title: A mutation in the gamma actin 1 (ACTG1) gene causes autosomal dominant hearing loss (DFNA20/26).
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.
authors.affiliation: Department of Otorhinolaryngology, University Medical Centre, Nijmegen, Netherlands.
authors.forename: E
authors.initials: E
authors.lastname: van Wijk
authors.forename: E
authors.initials: E
authors.lastname: Krieger
authors.forename: M H
authors.initials: MH
authors.lastname: Kemperman
authors.forename: E M R
authors.initials: EM
authors.lastname: De Leenheer
authors.forename: P L M
authors.initials: PL
authors.lastname: Huygen
authors.forename: C W R J
authors.initials: CW
authors.lastname: Cremers
authors.forename: F P M
authors.initials: FP
authors.lastname: Cremers
authors.forename: H
authors.initials: H
authors.lastname: Kremer
mesh_terms: D000199:Actins / Q000737:chemistry / Q000235:genetics*; D001483:Base Sequence; D005260:Female; D020022:Genetic Predisposition to Disease; D006319:Hearing Loss, Sensorineural / Q000235:genetics*; D006801:Humans; D008297:Male; D008958:Models, Molecular; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010375:Pedigree; D017421:Sequence Analysis
chemical_list: D000199:Actins