elements in intronic regions of KIND1, together with the identification of a large deletion, suggests that genomic rearrangements could be responsible for a significant proportion of KS cases. This finding has implications for optimal KIND1 mutational screening in KS individuals.

Adolescent↗
PubMed2003

Cone dystrophy phenotype associated with a frameshift mutation (M280fsX291) in the alpha-subunit of cone specific transducin (GNAT2).

AIM: To describe the phenotype of a three generation consanguineous Pakistani family containing six individuals with autosomal recessive cone dystrophy caused by mutation in GNAT2. METHODS: Five of the six affected individuals underwent an ophthalmological examination, electrodiagnostic testing, fundus photography, autofluorescence imaging, and detailed psychophysical testing. RESULTS: All five examined patients had a history of nystagmus from infancy, photophobia, defective colour vision, and poor visual acuity. The nystagmus in three of the individuals had lessened with time. Fundus examination revealed an abnormal foveal appearance, without frank atrophy or pigmentation. Electroretinography (ERG) revealed absent ISCEV cone flicker ERGs with some preservation of responses to short wavelength stimulation. Rod ERGs showed no definite abnormality, but maximal (mixed rod-cone) response a-wave amplitudes were mildly subnormal. Rudimentary residual colour vision was detected in three individuals. There is clinical evidence of progressive visual acuity reduction in two older individuals. CONCLUSION: Mutation in the alpha-subunit of cone specific transducin (GNAT2) is characterised by an infantile onset cone dystrophy. Some affected individuals may show deterioration of visual acuity with time.

Adult↗
PubMed1995

Primary familial polycythemia: a frameshift mutation in the erythropoietin receptor gene and increased sensitivity of erythroid progenitors to erythropoietin.

Primary familial and congenital polycythemia (PFCP) is characterized by erythrocytosis with normal arterial PO2, blood P50, and serum erythropoietin (EPO) levels. In two PFCP families EPO receptor (EPOR) polymorphisms cosegregated with PFCP. A heterozygous insertion of G at EPOR nucleotide 5975 was identified in genomic DNA from polycythemic members of family no. 2. 5974insG shifts the reading frame at codon 430, predicting amino acid substitutions and truncation of the last 64 amino acids. Wild-type and mutant EPOR transcripts were detected in erythroid progenitors from affected individuals. Burst-forming units-erythroid from patients exhibited increased colony size and sensitivity to EPO. Transfected Ba/F3 cells expressing EPOR 5974insG exhibited increased EPO sensitivity compared with cells expressing wild-type EPOR. The functional effect of this EPOR mutation was directly compared with the other C-terminal mutations reported in unrelated PFCP families by expression in Ba/F3 cells. The transfected cells with another primary polycythemia associated EPOR mutant construct (G6002A) also exhibited increased sensitivity to EPO.

Adult↗
PubMed1994

A deletional frameshift mutation in spectrin beta-gene associated with hereditary elliptocytosis in spectrin Napoli.

We studied a clinically manifest, dominantly transmitted elliptocytosis in an Italian family. We found a new spectrin variant, designated spectrin Napoli. Its beta-chain was truncated in its C-terminal region (apparent MW 216 kD). It displayed a low expression level (15%). There was a 8 nt deletion: CTTTTGAGAAGT-->CTGT (nt 6255-6262), starting after codon 2053. This deletion was followed by a 54 nt (18 amino acids) missense sequence and terminated by the TGA triplet which normally overlaps codons 2074 and 2075 (CTTGAG). The overall length of the mutated beta-chain was comparable to that found in spectrin Nice, spectrin Tokyo and spectrin Tandil, which are other variants with truncated beta-chains; however, a distinct nonsense codon was used in spectrin Napoli.

Adult↗
PubMed2000

Proposed mechanism for a novel insertion/deletion frameshift mutation (I414G415ATCG-->CCA) in the hepatocyte nuclear factor 1 alpha (HNF-1 alpha) gene which causes maturity-onset diabetes of the young (MODY).

Maturity-onset diabetes of the young (MODY) is a monogenic subgroup of non-insulin dependent diabetes (NIDDM) characterized by an early age of diagnosis (usually < 25 years) and an autosomal dominant mode of inheritance. Mutations in the hepatocyte nuclear factor 1 alpha (HNF-1alpha) [MODY3] gene represent the most common cause of MODY in the UK and a common cause of MODY in many other populations. Sixty-three different mutations have been described in a total of 112 families worldwide. This report describes two families, not known to be related, who carry a novel insertion/deletion mutation (I414G415ATCG-->CCA) and a 6bp intronic deletion of the HNF-1alpha gene in cis. We propose that the insertion/deletion mutation has arisen by formation of a hairpin loop due to the presence of a quasi-palindromic sequence, followed by insertion of CC and deletion of TCG resulting in the increased stability of the hairpin loop.

