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Results for “Frameshift variant”

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PubMed2005

A novel ancestral splicing mutation in the multidrug resistance protein 2 gene causes Dubin-Johnson syndrome in Ashkenazi Jewish patients.

Dubin-Johnson syndrome (DJS) is an inherited disorder characterized by chronic conjugated hyperbilirubinemia due to the absence or dysfunction of the multidrug resistance protein 2 (MRP2). We previously identified two distinct ancestral mutations causing DJS in 22 unrelated Iranian and five unrelated Moroccan Jewish patients, respectively. In this study we identified and characterized the mutation causing DJS in Ashkenazi Jewish patients and assessed a possible founder effect. Sequencing of all 32 exons of the MRP2 gene identified a novel IVS8+4A-->G mutation in three unrelated homozygotes. Haplotype analysis using four intragenic dimorphisms disclosed a founder effect for the mutation. RT-PCR and real time PCR analysis of mRNA from one patient revealed three splice variants all leading to frameshifts and predicting premature termination codons. The main splice variant was a consequence of the use of a cryptic donor splice site inside exon 8. Liver biopsy in one patient revealed complete absence of MRP2 from the canalicular membrane of hepatocytes. In conclusion, our results provide strong evidence that an ancestral IVS8+4A-->G mutation causes DJS in Ashkenazi Jewish patients by abolishing normal splicing of intron 8 leading to aberrantly spliced products that predict truncation of MRP2.

Journal Article↗

PubMed2000

Novel frameshift mutations in the RP2 gene and polymorphic variants.

Mutations in the RP2 gene located on Xp11.23 are associated with X-linked retinitis pigmentosa (XLRP), a severe form of progressive retinal degeneration which leads to complete loss of vision in affected males. To date, 14 different mutations in the RP2 gene have been reported to cause XLRP, the majority of which lead to a coding frameshift within the gene and predicted truncation of the protein product. We here report two novel frameshift mutations in RP2 identified in XLRP families by PCR-SSCP and direct sequencing, namely 723delT and 796-799del. Four single nucleotide polymorphisms (SNPs) within the coding region of RP2 are also described (105A>T, 597T>C, 844C>T, 1012G>T), the first polymorphisms to be reported within this gene of unknown function, two of which alter the amino acid sequence. The current study extends the XLRP mutation profile of RP2 and highlights non-pathogenic coding sequence variations which may facilitate both functional studies of the gene and analysis of intragenic allelic contribution to the phenotype.

Alternative Splicing↗

PubMed1998

Novel Gag-Pol frameshift site in human immunodeficiency virus type 1 variants resistant to protease inhibitors.

Human immunodeficiency virus type 1 (HIV-1) variants resistant to protease inhibitors have been shown to contain a mutation in the p1/p6 Gag precursor cleavage site. At the messenger RNA level, this mutation generates a U UUU UUU sequence that is reminiscent of the U UUU UUA sequence required for ribosomal frameshifting and Gag-Pol synthesis. To test whether the p1/p6 cleavage site mutation was generating a novel frameshift site, HIV sequences were inserted in translation vectors containing a chloramphenicol acetyltransferase (CAT) reporter gene requiring -1 frameshifting for expression. All sequences containing the original HIV frameshift site supported the synthesis of CAT but expression was increased 3- to 11-fold in the presence of the mutant p1/p6 sequence. When the original frameshift site was abolished by mutation, expression remained unchanged when using constructs containing the mutant p1/p6 sequence, whereas it was decreased 2- to 4.5-fold when using wild-type p1/p6 constructs. Similarly, when introduced into HIV molecular clones, the p1/p6 mutant sequence supported Gag-Pol synthesis and protease activity in the absence of the original frameshift site, indicating that this sequence could also promote ribosomal frameshifting in virus-expressing cells.

Amino Acid Sequence↗

PubMed2006

Profiling of length heteroplasmies in the human mitochondrial DNA control regions from blood cells in the Korean population.

