title: Human nonsyndromic hereditary deafness DFNA17 is due to a mutation in nonmuscle myosin MYH9.
abstract: The authors had previously mapped a new locus-DFNA17, for nonsyndromic hereditary hearing impairment-to chromosome 22q12.2-q13. 3. DFNA17 spans a 17- to 23-cM region, and MYH9, a nonmuscle-myosin heavy-chain gene, is located within the linked region. Because of the importance of myosins in hearing, MYH9 was tested as a candidate gene for DFNA17. Expression of MYH9 in the rat cochlea was confirmed using reverse transcriptase-PCR and immunohistochemistry. MYH9 was immunolocalized in the organ of Corti, the subcentral region of the spiral ligament, and the Reissner membrane. Sequence analysis of MYH9 in a family with DFNA17 identified, at nucleotide 2114, a G-->A transposition that cosegregated with the inherited autosomal dominant hearing impairment. 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 domain in myosin II. Both the precise role of MYH9 in the cochlea and the mechanism by which the R705H mutation leads to the DFNA17 phenotype (progressive hearing impairment and cochleosaccular degeneration) remain to be elucidated.
authors.affiliation: Laboratory of Molecular Otology, Epstein Laboratories, Department of Otolaryngology-Head and Neck Surgery, University of California, San Francisco, San Francisco, CA 94143, USA. lalwani@itsa.ucsf.edu
authors.forename: A K
authors.initials: AK
authors.lastname: Lalwani
authors.forename: J A
authors.initials: JA
authors.lastname: Goldstein
authors.forename: M J
authors.initials: MJ
authors.lastname: Kelley
authors.forename: W
authors.initials: W
authors.lastname: Luxford
authors.forename: C M
authors.initials: CM
authors.lastname: Castelein
authors.forename: A N
authors.initials: AN
authors.lastname: Mhatre
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution / Q000235:genetics; D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D004252:DNA Mutational Analysis; D003638:Deafness / Q000151:congenital / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D020409:Molecular Motor Proteins / Q000235:genetics; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D009218:Myosins / Q000235:genetics*; D009928:Organ Specificity; D009925:Organ of Corti / Q000378:metabolism; D010375:Pedigree; D010641:Phenotype; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016415:Sequence Alignment
chemical_list: D020409:Molecular Motor Proteins; D012333:RNA, Messenger; D009218:Myosins