The goal of this project is to find and characterize genes responsible for hereditary hearing impairment (HHI) in highly informative Middle Eastern kindreds. Genes identified in these consanguineous families are important to the non-consanguineous U.S. deaf population because all genes for HHI illuminate universal features of hearing biology and because such genes often harbor other mutations leading to recessive or dominant HHI in populations worldwide. We have thus far identified DFNA15 as POU4F3, DFNB30 as MYO3A, and now DFNB28 as a novel isoform of TARA, which we name OTOTARA. We are developing a mouse model of the MYO3A/DFNB30 nonsense mutation. In two other kindreds, we mapped genes for hearing loss to small intervals on chromosomes 2q31 and 11q14.3-q21. These regions do not harbor known deafness genes, so these kindreds will reveal two more novel genes for HHI. In four other families, we identified new alleles of known deafness genes, suggesting that genetic hearing loss in this population is similar to that elsewhere. In the 156 families with HHI enrolled in our project, GJB2 (connexin 26) is responsible for HHI in only 17 (11%) of families, reflecting the high frequency of HHI due to other genes. In the next cycle of this project, our collaboration proposes: (1) to further characterize wildtype and mutant OTOTARA (2) to identify genes for recessive, nonsyndromic HHI on chromosomes 2q31 and 11q14.3-q21 (3) to undertake positional identification of genes for HHI in four additional kindreds (4) to complete the MYO3A/DFNB30 knock-in mouse and characterize its phenotype The strengths of this collaboration are the enthusiastic participation in the project of extended informative kindreds with HHI, the large number of these kindreds likely to carry mutations in heretofore unknown hearing-related genes, and our demonstrated success in mapping, identifying, and characterizing genes for HHI in these families.

National Institute of Health (NIH)
National Institute on Deafness and Other Communication Disorders (NIDCD)
Research Project (R01)
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Auditory System Study Section (AUD)
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Watson, Bracie
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University of Washington
Internal Medicine/Medicine
Schools of Medicine
United States
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Jenkinson, Emma M; Rehman, Atteeq U; Walsh, Tom et al. (2013) Perrault syndrome is caused by recessive mutations in CLPP, encoding a mitochondrial ATP-dependent chambered protease. Am J Hum Genet 92:605-13
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