Novel compound heterozygous TMC1 mutations associated with autosomal recessive hearing loss in a Chinese family

PLoS One. 2013 May 14;8(5):e63026. doi: 10.1371/journal.pone.0063026. Print 2013.

Abstract

Hereditary nonsyndromic hearing loss is highly heterogeneous and most patients with a presumed genetic etiology lack a specific diagnosis. It has been estimated that several hundred genes may be associated with this sensory deficit in humans. Here, we identified compound heterozygous mutations in the TMC1 gene as the cause of recessively inherited sensorineural hearing loss by using whole-exome sequencing in a family with two deaf siblings. Sanger sequencing confirmed that both siblings inherited a missense mutation, c.589G>A p.G197R (maternal allele), and a nonsense mutation, c.1171C>T p.Q391X (paternal allele), in TMC1. We also used DNA from 50 Chinese familial patients with ARNSHL and 208 ethnicity-matched negative samples to perform extended variants analysis. Both variants co-segregated in family 1953, which had the hearing loss phenotype, but were absent in 50 patients and 208 ethnicity-matched controls. Therefore, we concluded that the hearing loss in this family was caused by novel compound heterozygous mutations in TMC1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Amino Acid Sequence
  • Animals
  • Asian People / genetics*
  • Base Sequence
  • DNA Mutational Analysis
  • Exome / genetics
  • Female
  • Hearing Loss, Sensorineural / genetics*
  • Hearing Loss, Sensorineural / pathology
  • Hearing Loss, Sensorineural / physiopathology
  • Heterozygote*
  • Humans
  • Male
  • Membrane Proteins / chemistry
  • Membrane Proteins / genetics*
  • Membrane Proteins / metabolism*
  • Mice
  • Molecular Sequence Data
  • Pedigree*
  • Polymorphism, Genetic
  • Rats
  • Siblings
  • Young Adult

Substances

  • Membrane Proteins
  • TMC1 protein, human

Grants and funding

This work was supported by grants from the Project of the National Natural Science Foundation of China (Grant Nos. 30801285, 31071099, 81230020, 81200751, 81070792, 81000414, 81070792, 81000415), a grant from State 863 High Technology R&D Key Project of China (2011AA02A112), a grant from Natural Science Foundation of Beijing (Grant No 7122172), a grant from Minister of Science and Technology of China (2012BAI09B02) and a grant from Minister of Health of China (201202005). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.