Adult↗
PubMed1996

Hereditary desmoid disease due to a frameshift mutation at codon 1924 of the APC gene.

Desmoid tumors are slowly growing fibrous tumors highly resistant to therapy and often fatal. Here, we report hereditary desmoid disease (HDD), a novel autosomal dominant trait with 100% penetrance affecting a three-generation kindred. Desmoid tumors are usually a complication of familial adenomatous polyposis, a predisposition to the early development of premalignant adenomatous polyps in the colorectum due to chain-terminating mutations of the APC gene. In general, one or more members in approximately 10% of the FAP families manifest desmoid tumors. Affected individuals from the HDD kindred are characterized by multifocal fibromatosis of the paraspinal muscles, breast, occiput, arms, lower ribs, abdominal wall, and mesentery. Osteomas, epidermal cysts, and other congenital features were also observed. We show that HDD segregates with an unusual germ-line chain-terminating mutation at the 3' end of the APC gene (codon 1924) with somatic loss of the wild-type allele leading to tumor development.

Adolescent↗
PubMed2000

A frameshift mutation in prominin (mouse)-like 1 causes human retinal degeneration.

The disks of vertebrate photoreceptors are produced by outgrowths of the plasma membrane. Hence genes that encode retinal proteins targeted to plasma membrane protrusions represent candidates for inherited retinal degenerations. One such candidate is the gene encoding human prominin (mouse)-like 1 (PROML1, previously known as AC133 antigen) which belongs to the prominin family of 5-transmembrane domain proteins. Murine prominin (prom) shows a strong preference for plasma membrane protrusions in a variety of epithelial cells whereas PROML1 is expressed in retinoblastoma cell lines and adult retina. In the present study, molecular genetic analyses of a pedigree segregating for autosomal recessive retinal degeneration indicated that the affected individuals were homozygous for a nucleotide 1878 deletion in PROML1. This alteration is predicted to result in a frameshift at codon 614 with premature termination of translation. Expression of a similar prom deletion mutant in CHO cells indicated that the truncated protein does not reach the cell surface. Immunocytochemistry revealed that prom is concentrated in the plasma membrane evaginations at the base of the outer segments of rod photoreceptors. These findings suggest that loss of prominin causes retinal degeneration, possibly because of impaired generation of the evaginations and/or impaired conversion of the evaginations to disks.

AC133 Antigen↗
PubMed1995

Aflatoxin B1, 2-aminoanthracene, and 7,12-dimethylbenz[a]anthracene-induced frameshift mutations in human APRT.

Aflatoxin B1, 2-aminoanthracene, and 7,12-dimethylbenz[a]anthracene have been implicated in the etiology of human cancers. In this study, we demonstrate that these three chemicals can be activated by rat liver homogenate S9 coupled with NADPH coenzymes to produce a dose-dependent increase in the frequency of APRT reversion in the APRT-deficient human cell line HTD114. HTD114 contains single nucleotide insertions at different positions in each APRT allele and the spontaneous reversion frequency is < 10(-8). However, the highest reversion frequency induced by these chemicals is 1.2-2.0 x 10(-5), at least a 10(3)-fold increase over the frequency of spontaneous reversion. Reversion of either mutant allele was observed to be a consequence of a frame-restoring loss of a single nucleotide, which indicates that these three chemicals can function as frameshift mutagens in human cells.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed2005

Novel insertion frameshift mutation of the LH receptor gene: problematic clinical distinction of Leydig cell hypoplasia from enzyme defects primarily affecting testosterone biosynthesis.

Leydig cell hypoplasia (LCH) is a rare autosomal recessive condition that interferes with normal development of male external genitalia in 46,XY individuals and is caused by inactivating mutations of the LH receptor gene. The clinical and biochemical diagnostic parameters of LCH are not always specific and may therefore show significant overlap with other causes of insufficient testicular steroid biosynthesis. We have studied a 46,XY newborn with completely female external genitalia and palpable testes. Due to an increased basal serum ratio of androstenedione/testosterone, 17 beta-hydroxysteroid dehydrogenase type 3 (17 beta-HSD 3) deficiency was initially suspected. DNA analysis of the corresponding HSD17B3 gene, however, showed no abnormalities in the entire coding region. In contrast, direct sequencing of the LH receptor gene revealed a novel homozygous single nucleotide insertion in exon 11 (codon A589fs) producing a frame shift in the open reading frame predicting for premature termination of translation 17 amino acids downstream. From the genetic perspective, this mutation represents the first frame shift mutation in the LH receptor gene ever reported to date. From the clinical standpoint, LCH should always be considered in the differential diagnosis as steroid profiles may not be informative. Therefore, molecular genetic analysis should be warranted for androgen biosynthesis defects in all cases.

