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PubMed2004

A novel frameshift mutation of FOXC2 gene in a family with hereditary lymphedema-distichiasis syndrome associated with renal disease and diabetes mellitus.

Lymphedema-distichiasis (LD) syndrome is a clinically variable autosomal dominant disorder. The disorder is caused by mutations in the forkhead transcription factor FOXC2 gene on chromosome band 16q24.3. Here, we report the sequence of the FOXC2 gene in a German-Irish family with LD in six affected relatives over three generations and identify a single adenine base pair insertion at nt 1006--1007. This insertion creates a frameshift mutation that predicts a premature stop at codon 462. In addition to LD, four of the affected family members have renal disease and three have diabetes mellitus (DM), not usually seen in the LD syndrome. Polymorphisms of FOXC2 in diabetics have been studied in different populations. Our sequence analysis of the 5' untranslated region (UTR) C-512T shows the homozygous T allele in all family members tested. The sequencing data in this family suggests the possibility of a novel phenotype-haplotype. This novel phenotype, LD/renal disease/type 2 diabetes, might be the result of a combination of the nt 1006--1007 insA and the upstream UTR homozygous T polymorphism.

5' Untranslated Regions↗
PubMed2001

Frameshift mutation in the collagen VI gene causes Ullrich's disease.

Patients with Ullrich's disease have generalized muscle weakness, multiple contractures of the proximal joints, and hyperextensibility of the distal joints. Recently, we found a deficiency of collagen VI protein in two patients with Ullrich's disease. In this study, we detected a homozygous 26 bp deletion in exon 14 of the collagen VI alpha 2 gene (COL6A2) in one patient. This mutation causes a frameshift and a premature termination codon, and results in a truncated collagen VI alpha 2 chain. Our data suggest that at least some cases of Ullrich's disease result from recessive mutations in COL6A2.

Adult↗
PubMed1998

Global analysis of genomic texts: the distribution of AGCT tetranucleotides in the Escherichia coli and Bacillus subtilis genomes predicts translational frameshifting and ribosomal hopping in several genes.

Present availability of the genomic text of bacteria allows assignment of biological known functions to many genes (typically, half of the genome's gene content). It is now time to try and predict new unexpected functions, using inductive procedures that allow correlating the content of the genomic text to possible biological functions. We show here that analysis of the genomes of Escherichia coli and Bacillus subtilis for the distribution of AGCT motifs predicts that genes exist for which the mRNA molecule can be translated as several different proteins synthesized after ribosomal frameshifting or hopping. Among these genes we found that several coded for the same function in E. coli and B. subtilis. We analyzed in depth the situation of the infB gene (experimentally known to specify synthesis of several proteins differing in their translation starts), the aceF/pdhC gene, the eno gene, and the rplI gene. In addition, genes specific to E. coli were also studied: ompA, ompFand tolA (predicting epigenetic variation that could help escape infection by phages or colicins).

Acetyltransferases↗
PubMed1995

Frameshift mutations in Salmonella induced by the extracts of medicinal herbs Lannea edulis (Sond.) Engl. and Monotes glaber Sprague.

Lannea edulis and Monotes glaber have been prescribed for various affectations in the traditional medical practice of Zimbabwe and other parts of Africa. Mutagenicity testing using Salmonella typhimurium strains TA97a, TA98, and TA100, indicated that the aqueous extracts of these plants induced frameshift mutations in Salmonella. The extract of L. edulis displayed marginal mutagenicity in strain TA97a while that of M. glaber showed a significant dose-dependent mutagenicity in both strains TA97a and TA98. There was no mutagenic effect observed in strain TA100. Two other plant extracts, those of Lannea discolor and Dolichos kilimandscharicus, were nonmutagenic in all three strains.

Dose-Response Relationship, Drug↗
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↗
PubMed2003

Identification of novel genes with somatic frameshift mutations within coding mononucleotide repeats in colorectal tumors with high microsatellite instability.