The length heteroplasmies in the hypervariable (HV) regions of mitochondrial DNA (mtDNA) from blood cells were examined in 57 healthy Korean donors. Interestingly, all the healthy Korean subjects displayed length heteroplasmies in both the HV1 and HV2 regions. Closer examination of the HV2 length heteroplasmies indicated that most of these donors (84%) exhibited a minimal 303-315 homopolymeric C (poly-C) tract frameshift of 1 bp (mixture of one major and minor mtDNA type). Sixteen percent of the donors however had poly-C tract frameshifts of 2 bp or more. The donor group with major length variants (two or more frameshifts) had about a two-fold decrease in mtDNA copy number compared with the group exhibiting only a 1 bp frameshift. This result supports the possibility that a severe frameshift in the 303-315 poly-C tract may also cause the impairment of mtDNA replication in hematopoietic tissue.

Adolescent↗

PubMed2003

Little evidence for involvement of MLH3 in colorectal cancer predisposition.

Mutations in the DNA MMR genes MSH2, MLH1, MSH6 and PMS2 underlie a large subset of HNPCC cases, and a hallmark of the tumors is MSI. In many HNPCC families, however, a causative mutation has not been found. Therefore, the involvement of additional, thus far unknown, genes in MSI as well as MSS colorectal tumor predisposition is possible. The role of a relatively recently cloned MMR gene, MLH3, in familial CRC has been studied; but the results appear somewhat conflicting. To further evaluate the role of MLH3 in CRC predisposition, we analyzed 30 Finnish CRC cases for germline mutations by sequencing. These cases were selected from a large series of Finnish CRC patients, to match features previously proposed to associate with MLH3 germline defects. We found 5 missense variants, 4 of which were also found in Finnish cancer-free controls. The only remaining variant does not appear to be an attractive candidate for a disease-associated mutation because the amino acid change is located outside the conserved residues. We also screened for the previously reported variants, including a frameshift change, the most likely pathogenic MLH3 mutation observed so far. The frameshift was not present in the 30 CRC cases or in 700 cancer-free controls. While it is a difficult task to exclude a role of MLH3 in HNPCC, our study could not confirm a role for MLH3 in CRC predisposition.

Carrier Proteins↗

PubMed1995

Differential expression of human Fas mRNA species upon peripheral blood mononuclear cell activation.

Human Fas/Apo-1 is a cell-surface protein that mediates apoptosis upon ligation with Fas ligand. The gene lies on the long arm of chromosome 10, consists of nine exons, and spans more than 26 kb of DNA. We previously reported the presence of a Fas variant mRNA, designated as Fas delta TM, in human peripheral blood mononuclear cells. Fas delta TM is generated by alternative splicing of the intact exon 6, which encodes the Fas transmembrane domain. In the present study, we describe three novel forms of Fas mRNA that are generated by alternative splicing of exons 3, 4, 6 and 7. These three mRNA variants undergo a frameshift and produce truncated polypeptides because of the appearance of a stop codon in the altered open reading frame. On activation of the peripheral blood mononuclear cells, a decreased expression of alternatively spliced Fas mRNA species correlated with increased cell-surface expression of Fas. These results suggest that differential expression of alternatively spliced Fas mRNAs may play a role in regulation of Fas function via regulation of the production of the membrane-bound and the soluble, secreted Fas protein products.

Alternative Splicing↗

PubMed1999

Germ-line mosaicism in tuberous sclerosis: how common?

Two-thirds of cases of tuberous sclerosis complex (TSC) are sporadic and usually are attributed to new mutations, but unaffected parents sometimes have more than one affected child. We sought to determine how many of these cases represent germ-line mosaicism, as has been reported for other genetic diseases. In our sample of 120 families with TSC, 7 families had two affected children and clinically unaffected parents. These families were tested for mutations in the TSC1 and TSC2 genes, by Southern blotting and by single-strand conformational analysis. Unique variants were detected in six families. Each variant was present and identical in both affected children of a family but was absent in both parents and the unaffected siblings. Sequencing of the variants yielded two frameshift mutations, one missense mutation, and two nonsense mutations in TSC2 and one nonsense mutation in TSC1. To determine which parent contributed the affected gametes, the families were analyzed for linkage to TSC1 and TSC2, by construction of haplotypes with markers flanking the two genes. Linkage analysis and loss-of-heterozygosity studies indicated maternal origin in three families, paternal origin in one family, and either being possible in two families. To evaluate the possibility of low-level somatic mosaicism for TSC, DNA from lymphocytes of members of the six families were tested by allele-specific PCR. In all the families, the mutant allele was detected only in the known affected individuals. We conclude that germ-line mosaicism was present in five families with mutations in the TSC2 gene and in one family with the causative mutation in the TSC1 gene. The results have implications for genetic counseling of families with seemingly sporadic TSC.

