Many proteins necessary for sound transduction have been discovered through positional cloning of genes that cause deafness1–3. In this study, we report that mutations of LRTOMT are associated with profound non-syndromic hearing loss at the DFNB63 locus on human chromosome 11q13.3-q13.4. LRTOMT has two alternative reading frames and encodes two different proteins, LRTOMT1 and LRTOMT2, that are detected by Western blot analyses. LRTOMT2 is a putative methyltransferase. During evolution, novel transcripts can arise through partial or complete coalescence of genes4. We provide evidence that in the primate lineage LRTOMT evolved from the fusion of two neighboring ancestral genes, which exist as separate genes (Lrrc51and Tomt) in rodents.
SummaryOtosclerosis is a common form of conductive hearing loss, caused by an abnormal bone remodelling in the otic capsule. Both environmental and genetic factors have been implicated in the etiology of this disease. A recent genome wide association study identified two regions associated with otosclerosis, one on chr7q22.1, located in the RELN gene, and one on chr11q13.1. A second study in four European populations has replicated the association of the RELN gene with otosclerosis. To investigate the association of these loci with otosclerosis in a non-European population, we tested 11 SNPs from the two regions in 149 unrelated Tunisian patients and 152 controls. Four SNPs were significantly associated with otosclerosis. Three SNPs are located in the RELN region and the last one is located in the region on chromosome 11. We also observed a significant interaction with gender for rs3914132. This suggests an influence of sex on the association of RELN with otosclerosis. A meta-analysis showed that the disease-associated alleles in the Tunisian sample are the same as in all previously reported associations. Our study provides additional evidence implicating RELN in the development of otosclerosis. Additional functional studies should determine the role of RELN in the physiopathology of this disease.
Hereditary nonsyndromic hearing impairment (HI) is extremely heterogeneous. Mutations of the transmembrane channel-like gene 1 (TMC1) have been shown to cause autosomal dominant and recessive forms of nonsyndromic HI linked to the loci DFNA36 and DFNB7/B11, respectively. TMC1 is 1 member of a family of 8 genes encoding transmembrane proteins. In the mouse, MmTmc1 and MmTmc2 are both members of Tmc subfamily A and are highly and almost exclusively expressed in the cochlea. The restricted expression of Tmc2 in the cochlea and its close phylogenetic relationship to Tmc1 makes it a candidate gene for nonsyndromic HI. We analyzed 3 microsatellite markers linked to the TMC1 and TMC2 genes in 85 Tunisian families with autosomal recessive nonsyndromic HI and without mutations in the protein-coding region of the GJB2 gene. Autozygosity by descent analysis of 2 markers bordering the TMC2 gene allowed us to rule out its association with deafness within these families. However, 5 families were found to segregate deafness with 3 different alleles of marker D9S1837, located within the first intron of the TMC1 gene. By DNA sequencing of coding exons of TMC1 in affected individuals, we identified 3 homozygous mutations, c.100C→T (p.R34X), c.1165C→T (p.R389X) and the novel mutation c.1764G→A (p.W588X). We additionally tested 60 unrelated deaf Tunisian individuals for the c.100C→T mutation. We detected this mutation in a homozygous state in 2 cases. This study confirms that mutations in the TMC1 gene may be a common cause for autosomal recessive nonsyndromic HI.
Pendred syndrome comprises congenital sensorineural hearing loss, thyroid goiter, and positive perchlorate discharge test. Recently, this autosomal recessive disorder was shown to be caused by mutations in the PDS gene, which encodes an anion transporter called pendrin. Molecular analysis of the PDS gene was performed in two consanguineous large families from Southern Tunisia comprising a total of 23 individuals affected with profound congenital deafness; the same missense mutation, L445W, was identified in all affected individuals. A widened vestibular aqueduct was found in all patients who underwent computed tomography (CT) scan exploration of the inner ear. In contrast, goiter was present in only 11 affected individuals, who interestingly had a normal result of the perchlorate discharge test whenever performed. The present results question the sensitivity of the perchlorate test for the diagnosis of Pendred syndrome and support the use of a molecular analysis of the PDS gene in the assessment of individuals with severe to profound congenital hearing loss associated with inner ear morphological anomaly even in the absence of a thyroid goiter.
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.
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