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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
5R01DC005641-08
Application #
7860340
Study Section
Auditory System Study Section (AUD)
Program Officer
Watson, Bracie
Project Start
2002-07-01
Project End
2011-06-30
Budget Start
2010-07-01
Budget End
2011-06-30
Support Year
8
Fiscal Year
2010
Total Cost
$519,334
Indirect Cost
Name
University of Washington
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
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
Yan, Denise; Zhu, Yan; Walsh, Tom et al. (2013) Mutation of the ATP-gated P2X(2) receptor leads to progressive hearing loss and increased susceptibility to noise. Proc Natl Acad Sci U S A 110:2228-33
Pierce, Sarah B; Gersak, Ksenija; Michaelson-Cohen, Rachel et al. (2013) Mutations in LARS2, encoding mitochondrial leucyl-tRNA synthetase, lead to premature ovarian failure and hearing loss in Perrault syndrome. Am J Hum Genet 92:614-20
Yariz, K O; Walsh, T; Akay, H et al. (2012) A truncating mutation in GPSM2 is associated with recessive non-syndromic hearing loss. Clin Genet 81:289-93
Yariz, Kemal O; Walsh, Tom; Uzak, Asli et al. (2011) Inherited mutation of the luteinizing hormone/choriogonadotropin receptor (LHCGR) in empty follicle syndrome. Fertil Steril 96:e125-30
Walsh, Vanessa L; Raviv, Dorith; Dror, Amiel A et al. (2011) A mouse model for human hearing loss DFNB30 due to loss of function of myosin IIIA. Mamm Genome 22:170-7
Pierce, Sarah B; Chisholm, Karen M; Lynch, Eric D et al. (2011) Mutations in mitochondrial histidyl tRNA synthetase HARS2 cause ovarian dysgenesis and sensorineural hearing loss of Perrault syndrome. Proc Natl Acad Sci U S A 108:6543-8
Brownstein, Zippora; Friedman, Lilach M; Shahin, Hashem et al. (2011) Targeted genomic capture and massively parallel sequencing to identify genes for hereditary hearing loss in Middle Eastern families. Genome Biol 12:R89
Paz, Arnon; Brownstein, Zippora; Ber, Yaara et al. (2011) SPIKE: a database of highly curated human signaling pathways. Nucleic Acids Res 39:D793-9
Lenz, Danielle R; Avraham, Karen B (2011) Hereditary hearing loss: from human mutation to mechanism. Hear Res 281:3-10

Showing the most recent 10 out of 34 publications