Adult↗

PubMed1992

Molecular abnormalities of a human glucose-6-phosphate dehydrogenase variant associated with undetectable enzyme activity and immunologically cross-reacting material.

Among a large number of glucose-6-phosphate dehydrogenase (G6PD) variants associated with different severity of clinical manifestations, enzyme deficiency, and kinetic abnormalities found in humans, only one variant exhibits no measurable activity and lacks an immunologically cross-reacting material in blood cells and other tissues. The mRNA content of the patient's lymphoblastoid cells was found to be normal, and the size of mRNA was also normal (i.e., approximately 2.4 kb). Western blot hybridization indicated that the patient's cells did not produce cross-reacting material. The variant mRNA was reverse transcribed and amplified by PCR. Nucleotide sequencing of the variant cDNA showed the existence of three nucleotide base changes, i.e., a C----G at nucleotide 317 (counting from adenine of the initiation codon), which should cause Ser----Cys substitution at the 106th position (counting from the initiation Met); a C----T at nucleotide 544, which induces the Arg----Trp at the 182d position; and a C----T at nucleotide 592, which induces Arg----Cys at the 198th position of the protein. The existence of three mutation sites was confirmed by sequencing of selected regions of the variant gene. No base deletion or frameshift mutation was found in the variant cDNA. No nucleotide change was detected in the extended 5' region, which included the most distal cap site. When the variant cDNA was expressed in Escherichia coli, the G6PD activity was approximately 2% of that expressed by the normal cDNA, and cross-reacting material was undetectable. However, when the variant mRNA was expressed in the in vitro translation system of rabbit reticulocytes, the variant protein was produced. These results suggest that extremely rapid in vivo degradation or precipitation of the variant enzyme induced by the three amino acid substitutions could be the major cause of the molecular deficiency.

Base Sequence↗

PubMed2004

Selective expansion of the newly evolved genomic variants of retrotransposon 1731 in the Drosophila genomes.

The structural variants of the regulatory and coding regions of the LTR-retrotransposon 1731 are described. Two classes of genomic copies of retrotransposon 1731, with and without frameshifting strategy to express Gag and Pol proteins, were earlier revealed in the D. melanogaster genome. Copies without frameshifting are shown to be evolved from an ancient variant with frameshifting and are widespread in the genomes of the melanogaster complex species. Position of a rare codon responsible for ribosome pausing and efficient frameshifting is identified. Two structural variants of 1731 LTRs were detected in the melanogaster complex species: the predominant structural variant A1A2 of 1731 LTR in the D. melanogaster, D. simulans, and D. sechellia genomes contains duplicated and diverged copies of 28 bp in the U3 region, whereas A1 variant lacking this duplication is expanded in the D. mauritiana genome. Selective expansion of the A1A2 variant was detected in the independently established D. melanogaster cell cultures. A1A2 variant is expressed in embryos, cell culture, and testes, whereas A1 is expressed only in testes of D. melanogaster. Relief of expression of the A1A2 but not A1 variant in the ovaries as a result of mutation in the RNA interference (RNAi) spn-E gene is shown. Thus, expansion of the recently evolved genomic variants of the LTR retrotransposon 1731 possessing a new translation strategy, duplication in the U3 region, and extended profile of expression is revealed.

Animals↗

PubMed2001

Germline and somatic mutations in hMSH6 and hMSH3 in gastrointestinal cancers of the microsatellite mutator phenotype.

