Abstract
The motor protein myosin IIIA is critical for maintenance of normal hearing. Homozygosity and compound heterozygosity for loss-of-function mutations in MYO3A, which encodes myosin IIIA, are responsible for inherited human progressive hearing loss DFNB30. To further evaluate this hearing loss, we constructed a mouse model, Myo3a KI/KI, that harbors the mutation equivalent to the nonsense allele responsible for the most severe human phenotype. Myo3a KI/KI mice were compared to their wild-type littermates. Myosin IIIA, with a unique N-terminal kinase domain and a C-terminal actin-binding domain, localizes to the tips of stereocilia in wild-type mice but is absent in the mutant. The phenotype of the Myo3a KI/KI mouse parallels the phenotype of human DFNB30. Hearing loss, as measured by auditory brainstem response, is reduced and progresses significantly with age. Vestibular function is normal. Outer hair cells of Myo3a KI/KI mice degenerate with age in a pattern consistent with their progressive hearing loss.
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Acknowledgments
We thank members of Family N for their continuous participation in our study. This work was supported by NIH grant R01DC005641 from the National Institute of Deafness and Communication Disorders. We thank Mario Capecchi for the ACN cassette; Richard Palmiter for plasmid p4317G9; Carlos Gordon for vestibular testing; and Yehoash Raphael, Edwin Rubel, Carol Ware, Carol Robbins, Bob Hunter, and Glenn MacDonald for technical help and advice.
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V. L. Walsh and D. Raviv contributed equally to this work.
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335_2010_9310_MOESM2_ESM.tiff
Supplementary Fig. 1. Vestibular phenotype of mutant and wild-type mice. The vestibular phenotype of the mice was assessed in 7-month-old mice (mutant N = 9; wild-type littermates N = 7) using the reaching response and swimming tests. Mutant and wild-type mice did not differ, demonstrating normal vestibular function (TIFF 1584 kb)
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Walsh, V.L., Raviv, D., Dror, A.A. et al. A mouse model for human hearing loss DFNB30 due to loss of function of myosin IIIA. Mamm Genome 22, 170–177 (2011). https://doi.org/10.1007/s00335-010-9310-6
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DOI: https://doi.org/10.1007/s00335-010-9310-6