Mouse models to study inherited forms of deafness

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DESCRIPTION (provided by applicant): Deafness is a major health problem. ~1 in 1000 children is born deaf and a large part of the aging population is afflicted by age-related hearing loss. Many forms of deafness are of genetic origin, but only a subset of the genes that are linked to deafness have been identified. There is also a pressing need for animal models to study gene function in the auditory system, to define the molecular pathogenesis of hearing loss, and to develop therapeutic approaches for treating deafness. The long-term goal of my laboratory is to elucidate the molecular mechanisms that control sound perception and the defects in this process that cause deafness. As a first step towards attaining this goal, we propose to carry out a ENU mutagenesis screen in mice to identify and study genes that control the development and function of the auditory system. We hypothesize that we will obtain valuable mouse models for analyzing the mechanisms that control auditory processing and for defining the molecular pathogenesis of deafness in humans. The hypothesis is based on the following data: i) mutations in orthologous genes frequently cause deafness in humans and mice; ii) ENU mutagenesis screens in mice for deafness traits have provided useful animal models for studying dominant forms of deafness in humans; iii) we have carried out an ENU mutagenesis screen to identify recessive and dominant deafness traits; we have identified 20 mouse strains that are deaf; iv) we have identified a novel allele of the cadherin 23 (CDH23) gene, a known deafness locus in humans; v) The cloning of additional deafness loci is nearing completion. Some of the chromosomal regions that we have identified have not been previously associated with deafness. We predict to identify novel genes that are associated with deafness.To reach the overall goal of this proposal, we have established a collaboration with Dr. R. Smith (University of Iowa) to analyze the extent to which mutations in human orthologs of the mouse genes cause deafness.