A Mutation in the Gamma Actin 1 (ACTG1) Gene Causes Autosomal Dominant Hearing Loss (DFNA20/26)

J Med Genet. 2003 Dec;40(12):879-84. doi: 10.1136/jmg.40.12.879.

Abstract

Linkage analysis in a multigenerational family with autosomal dominant hearing loss yielded a chromosomal localisation of the underlying genetic defect in the DFNA20/26 locus at 17q25-qter. The 6-cM critical region harboured the gamma-1-actin (ACTG1) gene, which was considered an attractive candidate gene because actins are important structural elements of the inner ear hair cells. In this study, a Thr278Ile mutation was identified in helix 9 of the modelled protein structure. The alteration of residue Thr278 is predicted to have a small but significant effect on the gamma 1 actin structure owing to its close proximity to a methionine residue at position 313 in helix 11. Met313 has no space in the structure to move away. Moreover, the Thr278 residue is highly conserved throughout eukaryotic evolution. Using a known actin structure the mutation could be predicted to impair actin polymerisation. These findings strongly suggest that the Thr278Ile mutation in ACTG1 represents the first disease causing germline mutation in a cytoplasmic actin isoform.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / chemistry
  • Actins / genetics*
  • Base Sequence
  • Female
  • Genetic Predisposition to Disease*
  • Hearing Loss, Sensorineural / genetics*
  • Humans
  • Male
  • Models, Molecular
  • Molecular Sequence Data
  • Mutation, Missense*
  • Pedigree
  • Sequence Analysis

Substances

  • Actins