The goal of the research proposed is to delineate the pathogenesis of the nonsyndromic autosomal dominant deafness disorder DFNA9 and to elucidate the functional role of the novel gene COCH in maintaining proper hearing and balance. This investigation will center upon the production and study of a mouse model for DFNA9. The mouse Coch gene has been cloned and characterized and provides an excellent reagent for this study. Three missense mutations that have been identified in patients with DFNA9 will be introduced into genomic subclones of the mouse Coch gene using targeted mutagenesis, and homologous recombination will be utilized to introduce the individual mutations into mouse embryonic stem (ES) cells. Mouse lines carrying the mutated Coch gene will then be produced from ES cells and evaluated. The pattern of mutant Coch expression will be determined in mice by RNA and protein analysis, including gross histopathological studies, in situ hybridization, and immunohistochemistry with a Coch-specific antibody. Mice will be extensively analyzed for hearing ability by a number of behavioral tests and by auditory brainstem threshold analysis.
