Abstract
Mutations in the transmembrane channel-like gene 1 (TMC1) can cause both DFNA36 and DFNB7/11 hearing loss. More than thirty DFNB7/11 mutations have been reported, but only three DFNA36 mutations were reported previously. In this study, we found a large Chinese family with 222 family members showing post-lingual, progressive sensorineural hearing loss which were consistent with DFNA36 hearing loss. Auditory brainstem response (ABR) test of the youngest patient showed a special result with nearly normal threshold but prolonged latency, decreased amplitude, and the abnormal waveform morphology. Exome sequencing of the proband found four candidate variants in known hearing loss genes. Sanger sequencing in all family members found a novel variant c.1253T>A (p.M418K) in TMC1 at DFNA36 that co-segregated with the phenotype. This mutation in TMC1 is orthologous to the mutation found in the hearing loss mouse model named Bth ten years ago. In another 51 Chinese autosomal dominant hearing loss families, we screened the segments containing the dominant mutations of TMC1 and no functional variants were found. TMC1 is expressed in the hair cells in inner ear. Given the already known roles of TMC1 in the mechanotransduction in the cochlea and its expression in inner ear, our results may provide an interesting perspective into its function in inner ear.
Highlights
Hearing loss is the most common sensory disorder affecting one in 1000 births [1] and the prevalence rises to 2.7 per 1000 by the age of four [2]
In a large Chinese family (1304) of six-generation with autosomal dominant hereditary hearing loss, we identified a novel mutation of p.M418K in transmembrane channel-like gene 1 (TMC1) through sequencing the whole exome of the proband, which is important and beneficial to discover the pathologic mechanism of DFNA36 hearing loss caused by TMC1 mutation
We identified a novel mutation p.M418K in TMC1 in a Chinese family of six generation using the strategy of exome sequencing to the proband
Summary
Hearing loss is the most common sensory disorder affecting one in 1000 births [1] and the prevalence rises to 2.7 per 1000 by the age of four [2]. A total of 76 non-syndromic hearing loss genes have been identified, including 31 autosomal dominant, 47 autosomal recessive and four X-linked genes (http://hereditaryhearingloss.org). TMC1 was identified as a causative gene for both autosomal dominant (DFNA36) and autosomal recessive (DFNB7/11) nonsyndromic hearing loss by Kurima and colleagues in 2002[3]. Based on their results, Vreugde and colleagues screened the Tmc gene and found the p.M412K mutation in a hearing loss mouse model named Bth which was arisen in a large-scale ENU mutagenesis program [4,5]. Only two amino acid residues with three mutations have been reported to be associated with autosomal dominant hearing loss [3,14,18,19]. In a large Chinese family (1304) of six-generation with autosomal dominant hereditary hearing loss, we identified a novel mutation of p.M418K in TMC1 through sequencing the whole exome of the proband, which is important and beneficial to discover the pathologic mechanism of DFNA36 hearing loss caused by TMC1 mutation
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