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.
|Ealy, Megan; Meyer, Nicole C; Corchado, Johnny Cruz et al. (2014) Rare variants in BMP2 and BMP4 found in otosclerosis patients reduce Smad signaling. Otol Neurotol 35:395-400|
|Shearer, A Eliot; Eppsteiner, Robert W; Booth, Kevin T et al. (2014) Utilizing ethnic-specific differences in minor allele frequency to recategorize reported pathogenic deafness variants. Am J Hum Genet 95:445-53|
|Azaiez, Hela; Booth, Kevin T; Bu, Fengxiao et al. (2014) TBC1D24 mutation causes autosomal-dominant nonsyndromic hearing loss. Hum Mutat 35:819-23|
|Brophy, Patrick D; Alasti, Fatemeh; Darbro, Benjamin W et al. (2013) Genome-wide copy number variation analysis of a Branchio-oto-renal syndrome cohort identifies a recombination hotspot and implicates new candidate genes. Hum Genet 132:1339-50|
|Shearer, A Eliot; Black-Ziegelbein, E Ann; Hildebrand, Michael S et al. (2013) Advancing genetic testing for deafness with genomic technology. J Med Genet 50:627-34|
|Hildebrand, Michael S; Morin, Matias; Meyer, Nicole C et al. (2011) DFNA8/12 caused by TECTA mutations is the most identified subtype of nonsyndromic autosomal dominant hearing loss. Hum Mutat 32:825-34|
|Sheffield, Abraham M; Gubbels, Samuel P; Hildebrand, Michael S et al. (2011) Viral vector tropism for supporting cells in the developing murine cochlea. Hear Res 277:28-36|
|Shearer, A Eliot; Hildebrand, Michael S; Sloan, Christina M et al. (2011) Deafness in the genomics era. Hear Res 282:1-9|
|Zheng, Jing; Miller, Katharine K; Yang, Tao et al. (2011) Carcinoembryonic antigen-related cell adhesion molecule 16 interacts with alpha-tectorin and is mutated in autosomal dominant hearing loss (DFNA4). Proc Natl Acad Sci U S A 108:4218-23|
|Bazazzadegan, Niloofar; Sheffield, Abraham M; Sobhani, Masoomeh et al. (2011) Two Iranian families with a novel mutation in GJB2 causing autosomal dominant nonsyndromic hearing loss. Am J Med Genet A 155A:1202-11|
Showing the most recent 10 out of 62 publications