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 300 different syndromes have been described, yet syndromic forms account for only ~30% of all genetic cases. Unparalleled genetic heterogeneity is a hallmark of genetic deafness, and over 70 genes have been identified largely within the last decade. Despite the significant role of genetic factors in the etiology of deafness, and the dramatic success that has been achieved 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 goals of this application are to identify and characterize genes involved in hearing using a variety of genetic and genomics based approaches. 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 continue our study of the biology of COCH, an abundantly expressed cochlear gene pathogenetic for the deafness and vestibular disorder DFNA9, using various experimental systems including investigation of a knock-in mouse model for a COCH missense mutation observed in DFNA9 by expression and proteomic analyses, (2) to continue to investigate human cochlear and mouse organ of Corti ESTs using bioinformatics approaches including use of custom cDNA microarrays, and to search for "new" auditory genes by expression analyses, and 3) to characterize additional cochlear genes selected from chromosomal rearrangements in individuals with hearing impairment.

Public Health Relevance

The importance of this research is the identification and characterization of genes involved in hearing in an effort to enhance our understanding of the normal hearing process and the genetic aberrations that result in hearing impairments. A more complete knowledge of the genes involved in the auditory system will provide a foundation for future diagnosis, management and treatment of hearing loss.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
5R01DC003402-13
Application #
8307416
Study Section
Genetics of Health and Disease Study Section (GHD)
Program Officer
Watson, Bracie
Project Start
1997-08-01
Project End
2014-08-31
Budget Start
2012-09-01
Budget End
2014-08-31
Support Year
13
Fiscal Year
2012
Total Cost
$331,938
Indirect Cost
$128,295
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
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 35:1506-13
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) 90:1321-31
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
Robertson, Nahid G; Jones, Sherri M; Sivakumaran, Theru A et al. (2008) A targeted Coch missense mutation: a knock-in mouse model for DFNA9 late-onset hearing loss and vestibular dysfunction. Hum Mol Genet 17:3426-34
Williamson, Robin E; Darrow, Keith N; Giersch, Anne B S et al. (2008) Expression studies of osteoglycin/mimecan (OGN) in the cochlea and auditory phenotype of Ogn-deficient mice. Hear Res 237:57-65

Showing the most recent 10 out of 36 publications