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J Med Genet 2003;40:879-884 doi:10.1136/jmg.40.12.879
  • Original article

A mutation in the gamma actin 1 (ACTG1) gene causes autosomal dominant hearing loss (DFNA20/26)

  1. E van Wijk1,
  2. E Krieger2,
  3. M H Kemperman1,
  4. E M R De Leenheer1,4,
  5. P L M Huygen1,
  6. C W R J Cremers1,
  7. F P M Cremers3,
  8. H Kremer1
  1. 1Department of Otorhinolaryngology, University Medical Centre, Nijmegen, Netherlands
  2. 2Centre for Molecular and Biomolecular Informatics, University of Nijmegen
  3. 3Department of Human Genetics, University Medical Centre Nijmegen
  4. 4Department of Otorhinolaryngology, Head and Neck surgery, Ghent University Hospital, Ghent, Belgium
  1. Correspondence to:
 Dr H Kremer
 Department of Otorhinolaryngology, UMC Nijmegen, PO Box 9101, 6500 HB Nijmegen, Netherlands\|[semi]\|h.kremerantrg.umcn.nl
  • Received 12 July 2003
  • Accepted 5 September 2003

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 γ-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 γ 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.

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