Recent advances in the molecular genetics of deafness have vastly improved our ability to identify heritable hearing losses and have had several important consequences. First, the use of genetic testing to diagnose non-syndromic hearing loss (NSHL) has changed the medical evaluation of the deaf / hard-of-hearing person - after a history, physical examination and audiogram, genetic testing has become the next test ordered in the care of patients with presumed hereditary hearing impairment. Second, the identification of nearly one hundred genes that cause NSHL, coupled with technological advances in sequence capture and deep sequencing, has made robust epidemiological studies of genetic deafness possible for the first time. Third, understanding the genetic basis for normal auditory function is providing insight into inner ear physiology at the molecular level that will lad one day to the development of novel gene-specific and even mutation-specific therapies to treat hearing loss. Over the past granting period, we have focused on the following three specific aims: (1) To identify novel genetic causes of autosomal recessive non-syndromic hearing loss (ARNSHL);(2) To complete mutation screening of the coding sequence of all genes implicated in NSHL;(3) To study the Pendred syndrome / DFNB4 disease spectrum. In this competitive renewal, we will build on these accomplishments by completing the following specific aims:
Specific Aim 1. To identify genetic mutations in regulatory elements that contribute to NSHL Hypothesis. Mutations in regulatory elements contribute to NSHL. These mutations can be identified by: a) studying a carefully selected patient population that is enriched for non-coding disease-causing variants and for whom full phenotypic and clinical data are available;and, b) applying targeted sequence capture and massively parallel sequencing to regulatory regions coupled with integrated analysis of murine ChIP-Seq data, ENCODE data and in silico data.
Specific Aim 2. To compare simple and complex haplotypes in two well-defined populations - one with age-related hearing loss and one with normal hearing. Hypothesis. Custom modifications of the Galaxy pipeline make it possible to reconstruct unphased haplotypes for all NSHL genes included on OtoSCOPE(R). By studying two well-defined populations, one with and the other without age-related hearing loss, we will be able to identify at-risk and protective haplotypes and haplotype combinations that are associated with age-related hearing loss. The successful completion of these aims will have a major impact on our understanding of genetic deafness and offer novel insights into how specific protein-protein interactions contribute to age-related hearing loss.

Public Health Relevance

This competitive renewal is focused on two questions germane to non-syndromic hearing loss: 1) the identification of non-coding deafness-causing mutations in regulatory elements, with a particular focus on promoters;and, 2) the evaluation of simple and complex haplotypes as contributing factors to age-related hearing loss (ARHL). The successful completion of these aims will have a major impact on our understanding of the genetics of hearing loss and offer novel insights into how specific protein-protein interactions contribute to ARHL.

National Institute of Health (NIH)
Research Project (R01)
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Study Section
Auditory System Study Section (AUD)
Program Officer
Watson, Bracie
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University of Iowa
Schools of Medicine
Iowa City
United States
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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
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
Taylor, Kyle R; Deluca, Adam P; Shearer, A Eliot et al. (2013) AudioGene: predicting hearing loss genotypes from phenotypes to guide genetic screening. Hum Mutat 34:539-45
Charizopoulou, Nikoletta; Lelli, Andrea; Schraders, Margit et al. (2011) Gipc3 mutations associated with audiogenic seizures and sensorineural hearing loss in mouse and human. Nat Commun 2:201
Shearer, A Eliot; Hildebrand, Michael S; Sloan, Christina M et al. (2011) Deafness in the genomics era. Hear Res 282:1-9
Borck, Guntram; Ur Rehman, Atteeq; Lee, Kwanghyuk et al. (2011) Loss-of-function mutations of ILDR1 cause autosomal-recessive hearing impairment DFNB42. Am J Hum Genet 88:127-37
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
Hildebrand, Michael S; Kahrizi, Kimia; Bromhead, Catherine J et al. (2010) Mutations in TMC1 are a common cause of DFNB7/11 hearing loss in the Iranian population. Ann Otol Rhinol Laryngol 119:830-5
Maeda, Yukihide; Fukushima, Kunihiro; Hirai, Misato et al. (2010) Microarray analysis of the effect of dexamethasone on murine cochlear explants. Acta Otolaryngol 130:1329-34

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