We have systematically retrieved genes with coding mononucleotide repeats from sequence databases and analyzed them for mutations in tumors with high levels of microsatellite instability (MSI-H). We found somatic frameshift mutations in 7/13 genes previously not analyzed in MSI-H tumors. According to the frequency of mutations in MSI-H tumors, these genes could be divided into genes with high coding mononucleotide repeat instability (CMRI-H) and genes with low coding mononucleotide instability (CMRI-L). CMR-H genes were mutated in more than 9/38 and CMRI-L in less than 4/38 of MSI-H tumors. Four genes in our study were CMRI-H and could thus possibly play a role in the development of MSI-H tumors: TFE3 (9/38), TEF4 (12/38), RGS12 (11/38), and TCF1 (12/38). Our results suggest that systematic identification of genes with CMR in the sequence databases and determination of mutation frequency in MSI-H tumors might be a powerful tool for identification of new molecular targets in the development of MSI-H tumors.

Adenocarcinoma↗
PubMed2002

Intron retention and frameshift mutations result in severe pyruvate carboxylase deficiency in two male siblings.

This paper describes the molecular characterization of two male siblings displaying the complex (Type B) form of pyruvate carboxylase (PC) deficiency in which severe neonatal lactic acidosis and redox abnormalities results in death within the first few weeks of life. The two male siblings were found to be compound heterozygous for a TAGG deletion at the exon15/intron15 splice site (IVS15+2-5delTAGG) and a dinucleotide deletion in exon 16 (2491-2492delGT) of the PC gene. We also demonstrate through RT-PCR and sequencing of aberrant transcripts that the IVS15+2-5delTAGG results in the retention of intron 15 during pre-mRNA splicing. In addition, both deletions are predicted to result in a frameshift to generate a premature termination codon such that the encoded mRNA could be subject to nonsense mediated decay.

Alternative Splicing↗
PubMed2001

Five novel frameshift mutations in exon 3 and 4 of the MECP2 gene identified in Rett patients: Consequences for the molecular diagnosis strategy.

Rett syndrome (RTT) is a severe progressive neurological disorder that affects almost exclusively females. The gene responsible for this disorder, MECP2, was recently identified by candidate gene strategy. Mutations were detected in 70-85% of RTT cases. We report here five novel frameshift mutations (named 345delC, 895del202, 989ins18del8, 996insAG and 1124del53) in exon 3 and 4 of the MECP2 gene. To avoid the missing of few small deletions in RTT patients using classical mutation screening approaches, we suggest that screening of the mutations in the MECP2 gene in RTT girls should include at least a large PCR to amplify exon 4 entirely.

Chromosomal Proteins, Non-Histone↗
PubMed2001

Novel frameshift mutations in CRX associated with Leber congenital amaurosis.

Mutations in CRX, a photoreceptor-specific transcription factor, can cause Leber congenital amaurosis (LCA), cone-rod dystrophy (CORD), and retinitis pigmentosa (RP), all of which feature severe visual impairment. Upon screening 55 patients with Leber congenital amaurosis, 75 patients with cone-rod dystrophy, 13 with cone dystrophy, and 36 with recessive or isolate RP for changes in the CRX sequence, we found two patients with Leber congenital amaurosis who carried heterozygously one of two novel frameshift mutations. The first mutation, Tyr191(1-bp del), was a de novo change and the second change, Pro263(1-bp del) was inherited from the proband's affected father. Both mutations are predicted to encode mutant versions of CRX with altered carboxy termini. We also found a previously reported missense mutation, Arg41Gln, heterozygously in a 47-year-old patient with a form of RP. The missense change Val242Met was found in an isolate case of CORD and no controls; however, its pathogenicity remains uncertain because only limited segregation analysis was possible. A nonpathogenic missense change, Ala158Thr, was found to be a variant present at relatively high frequency among African-Americans.

DNA↗
PubMed1993

Identification of two novel beta zero-thalassemia mutations in a Filipino family: frameshift codon 67 (-TG) and a beta-globin gene deletion.

The frequency of beta-thalassemia alleles among Filipinos is estimated to be 0.02, although little is known about the actual mutations represented in this population. Here, we describe a Filipino family in which a child has severe beta-thalassemia major. Molecular studies of the family revealed that the proband is a compound heterozygote for two previously unreported beta zero-thalassemia alleles: a frameshift mutation (-TG) at codon 67 and a deletion of the entire beta-globin gene. The 5' endpoint of this novel deletion is located approximately 3.9 kb to approximately 4.3 kb upstream of beta-globin gene, and the deletion extends 3' beyond the beta-globin gene for an undetermined distance. The occurrence of two novel beta-thalassemia alleles in a single family suggests that the Filipino population may have a unique spectrum of beta-thalassemia alleles.

