title: Mutations in the gamma-actin gene (ACTG1) are associated with dominant progressive deafness (DFNA20/26).
abstract: Age-related hearing loss (presbycusis) is a significant problem in the population. The genetic contribution to age-related hearing loss is estimated to be 40%-50%. Gene mutations that cause nonsyndromic progressive hearing loss with early onset may provide insight into the etiology of presbycusis. We have identified four families segregating an autosomal dominant, progressive, sensorineural hearing loss phenotype that has been linked to chromosome 17q25.3. The critical interval containing the causative gene was narrowed to approximately 2 million bp between markers D17S914 and D17S668. Cochlear-expressed genes were sequenced in affected family members. Sequence analysis of the gamma-actin gene (ACTG1) revealed missense mutations in highly conserved actin domains in all four families. These mutations change amino acids that are conserved in all actins, from protozoa to mammals, and were not found in >100 chromosomes from normal hearing individuals. Much of the specialized ultrastructural organization of the cells in the cochlea is based on the actin cytoskeleton. Many of the mutations known to cause either syndromic or nonsyndromic deafness occur in genes that interact with actin (e.g., the myosins, espin, and harmonin). The mutations we have identified are in various binding domains of actin and are predicted to mildly interfere with bundling, gelation, polymerization, or myosin movement and may cause hearing loss by hindering the repair or stability of cochlear cell structures damaged by noise or aging. This is the first description of a mutation in cytoskeletal, or nonmuscle, actin.
mesh_terms: D000199:Actins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D000328:Adult; D000595:Amino Acid Sequence; D001483:Base Sequence; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics; D003051:Cochlea / Q000033:anatomy & histology; D005260:Female; D005799:Genes, Dominant / Q000235:genetics*; D006319:Hearing Loss, Sensorineural / Q000235:genetics* / Q000503:physiopathology; D006801:Humans; D008297:Male; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D011487:Protein Conformation
chemical_list: D000199:Actins