Amino Acid Sequence↗
PubMed2006

A homozygous frameshift mutation in the ESCO2 gene: evidence of intertissue and interindividual variation in Nmd efficiency.

Roberts syndrome (RS) is a rare disorder characterized by tetraphocomelia and several other clinical features. Cells from RS patients exhibit characteristic premature separation of heterochromatic region of many chromosomes and abnormalities in cell cycle. Mutations in the ESCO2 gene have recently been identified in 20 RS families. We performed mutational analysis of the ESCO2 gene in two fetuses diagnosed with RS and their normal parents. In both fetuses, we identified homozygosity for the c. 745_746delGT mutation, while the non-consanguineous parents were both heterozygous for the same mutation. Considering the position of the mutation identified, we carried out qualitative and quantitative real-time ESCO2 cDNA analysis on RNA isolated from CVS-stromal cells in one fetus, amniocytes in the second fetus, and lymphocytes from the heterozygous parents. The results of this analysis showed that despite the presence of a premature termination codon (PTC) 112 nucleotides upstream of the next exon3-exon4 junction, the mutant ESCO2 mRNA was present in both fetuses, albeit at low levels, indicating a partial resistance to nonsense mediated decay (NMD). Interestingly, when cells derived from the two fetuses were treated with an inhibitor of translation, they revealed the presence of tissue and individual variability in NMD efficiency, despite the identical mutational status. The existence of such a variation in the NMD efficiency could explain the broad intrafamilial and interfamilial variability in the clinical presentation of RS patients, and in other genetic diseases where nonsense mutations are responsible for most of the mutation load. Moreover, considering that a mutated full length mRNA was produced in both fetuses, we used Western blot analysis to demonstrate the absence of the ESCO2-truncated protein in cells derived from both fetuses and in a lymphoblastoid cell line derived from the parents.

Abnormalities, Multiple↗
PubMed1997

Chain termination codons and polymerase-induced frameshift mutations.

The consensus sequence for single-base deletions in non-reiterated runs during in vitro DNA-dependent DNA polymerisation is refined using data available in the literature. This leads to the observation that chain termination codons are hotspots for single-base deletions. The evolutionary implications are discussed in two models which differ in whether polymerases evolved while the genetic code emerged or after the genetic code was fixed. A possible answer to the question 'Why are stop codons just what they are?' is suggested.

Animals↗
PubMedDate not supplied

Absence of frameshift mutations in the bax gene in renal cell cancer (RCC) and transitional cell cancer (TCC).

BACKGROUND: Bax protein, a member of the Bcl-2 family, regulates the apoptotic pathway that involves both Bcl-2 and p53. bax mutations are found in hematological malignancies, colon cancer with microsatellite mutator phenotype, and some other cancers. We evaluated the possibility that Bax functions as a TCC or RCC tumor suppressor gene. MATERIALS AND METHODS: Using Western blot and polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) we looked for somatic mutations in a tract of eight deoxyguanosines (G)8 within third exon of bax in TCC and RCC cell lines and tumor specimens. RESULTS: We failed to reveal genetic alterations, at least in this specific region of bax gene in urological cancers. CONCLUSION: Alterations of bax, at least at investigated specific region, do not play considerable role in RCC or TCC tumorigenesis.

Adult↗
PubMed2003

Phenotypic variability in three carriers from a family with choroideremia and a frameshift mutation 1388delCCinsG in the REP-1 gene.

PURPOSE: To perform genotype-phenotype correlations in a family with choroideremia. METHODS: A three-generation family with two affected males and five carriers was the subject of the study. Molecular genetic analysis using single-strand conformation polymorphism analysis (SSCP) was conducted in all subjects, while electroretinography (ERG), multifocal ERG (mfERG), scanning laser ophthalmoscope microperimetry (SLO perimetry), fluorescein angiography, and Arden contrast color testing were performed in one male and three carriers. RESULTS: The findings in the affected male were typical for advanced choroideremia. The three carriers demonstrated a variable clinical phenotype including reduction of visual acuity and ERG and angiographic changes in one. Molecular genetic analysis revealed a functional null mutation (1388delCCinsG) in the REP-1 gene. CONCLUSIONS: A severe retinal pathology was found in the affected male, indicating that the 1388delCCinsG is a severe mutation. Varying phenotypes were present in the three carriers examined. The phenotype in carriers has been explained by random X-inactivation with varying expression of the inactivated and activated gene copy inside the same cell of both the retinal pigment epithelium and the rods. This thesis is in agreement with the clinical data obtained here.

Adaptor Proteins, Signal Transducing↗
PubMed1999

Identification and complementation of frameshift mutations associated with loss of cytadherence in Mycoplasma pneumoniae.

