International Mammalian Genome Society

The 15th International Mouse Genome Conference (2001)


Dr Sally Camper
University of Michigan
4301 MSRB 3
1500 W. Med. Ctr. Dr.
Ann Arbor 48109-0638

Co-Authors:  Karolyi IJ, and Rapael Y
Institution:   University of Michigan

Genetics of deafness: role of myosin 15 (myo15)

Shaker 2 mice have profound congenital deafness and vestibular dysfunction. We mapped sh2 on mouse Chr11 in a region homologous to human Chr 17, which implicated sh2 as a model for DFNB3. The hunt for the mutated gene was simplified by complementation with a BAC transgene. DNA sequence analysis revealed mutations in the MYO15 gene in sh2 mice and individuals with DFNB3. Myosins contain molecular motors that bind cytoskeletal actin and hydrolyze ATP to produce force and movement. The tail domains are heterogeneous and poorly understood. The sh2 allele has a missense mutation in the motor domain. The sh2J lesion is a deletion of the last six exons, which encode a FERM domain that interacts with integral membrane proteins. The FERM domain is as critical as the motor for hearing and balance. Both the sh2 and sh2J alleles result in abnormally short hair cell stereocilia, suggesting that Myo15 is important for the structure and function of these sensory epithelia. Mouse genetics identified two other myosin genes required for normal hearing in humans and mice; Myo6 and Myo7a. The long stereocilia in Myo6 mutants suggest involvement in membrane anchoring. The highly disorganized stereocilia of Myo7a mutants suggests a role in patterning stereocilia.  Double mutant phenotypes suggest each myosin has a specialized role, with few overlapping functions that are compensated for in single mutants.

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