Unconventional myosins and the genetics of hearing loss

Mutations of the unconventional myosins genes encoding myosin VI, myosin VI IA and myosin XV cause hearing loss and thus these motor proteins perform f undamental functions in the auditory system. A null mutation in myosin VI i n the congenitally deaf Snell's waltzer mice (Myo6(sv)) results in fusion o f stereocilia and subsequent progressive loss of hair cells, beginning soon after birth, thus reinforcing the vital role of cytoskeletal proteins in i nner ear hair cells. To date, there are no human families segregating hered itary hearing loss that show linkage to MYO6 on chromosome 6q13. The discov ery that the mouse shaker1 (Myo7(ash1)) locus encodes myosin VIIA led immed iately to the identification of mutations in this gene in Usher syndrome ty pe 1B; subsequently, mutations in this gene were also found associated with recessive and dominant nonsyndromic hearing loss (DFNB2 and DFNA11). Stere ocilla of sh1 mice are severely disorganized, and eventually degenerate as well. Myosin VIIA has been implicated in membrane trafficking and/or endocy tosis in the inner ear. Mutant alleles of a third unconventional myosin, my osin XV, are associated with nonsyndromic, recessive, congenital deafness D FNB3 on human chromosome 17p11.2 and deafness in shaker2 (Myo15(sh2)) mice. In outer and inner hair cells, myosin XV protein is detectable in the cell body and stereocilia. Hair cells are present in homozygous sh2 mutant mice , but the stereocilia are approximately 1/10 of the normal length. This rev iew focuses on what we know about the molecular genetics and biochemistry o f myosins V1, VIIA and XV as relates to hereditary hearing loss. Published 2000 Wiley-Liss, Inc.(dagger)