The relative contribution of heredity to age-related hearing loss is not known, however the majority of inherited late-onset deafness is autosomal dominant and non-syndromic. Over 50 genes associated with autosomal dominant non-syndromic hearing loss (ADNSHL) have been localized and of these, 21 have been cloned. Although the function of many of these genes in the inner ear is unclear, an understanding of the biology of hearing and deafness at a molecular level is emerging. In this competitive renewal, we propose to continue our work localizing and cloning genes that cause ADNSHL. We will also expand the phenotype-genotype studies we have done to facilitate gene identification in small families and continue the RNA interference experiments we initiated to explore novel treatment options for select types of hearing loss.
The specific aims of this proposal are: 1) Specific Aim 1: To continue to localize and clone genes that cause ADNSHL; 2) Specific Aim 2: To develop audioprofiling as a method to prioritize genes for mutation screening in families segregating ADNSHL but with an insufficient number of informative meioses for linkage analysis; 3) Specific Aim 3: To test the efficacy of RNA interference as a potential therapy in modifying the hearing loss phenotype in a type of ADNSHL caused by a dominant-negative mechanism of action. Completion of these specific aims will not only increase our understanding of the pathogenesis of deafness, but will be highly translational by targeting small families segregating ADNSHL. Most inherited late-onset deafness is autosomal dominant and non-syndromic. Over 50 genes associated with autosomal dominant non-syndromic hearing loss (ADNSHL) have been localized and of these, 21 have been cloned. Studying these genes will increase our understanding of deafness and ultimately lead to novel methods of preventing ADNSHL.

National Institute of Health (NIH)
National Institute on Deafness and Other Communication Disorders (NIDCD)
Research Project (R01)
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Genetics of Health and Disease Study Section (GHD)
Program Officer
Watson, Bracie
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University of Iowa
Schools of Medicine
Iowa City
United States
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Shibata, Seiji B; Ranum, Paul T; Moteki, Hideaki et al. (2016) RNA Interference Prevents Autosomal-Dominant Hearing Loss. Am J Hum Genet 98:1101-13
Taylor, Kyle R; Booth, Kevin T; Azaiez, Hela et al. (2016) Audioprofile Surfaces: The 21st Century Audiogram. Ann Otol Rhinol Laryngol 125:361-8
Moteki, Hideaki; Yoshimura, Hidekane; Azaiez, Hela et al. (2015) USH2 caused by GPR98 mutation diagnosed by massively parallel sequencing in advance of the occurrence of visual symptoms. Ann Otol Rhinol Laryngol 124 Suppl 1:123S-8S
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Elkon, Ran; Milon, Beatrice; Morrison, Laura et al. (2015) RFX transcription factors are essential for hearing in mice. Nat Commun 6:8549

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