Hereditary and sporadic gastrointestinal cancer of the microsatellite mutator phenotype (MMP) is characterized by a remarkable genomic instability at simple repeated sequences. The genomic instability is often caused by germline and somatic mutations in DNA mismatch repair (MMR) genes hMSH2 and hMLH1. The MMP can be also caused by epigenetic inactivation of hMLH1. The MMP generates many somatic frameshift mutations in genes containing mononucleotide repeats. We previously reported that in MMP tumors the hMSH6 and hMSH3 MMR genes often carry frameshift mutations in their (C)(8) and (A)(8) tracks, respectively. We proposed that these 'secondary mutator mutations' contribute to a gradual manifestation of the MMP. Here we report the detection of other frameshift, nonsense, and missense mutations in these genes in colon and gastric cancers of the MMP. A germline frameshift mutation was found in hMSH6 in a colon tumor harboring another somatic frameshift mutation. Several germline sequence variants and somatic missense mutations at conserved residues were detected in hMSH6 and only one was detected in hMSH3. Of the three hMSH6 germline variants in conserved residues, one coexisted with a somatic mutation at the (C)(8) track and another had a somatic missense mutation. We suggest that some of these germline and somatic missense variants are pathogenic. While biallelic hMSH6 and hMSH3 frameshift mutations were found in some tumors, many tumors seemed to contain only monoallelic mutations. In some tumors, these somatic monoallelic frameshift mutations at the (C)(8) and (A)(8) tracks were found to coexist with other somatic mutations in the other allele, supporting their functionality during tumorigenesis. However, the low incidence of these additional somatic mutations in hMSH6 and hMSH3 leaves many tumors with only monoallelic mutations. The impact of the frameshift mutations in gene expression was studied by comparative analysis of RNA and protein expression in different tumor cell clones with different genotypes. The results show that the hMSH6 (C)(8) frameshift mutation abolishes protein expression, ruling out a dominant negative effect by a truncated protein. We suggest the functionality of these secondary monoallelic mutator mutations in the context of an accumulative haploinsufficiency model.

Amino Acid Sequence↗

PubMed1998

Hb Tak confirmed by DNA analysis: not expressed as thalassemia in a Hb Tak/Hb E compound heterozygote.

Hemoglobin variants in which a frameshift results in chain elongation are unusual and also have a low population frequency. Hb Tak was previously characterized by amino acid analysis, and it was assumed to be due to an insertion of the dinucleotide CA into codon 146 [CAC-->CA(CA)C] which abolishes the normal stop codon at position 147. This insertion causes a frameshift which results in elongation of the beta chain by 11 amino acids. This variant has previously been described in a few Thai families. We report the DNA sequence of Hb Tak in an individual of Cambodian descent who is a Hb E/Hb Tak compound heterozygote. In contrast with extended variants of the alpha-globin chain that are expressed as alpha-thalassemias, the hematologic effect of Hb Tak/Hb E is a mild polycythemia. The combination of Hb Tak/Hb E is not expressed as a thalassemia.

Adult↗

PubMed2003

Evaluation of Fanconi Anemia genes in familial breast cancer predisposition.

Fanconi Anemia (FA) is an autosomal recessive syndrome characterized by congenital abnormalities, progressive bone marrow failure, and susceptibility to cancer. FA has eight known complementation groups and is caused by mutations in at least seven genes. Biallelic BRCA2 mutations were shown recently to cause FA-D1. Monoallelic (heterozygous) BRCA2 mutations confer a high risk of breast cancer and are a major cause of familial breast cancer. To investigate whether heterozygous variants in other FA genes are high penetrance breast cancer susceptibility alleles, we screened germ-line DNA from 88 BRCA1/2-negative families, each with at least three cases of breast cancer, for mutations in FANCA, FANCC, FANCD2, FANCE, FANCF, and FANCG. Sixty-nine sequence variants were identified of which 25 were exonic. None of the exonic variants resulted in translational frameshifts or nonsense codons and 14 were polymorphisms documented previously. Of the remaining 11 exonic variants, 2 resulted in synonymous changes, and 7 were present in controls. Only 2 conservative missense variants, 1 in FANCA and 1 in FANCE, were each found in a single family and were not present in 300 controls. The results indicate that FA gene mutations, other than in BRCA2, are unlikely to be a frequent cause of highly penetrant breast cancer predisposition.

Breast Neoplasms↗

PubMed1997

Expression of a coronavirus ribosomal frameshift signal in Escherichia coli: influence of tRNA anticodon modification on frameshifting.