Mycoplasma pneumoniae cytadherence is mediated by a specialized, polar attachment organelle. Certain spontaneously arising cytadherence mutants (designated class I) lack HMW2, fail to localize the adhesin protein P1 to the attachment organelle, and exhibit accelerated turnover of proteins HMW1, HMW3, and P65. Insertional inactivation of hmw2 by Tn4001 results in a phenotype nearly identical to that of the class I mutants, suggesting that the latter may result from a defect in hmw2. In this study, the recombinant wild-type hmw2 allele successfully complemented a class I mutant when introduced by transposon delivery. Synthesis of recombinant HMW2 at wild-type levels resulted in reacquisition of hemadsorption and normal levels of HMW1, HMW3, and P65. Low-level production of HMW2 in some transformants resulted in only an intermediate capacity to hemadsorb. Furthermore, full restoration of HMW1 and P65, but not that of HMW3, was directly proportional to the amount of recombinant HMW2 produced, reflecting the importance of proper stoichiometry for certain cytadherence-associated proteins. The recombinant class I hmw2 allele did not restore cytadherence, consistent with a defect in hmw2 in this mutant. A frameshift was discovered in different oligoadenine tracts in hmw2 from two independent class I mutants. Finally, protein P28 is thought to be the product of internal translation initiation in hmw2. A transposon excision-deletion mutant produced a truncated HMW2 but no P28, consistent with this conclusion. However, this deletion mutant was hemadsorption positive, indicating that P28 may not be required for cytadherence.

Adhesins, Bacterial↗
PubMed1998

[Proteins with frameshift mutations in Alzheimer's disease; cause or effect?].

In a recent paper in Science, a novel finding was presented on Alzheimer's disease. The authors describe mutant proteins, brought about by a change in the mRNA reading frame. These so-called +I proteins appear to be associated with neuropathological changes in Alzheimer's disease brains. Two proteins involved in the pathogenesis of the disease were studied: beta-amyloid precursor protein en ubiquitin-B. For both proteins, a deletion of two bases in a small percentage of the mRNAs caused the frame shift. Possible mechanisms and implications are discussed.

Alzheimer Disease↗
PubMed2003

Polyalanine expansion and frameshift mutations of the paired-like homeobox gene PHOX2B in congenital central hypoventilation syndrome.

Congenital central hypoventilation syndrome (CCHS or Ondine's curse; OMIM 209880) is a life-threatening disorder involving an impaired ventilatory response to hypercarbia and hypoxemia. This core phenotype is associated with lower-penetrance anomalies of the autonomic nervous system (ANS) including Hirschsprung disease and tumors of neural-crest derivatives such as ganglioneuromas and neuroblastomas. In mice, the development of ANS reflex circuits is dependent on the paired-like homeobox gene Phox2b. Thus, we regarded its human ortholog, PHOX2B, as a candidate gene in CCHS. We found heterozygous de novo mutations in PHOX2B in 18 of 29 individuals with CCHS. Most mutations consisted of 5-9 alanine expansions within a 20-residue polyalanine tract probably resulting from non-homologous recombination. We show that PHOX2B is expressed in both the central and the peripheral ANS during human embryonic development. Our data support an essential role of PHOX2B in the normal patterning of the autonomous ventilation system and, more generally, of the ANS in humans.

Alanine↗
PubMed2003

Congenital hydrocephalus in hy3 mice is caused by a frameshift mutation in Hydin, a large novel gene.

The autosomal-recessive mutation hydrocephalus3 (hy3) results in lethal communicating hydrocephalus with perinatal onset. We recently described a hydrocephalus-inducing transgenic insertional mutation, OVE459, which represents a new allele of hy3. Direct cDNA selection performed on a wild-type mouse BAC clone spanning the OVE459 insertion locus on chromosome 8 led to the identification of two novel candidate genes, Hydin and Vac14. The transgene insertion resulted in a rearrangement of Hydin exons in OVE459 mice. Hydin consists of at least 86 exons spanning over 340 kb of genomic DNA. The full-length Hydin transcript is nearly 16 kb, encoding a putative 5099 amino acid protein. Northern analysis revealed a marked reduction of Hydin mRNA in both OVE459 and hy3 homozygotes relative to wild-type littermates. A single CG base-pair deletion in exon 15 of Hydin was discovered specifically in mice carrying the spontaneous hy3 mutant allele. This deletion creates a premature termination signal two codons downstream of the mutation, likely resulting in the loss of 89% of the full-length gene product. Within the neonatal brain, Hydin expression is confined to the ciliated ependymal cell layer lining the lateral, third and fourth ventricles. Other sites of Hydin expression include the ciliated epithelial cells lining the bronchi and oviduct, as well as in the developing spermatocytes in the testis. The Hydin gene product is not closely related to any previously identified protein, with the exception of a 314 amino acid domain with homology to caldesmon, an actin-binding protein, suggesting an interaction with the cytoskeleton.

Animals↗