Alleles↗
PubMed1994

FH-Sydney 1 and 2: two novel frameshift mutations in exon 10 of the low-density lipoprotein receptor gene detected by heteroduplex formation.

We report two novel frameshift mutations in exon 10 of the low-density lipoprotein receptor gene that lead to familial hypercholesterolemia in separate lineages. The lesions, FH-Sydney 1 and FH-Sydney 2, were detected by a modified heteroduplex analysis of exon-specific polymerase chain reaction (PCR) amplified DNA, and characterized at the molecular level by sequencing. Restriction enzyme digestion of PCR amplified DNA confirmed the presence of the mutant alleles in affected family members and their absence in nonaffected family members in both lineages. FH-Sydney 1 is a 4-bp duplication at position 1373, while FH-Sydney 2 is a 2-bp deletion at position 1478. The predicted result of both mutations is the premature truncation of the receptor at stop codons generated downstream of the mutations. Neither mutation was detected in a survey of 54 unrelated familial hypercholesterolemia patients.

Base Sequence↗
PubMed2002

A common frameshift mutation and other variants in GJB4 (connexin 30.3): Analysis of hearing impairment families.

Mutations in GJB1, GJB2, GJB3 and GJB6 are involved in hearing impairment. GJB2, GJB3 and GJB6 are also mutated in patients with hyperproliferative skin disorders. The human GJB4 gene has been deduced in silico and a mutation in a family with erythrokeratodermia variabilis has been reported. We describe here the analysis of the GJB4 gene in hearing impairment patients and control subjects. We have identified a common (4%) frameshift mutation (154del4) in GJB4 in both affected and hearing subjects, one patient being homozygous for the mutation. We have also detected five amino acid variants (R103C, R124Q, R160C, C169W and E204A) in individuals that have not skin disorders. While mutation 154del4 is not associated with hearing impairment the involvement of some of the amino acid variants detected here is uncertain. These GJB4 variants should help to define the putative role of connexin 30.3 in both skin disorders and hearing impairment.

Amino Acid Sequence↗
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↗
PubMed1991

Phase variation of gonococcal pili by frameshift mutation in pilC, a novel gene for pilus assembly.

Pili prepared from Neisseria gonorrhoeae contain minor amounts of a 110 kd outer membrane protein denoted PilC. The corresponding gene exists in two copies, pilC1 and pilC2, in most strains of N.gonorrhoeae. In the piliated strain MS11(P+), only one of the genes, pilC2, was expressed. Inactivation of pilC2 by a mTnCm insertion resulted in a nonpiliated phenotype, while a mTnCm insertion in pilC1 had no effect on piliation. Expression of pilC was found to be controlled at the translational level by frameshift mutations in a run of G residues positioned in the region encoding the signal peptide. Nonpilated (P-), pilin expressing colony variants that did not express detectable levels of PilC were selected; all P+ backswitchers from these P-, PilC- clones were found to be PilC+. The structural gene for pilin, pilE, was sequenced and found to be identical in one P-, PilC- and P+, PilC+ pair. Most PilC- cells were completely bald whereas the PilC+ backswitcher had 10-40 pili per cell. Thus, a turn ON and turn OFF in the expression of PilC results in gonococcal pili phase variation. These results suggest that PilC is required for pilus assembly and/or translocation across the gonococcal outer membrane.

Amino Acid Sequence↗
PubMed1995

Frameshift mutation in codon 176 of the p53 gene in rat esophageal epithelial cells transformed by benzo[a]pyrene dihydrodiol.

Mutations in the p53 tumor suppressor gene have been associated with exposure to environmental chemical carcinogens. Cultured rat esophageal epithelial cells were transformed in vitro by treatment with benzo[a]pyrene dihydrodiol (BP-DHD). A BP-DHD-transformed cell line and control cell lines were analyzed for mutations in the p53 gene and in the Ha-ras gene by single-strand conformation polymorphism analysis of polymerase chain reaction-amplified products and direct DNA sequencing. The deletion of one cytosine in codons 174-176 (TGCCCCCAC-->TGCCCCAC) of the p53 gene was found only in the BP-DHD-transformed cell line. The BP-DHD-transformed cells were highly invasive and tumorigenic when transplanted into syngeneic rats, whereas control lines either were nontumorigenic or formed epithelial cysts. BP-DHD-transformed cells and control lines were negative for mutations in the Ha-ras gene. Our results suggest that the tumorigenic potential of the BP-DHD-transformed cell line is associated with a frameshift mutation in codon 176 of the p53 gene but not with mutations in the Ha-ras gene. The G/C-rich codons 174-176 in the rat p53 gene may be specific targets for BP-DHD.