Eukaryotic ribosomal frameshift signals generally contain two elements, a heptanucleotide slippery sequence (XXXYYYN) and an RNA secondary structure, often an RNA pseudoknot, located downstream. Frameshifting takes place at the slippery sequence by simultaneous slippage of two ribosome-bound tRNAs. All of the tRNAs that are predicted to decode frameshift sites in the ribosomal A-site (XXXYYYN) possess a hypermodified base in the anticodon-loop and it is conceivable that these modifications play a role in the frameshift process. To test this, we expressed slippery sequence variants of the coronavirus IBV frameshift signal in strains of Escherichia coli unable to modify fully either tRNA(Lys) or tRNA(Asn). At the slippery sequences UUUAAAC and UUUAAAU (underlined codon decoded by tRNA(Asn), anticodon 5' QUU 3'), frameshifting was very inefficient (2 to 3%) and in strains deficient in the biosynthesis of Q base, was increased (AAU) or decreased (AAC) only two-fold. In E. coli, therefore, hypomodification of tRNA(Asn) had little effect on frameshifting. The situation with the efficient slippery sequences UUUAAAA (15%) and UUUAAAG (40%) (underlined codon decoded by tRNA(Lys), anticodon 5' mnm5s2UUU 3') was more complex, since the wobble base of tRNA(Lys) is modified at two positions. Of four available mutants, only trmE (s2UUU) had a marked influence on frameshifting, increasing the efficiency of the process at the slippery sequence UUUAAAA. No effect on frameshifting was seen in trmC1 (cmnm5s2UUU) or trmC2 (nm5s2UUU) strains and only a very small reduction (at UUUAAAG) was observed in an asuE (mnm5UUU) strain. The slipperiness of tRNA(Lys), therefore, cannot be ascribed to a single modification site on the base. However, the data support a role for the amino group of the mnm5 substitution in shaping the anticodon structure. Whether these conclusions can be extended to eukaryotic translation systems is uncertain. Although E. coli ribosomes changed frame at the IBV signal (UUUAAAG) with an efficiency similar to that measured in reticulocyte lysates (40%), there were important qualitative differences. Frameshifting of prokaryotic ribosomes was pseudoknot-independent (although secondary structure dependent) and appeared to require slippage of only a single tRNA.

Anticodon↗

PubMed2004

Fine mapping and identification of a candidate gene SSH1 in disseminated superficial actinic porokeratosis.

Disseminated superficial actinic porokeratosis (DSAP) is an uncommon autosomal dominant chronic keratinization disorder, characterized by multiple superficial keratotic lesions surrounded by a slightly raised keratotic border. Thus far, although two loci for DSAP have been identified, the genetic basis and pathogenesis of this disorder have not been elucidated yet. In this study, we performed a genome-wide linkage analysis in three Chinese affected families and localized the gene in an 8.0 cM interval defined by D12S330 and D12S354 on chromosome 12. Upon screening 30 candidate genes, we identified a missense mutation, p.Ser63Asn in SSH1 in one family, a frameshift mutation, p.Ser19CysfsX24 in an alternative variant (isoform f) of SSH1 in another family, and a frameshift mutation, p.Pro27ProfsX54 in the same alternative variant in one non-familial case with DSAP. SSH1 encodes a phosphatase that plays a pivotal role in actin dynamics. Our data suggested that cytoskeleton disorganization in epidermal cells is likely associated with the pathogenesis of DSAP.

Age of Onset↗

PubMed2006

Homozygosity for the CARD15 frameshift mutation 1007fs is predictive of early onset of Crohn's disease with ileal stenosis, entero-enteral fistulas, and frequent need for surgical intervention with high risk of re-stenosis.

