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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
5R01DC003544-14
Application #
8247763
Study Section
Genetics of Health and Disease Study Section (GHD)
Program Officer
Watson, Bracie
Project Start
1998-08-01
Project End
2013-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
14
Fiscal Year
2012
Total Cost
$507,024
Indirect Cost
$142,392
Name
University of Iowa
Department
Otolaryngology
Type
Schools of Medicine
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52242
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
Jayawardena, Asitha D L; Shearer, A Eliot; Smith, Richard J H (2015) Sensorineural Hearing Loss: A Changing Paradigm for Its Evaluation. Otolaryngol Head Neck Surg 153:843-50
Mori, Kentaro; Moteki, Hideaki; Kobayashi, Yumiko et al. (2015) Mutations in LOXHD1 gene cause various types and severities of hearing loss. Ann Otol Rhinol Laryngol 124 Suppl 1:135S-41S
Moteki, Hideaki; Azaiez, Hela; Booth, Kevin T et al. (2015) Hearing loss caused by a P2RX2 mutation identified in a MELAS family with a coexisting mitochondrial 3243AG mutation. Ann Otol Rhinol Laryngol 124 Suppl 1:177S-83S
Azaiez, Hela; Decker, Amanda R; Booth, Kevin T et al. (2015) HOMER2, a stereociliary scaffolding protein, is essential for normal hearing in humans and mice. PLoS Genet 11:e1005137
Shearer, A Eliot; Smith, Richard J H (2015) Massively Parallel Sequencing for Genetic Diagnosis of Hearing Loss: The New Standard of Care. Otolaryngol Head Neck Surg 153:175-82
Sloan-Heggen, Christina M; Babanejad, Mojgan; Beheshtian, Maryam et al. (2015) Characterising the spectrum of autosomal recessive hereditary hearing loss in Iran. J Med Genet 52:823-9
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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