Hearing loss is a major health problem that affects more than 28 million Americans; two million persons are profoundly deaf. Approximately 1 in 1,000 infants has profound prelingual deafness and about 40-60% of cases is attributed to genetic causes. Among heritable cases, more than 175 different syndromes have been described, yet syndromic forms account for only 10-20% of all genetic cases. Unparalleled genetic heterogeneity is a hallmark of genetic deafness, and over 50 genes have been identified largely within the past five years. Despite the significant role of genetic factors in the etiology of deafness, and the dramatic success that has been achieved in the last few years in mapping and cloning genes for both syndromic and non-syndromic forms of deafness, much remains to be known about genes involved in the hearing process and the molecular nature of disorders of these genes. ? ? In overview, the major goal of this application is to pursue identification, isolation and characterization of genes involved in hearing. This knowledge will undoubtedly contribute to better methods for earlier diagnosis. More precise genetic counseling, improved medical treatment, and, perhaps, even the prevention of some forms of deafness. The proposed experimental design and methods are: (1) to study the biology of COCH, an abundantly expressed cochlear gene pathogenetic for the deafness and vestibular disorder DFNA9, using various experimental systems including construction of a knock-in mouse model for COCH missense mutations observed in DFNA, (2) to study the biology of OTOR, a p highly expressed cochlear gene with a potential growth regulatory role in the inner ear, (3) to develop further the cochlear EST resource for identification of genes involved in hearing and deafness, including making a cochlear cDNA microarray, and (4) to characterize additional cochlear genes selected from the cochlear ESTs with intriguing patterns of expression, motifs or chromosomal locations where deafness genes are mapped.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
5R01DC003402-08
Application #
6793685
Study Section
Mammalian Genetics Study Section (MGN)
Program Officer
Watson, Bracie
Project Start
1997-08-01
Project End
2008-06-30
Budget Start
2004-07-01
Budget End
2008-06-30
Support Year
8
Fiscal Year
2004
Total Cost
$510,590
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Currall, Benjamin B; Chen, Ming; Sallari, Richard C et al. (2018) Loss of LDAH associated with prostate cancer and hearing loss. Hum Mol Genet 27:4194-4203
Diaz-Horta, Oscar; Abad, Clemer; Sennaroglu, Levent et al. (2016) ROR1 is essential for proper innervation of auditory hair cells and hearing in humans and mice. Proc Natl Acad Sci U S A 113:5993-8
Burgess, Barbara J; O'Malley, Jennifer T; Kamakura, Takefumi et al. (2016) Histopathology of the Human Inner Ear in the p.L114P COCH Mutation (DFNA9). Audiol Neurootol 21:88-97
Bae, Seung-Hyun; Robertson, Nahid G; Cho, Hyun-Ju et al. (2014) Identification of pathogenic mechanisms of COCH mutations, abolished cochlin secretion, and intracellular aggregate formation: genotype-phenotype correlations in DFNA9 deafness and vestibular disorder. Hum Mutat 35:1506-1513
Robertson, Nahid G; O'Malley, Jennifer T; Ong, Cheng Ai et al. (2014) Cochlin in normal middle ear and abnormal middle ear deposits in DFNA9 and Coch (G88E/G88E) mice. J Assoc Res Otolaryngol 15:961-74
Currall, Benjamin B; Chiang, C; Talkowski, Michael E et al. (2013) Mechanisms for Structural Variation in the Human Genome. Curr Genet Med Rep 1:81-90
Cho, Hyun-Ju; Park, Hong-Joon; Trexler, Maria et al. (2012) A novel COCH mutation associated with autosomal dominant nonsyndromic hearing loss disrupts the structural stability of the vWFA2 domain. J Mol Med (Berl) 90:1321-1331
Jones, Sherri M; Robertson, Nahid G; Given, Shelly et al. (2011) Hearing and vestibular deficits in the Coch(-/-) null mouse model: comparison to the Coch(G88E/G88E) mouse and to DFNA9 hearing and balance disorder. Hear Res 272:42-8
Brown, Kerry K; Reiss, Jacob A; Crow, Kate et al. (2010) Deletion of an enhancer near DLX5 and DLX6 in a family with hearing loss, craniofacial defects, and an inv(7)(q21.3q35). Hum Genet 127:19-31
Brown, Kerry K; Alkuraya, Fowzan S; Matos, Michael et al. (2009) NR2F1 deletion in a patient with a de novo paracentric inversion, inv(5)(q15q33.2), and syndromic deafness. Am J Med Genet A 149A:931-8

Showing the most recent 10 out of 38 publications