OBJECTIVE: The identification of CARD15 as a susceptibility gene for Crohn's disease (CD) offers new possibilities for patient classification and risk assessment. The purpose of this study was to carry out a CARD15 sequence analysis in a large single-center IBD cohort and to investigate the impact of different genotypes on disease phenotypes. MATERIAL AND METHODS: A total of 445 unrelated patients with IBD (68.1% CD, 28.5% ulcerative colitis (UC), 3.4% indeterminate colitis (IC)) were included in the study. Clinical data were recorded by detailed questionnaire and analysis of the charts. CARD15 variants (R702W, G908R, 1007fs (frameshift)) were identified by DNA sequence analysis. RESULTS: CARD15 variants were found in 142 inflammatory bowel disease (IBD) patients (31.9%) including 120 CD patients (39.6%). In CD, the presence of two CARD15 variants was associated with ileal disease (p=0.008 versus wild-type (wt); OR 4.04; 95% CI 1.36-11.96) and a fibrostenotic phenotype (p=0.002 versus wt; OR 5.47; 95% CI 1.61-18.58). Subgroup analysis of 19 patients (4.3%) homozygous for the CARD15 variant 1007fs (3020ins C) revealed an association with onset of CD at an early age (p=0.014 versus wt), ileal involvement (p=0.001), and intestinal stenoses in all patients (p=0.001) frequently requiring surgery (73.7%; p=0.093). Of these patients 78.6% developed re-stenoses after surgical resection; 52.6% of the homozygotes were diagnosed as having entero-enteral fistulas. CONCLUSIONS: Patients homozygous for the 1007fs mutation had an early disease onset with long-segment ileal stenoses and entero-enteral fistulas. They frequently needed surgical intervention and had a high risk of re-stenosis. Genotyping therefore appears to be an important diagnostic tool in identifying severely affected patients requiring individualized treatment strategies at an early stage of the disease.

Adolescent↗

PubMed1992

Spectrin beta Tandil, a novel shortened beta-chain variant associated with hereditary elliptocytosis is due to a deletional frameshift mutation in the beta-spectrin gene.

An Argentinian family with hereditary elliptocytosis (HE) associated with a shortened beta-spectrin (Sp) chain was studied. As with most of the other shortened Sp beta-chains that have been described, this variant, called SpTandil, has impaired ability to participate in Sp dimer self-association, has lost its ability to become phosphorylated, and is associated with the presence of increased amounts of the alpha I 74-Kd fragment after partial tryptic digestion of Sp. The 3' ends of the beta-Sp gene of affected patients were analyzed. cDNA was prepared by reverse transcription of peripheral blood mRNA and amplified by the polymerase chain reaction (PCR) using primers corresponding to sequences 400 bp apart on the cDNA, spanning the last three exons (X, Y, Z) of the beta-Sp gene. Agarose gel electrophoresis of the cDNA amplification showed the presence of one band, the size of which was apparently the same as the band amplified from mRNA of a normal control. cDNA from one HE patient was subcloned and sequenced. Several clones showed the presence of a 7-bp deletion at codon 2041 in exon X. Genomic DNA of all the affected members of the family were amplified by PCR using primers flanking the deletion and corresponding to sequences 128 bp apart on exon X. Analysis of the PCR products using electrophoresis on polyacrylamide gel showed the presence of 121- and 128-bp bands in all HE subjects, and an additional doublet migrating more slowly than the two bands, which corresponded to the presence of heteroduplexes. The mutation results in a shift of the normal reading frame and leads to a new amino acid sequence at the C-terminus of the mutant beta-Sp chain. A new in-frame stop codon is encountered downstream, leading to premature chain termination. The identification of the molecular defect in Sp beta Tandil provides information regarding the region of the beta-Sp chain that is important for both Sp dimer self-association and an indication of potential sites of phosphorylation of the chain.

Amino Acid Sequence↗

PubMed2004

Mutation of GATA3 in human breast tumors.

GATA3 is an essential transcription factor that was first identified as a regulator of immune cell function. In recent microarray analyses of human breast tumors, both normal breast luminal epithelium and estrogen receptor (ESR1)-positive tumors showed high expression of GATA3. We sequenced genomic DNA from 111 breast tumors and three breast-tumor-derived cell lines and identified somatic mutations of GATA3 in five tumors and the MCF-7 cell line. These mutations cluster in the vicinity of the highly conserved second zinc-finger that is required for DNA binding. In addition to these five, we identified using cDNA sequencing a unique mis-splicing variant that caused a frameshift mutation. One of the somatic mutations we identified was identical to a germline GATA3 mutation reported in two kindreds with HDR syndrome/OMIM #146255, which is an autosomal dominant syndrome caused by the haplo-insufficiency of GATA3. The ectopic expression of GATA3 in human 293T cells caused the induction of 73 genes including six cytokeratins, and inhibited cell line doubling times. These data suggest that GATA3 is involved in growth control and the maintenance of the differentiated state in epithelial cells, and that GATA3 variants may contribute to tumorigenesis in ESR1-positive breast tumors.

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↗