A novel type of myosin encoded by the mouse deafness gene shaker-2

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Genetic hearing impairment affects about one in 2,000 children at birth. The majority of genetic deafness is non-syndromic, in which hearing loss is not associated with any other abnormalities. Autosomal recessive forms of non-syndromic deafness (DFNB) account for most profound deafness and are almost exclusively due to abnormalities of the sensory neuroepithelia of the inner ear. Ten loci for such deafness have been mapped and mutations in two genes encoding unconventional myosin VIIA and connexin 26 have been identified. One locus, DFNB3, is assigned to 17p11.2-17q12 which is homologous to the shaker-2 (sh-2) locus on mouse chromosome 11. Homozygous sh-2 mice exhibit the circling, headtossing, deafness, and hyperactivity seen in mice with inner ear defects and some of these symptoms resemble those of DFNB3, implying that the same unidentified gene underlies DFNB3 and sh-2.We constructed a contig consisting of 21 BAC clones across an approximately 700-kb region which covers the entire nonrecombinant region of sh-2. With this genetic and physical maps, we carried out a positional cloning approach to identify the sh-2 mutation. Here we report the use of a positional cloning approach to show that the gene mutated in sh-2 mice encodes a novel type of unconventional myosin. A G-to-A transition changing cysteine to tyrosine in the conserved actin binding domain is detected in sh-2 but absent in laboratory strains and wild mice belonging to different mouse subspecies and species. Based on conserved synteny and the mutation, the novel myosin gene is a strong candidate for DFNB3.