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.
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