Advances in the molecular genetics of deafness have vastly improved our ability to identify heritable hearing losses. Most familial moderate-to-profound congenital losses are inherited as an autosomal recessive trait. Heterogeneity is high, and to date 77 non-syndromic recessive loci have been identified and numbered sequentially DFNB1 through DFNB77 (DFN, deafness;B, recessive;integer, order of discovery). Twenty-eight causally-related genes have been cloned and encode proteins with a wide range of functions. Mutations in one gene, GJB2 at the DFNB1 locus, are responsible for half of moderate-to-profound autosomal recessive non-syndromic deafness (ARNSD) in many developed countries, making DFNB1 the most common type of hereditary congenital hearing loss. Mutations in SLC26A4 at the DFNB4 locus rank second and are associated with a Pendred Syndrome (PS)-DFNB4 phenotype. In aggregate, these advances have numerous important consequences. First, the identification of genes essential for normal auditory function has provided valuable insight into inner ear physiology at the molecular level and may one day lead to the development of novel therapies to treat deafness. Second, the use of genetic testing to diagnose ARNSD has changed the medical evaluation of the deaf person. Third, the identification of numerous genes that cause ARNSD, coupled with recent technological advances in microarray sequence capture and deep sequencing, is now making epidemiological studies of genetic deafness possible for the first time. This renewal application will focus on these three areas by completing specific aims: (1) To identify novel ARNSD genes;(2) To complete mutation screening of all genes implicated in non-syndromic deafness;(3) To study PS-DFNB4 as a complex disease. Completion of these specific aims will not only increase our understanding of the biology of hearing and deafness, but will be highly translational by improving the clinical diagnosis of non-syndromic deafness.

Public Health Relevance

Autosomal recessive non-syndromic deafness (ARNSD) is extremely heterogeneous. To date 77 loci have been identified and 28 causally-related genes have been cloned. Studying these genes will increase our understanding of deafness, improve patient care, and ultimately lead to novel methods of treating ARNSD.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
5R01DC002842-17
Application #
8302165
Study Section
Special Emphasis Panel (ZRG1-GGG-A (62))
Program Officer
Watson, Bracie
Project Start
1996-09-30
Project End
2014-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
17
Fiscal Year
2012
Total Cost
$538,365
Indirect Cost
$134,627
Name
University of Iowa
Department
Otolaryngology
Type
Schools of Medicine
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52242
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

Showing the most recent 10 out of 97 publications