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

被引:177
作者
Lalwani, AK
Goldstein, JA
Kelley, MJ
Luxford, W
Castelein, CM
Mhatre, AN
机构
[1] Univ Calif San Francisco, Dept Otolaryngol Head & Neck Surg, Mol Oncol Lab, Epstein Labs, San Francisco, CA 94143 USA
[2] Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA
[3] House Ear Clin, Los Angeles, CA USA
关键词
D O I
10.1016/S0002-9297(07)62942-5
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
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.
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页码:1121 / 1128
页数:8
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