Human nonsyndromic hereditary deafness DFNA17 is due to a mutation in nonmuscle myosin MYH9

The authors had previously mapped a new locus-DFNA17, for nonsyndromic here ditary hearing impairment-to chromosome 22q12.2-q13.3. DFNA17 spans a 17- t o 23-cM region, and MYH9, a nonmuscle-myosin heavy-chain gene, is located w ithin the linked region. Because of the importance of myosins in hearing, M YH9 was tested as a candidate gene for DFNA17. Expression of MYH9 in the ra t cochlea was confirmed using reverse transcriptase-PCR and immunohistochem istry. MYH9 was immunolocalized in the organ of Corti, the subcentral regio n of the spiral ligament, and the Reissner membrane. Sequence analysis of M YH9 in a family with DFNA17 identified, at nucleotide 2114, a G-->A transpo sition that cosegregated with the inherited autosomal dominant hearing impa irment. This missense mutation changes codon 705 from an invariant arginine (R) to histidine (H), R705H, within a highly conserved SH1 linker region. Previous studies have shown that modification of amino acid residues within the SH1 helix causes dysfunction of the ATPase activity of the motor domai n in myosin II. Both the precise role of MYH9 in the cochlea and the mechan ism by which the R705H mutation leads to the DFNA17 phenotype (progressive hearing impairment and cochleosaccular degeneration) remain to be elucidate d.