A novel DFNA36 mutation in TMC1 orthologous to the Beethoven (Bth) mouse associated with autosomal dominant hearing loss in a Chinese family

PLoS One. 2014 May 14;9(5):e97064. doi: 10.1371/journal.pone.0097064. eCollection 2014.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Amino Acid Sequence
  • Animals
  • Asian Continental Ancestry Group / genetics
  • Child, Preschool
  • Ear, Inner / metabolism
  • Evoked Potentials, Auditory, Brain Stem / genetics
  • Exome / genetics
  • Female
  • Genetic Predisposition to Disease / genetics*
  • Hair Cells, Auditory / metabolism
  • Hearing Loss / genetics*
  • Hearing Loss, Sensorineural / genetics*
  • Humans
  • Male
  • Membrane Proteins / genetics*
  • Mice
  • Middle Aged
  • Molecular Sequence Data
  • Mutation / genetics*
  • Pedigree
  • Phenotype
  • Sequence Alignment
  • Young Adult

Substances

  • Membrane Proteins
  • TMC1 protein, human

Supplementary concepts

  • Deafness, Autosomal Dominant 36
  • Deafness, Autosomal Recessive 7

Grant support

This work was supported by the grants of the National Key Basic Research Program of China, No. 2014CB943001, the National Natural Science Foundation of China, Major Project, No. 81120108009. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.