Animals↗
PubMed2026

Novel TCOF1 Frameshift Variant and Phenotypic Heterogeneity in a Chinese Family With Treacher Collins Syndrome.

BACKGROUND: Treacher Collins syndrome (TCS) is a congenital craniofacial disorder characterized by malar and mandibular hypoplasia, downward-slanting palpebral fissures, and conductive hearing loss. Pathogenic variants in TCOF1 account for most cases, with POLR1D, POLR1C, and POLR1B also implicated. METHODS: Whole-exome sequencing was performed in a two-generation Chinese family with TCS, followed by Sanger sequencing validation. Clinical features were systematically evaluated, and bioinformatic analyses combined with structural modeling were employed to assess the potential pathogenicity of the identified variant. RESULTS: In this study, a novel heterozygous frameshift variant in TCOF1 (NM_001371623.1:c.1601_1602delCC, p.Pro534Leufs*15) was identified in the proband and his affected father. The proband presented classic TCS features including craniofacial skeletal hypoplasia, downward-slanting palpebral fissures, and conductive hearing loss. He also carried a right-sided preauricular fistula, a nonclassical feature of TCS. The same variant was detected in his affected father with a substantially milder phenotype, indicating marked intrafamilial phenotypic variability. Bioinformatic analysis and structural modeling predicted that this variant produces a severely truncated Treacle protein lacking key functional domains, which is predicted to disrupt nucleolar localization and ribosome biogenesis. CONCLUSION: Our findings expand the variant spectrum of TCOF1, highlight phenotypic heterogeneity in TCS, and reinforce the critical role of molecular diagnosis in distinguishing TCS from phenotypically overlapping craniofacial syndromes.

Humans↗
PubMed1995

Sequence analysis of a 44 kb DNA fragment of yeast chromosome XV including the Tyl-H3 retrotransposon, the suf1(+) frameshift suppressor gene for tRNA-Gly, the yeast transfer RNA-Thr-1a and a delta element.

We have sequenced on both strands a 44,019 bp fragment located on the left arm of Saccharomyces cerevisiae chromosome XV. The sequenced segment contains 22 open reading frames (ORFs) of at least 100 amino acids long, one of which probably contains an intron. Six of the 22 ORFs correspond to known proteins: the multicopy suppressor of Snf1 protein 1, the two Tyl-H3 transposon proteins TyA and TyB, the myo-inositol transporter 2, the transcription factor protein Ino4 and the 3,4-dihydroxy-5-hexaprenylbenzoate methyltransferase. Of the 16 remaining ORFs, two show highest homologies with the yeast serine/threonine protein kinase Ste20 and the human tryptophanyl-tRNA synthetase. Eight ORFs show slight similarities with protein sequences described in data banks. DNA sequence comparison reveals also the presence of three known sequences: the Tyl-H3 transposable element, the yeast suf1(+) frameshift suppressor gene for tRNA-Gly and the yeast transfer RNA-Thr-1a. A fourth DNA sequence shows striking identities with the yeast delta elements.

Amino Acid Sequence↗
PubMed2001

Molecular analysis of endogenous retrovirus HRES-1: identification of frameshift mutations in region encoding putative 28-kDa autoantigen.

A possible involvement of HTLV-1-related endogenous sequence 1 (HRES-1) in autoimmune diseases has been recently reported. In primate cells, PCRs and RT-PCRs using specific primers reveal the presence and the transcription of gag-related sequences. However antisera generated against selected HRES-1 peptides failed to detect a 28-kDa protein deduced from the translated gag ORF and described previously. Such discordant results led us to perform DNA cloning and sequencing of LTR- and gag-related nucleotidic fragments. Repeated sequence analyses on distinct samples revealed frameshift mutations in the gag and LTR ORFs. Our sequence analyses detected a stop codon in the gag-related ORF, which is inconsistent with the expression of a 28-kDa protein. Instead of the two ORFs previously found, our gag-related region contained three ORFs. One of them demonstrated higher nucleotidic and peptidic homologies with the p19 gag of HTLV-I. However, the molecular analyses of our new sequence did not show evidence of potent translation capacities.

Amino Acid Sequence↗