Mutations that affect the inner ear neuroepithelia are a major cause of hearing and balance disorders in humans, yet the specific molecular defects in these cases remain largely unknown. Molecular characterization of a mouse mutation showing neuroepithelial defects would expedite the search for genes involved in human inner ear disorders. A critical aspect of the proposal is to identify and characterize the gene responsible for neuroepithelial defects in the classic mouse mutant Ames waltzer (av) by using a unique mouse insertional mutation in the transgenic line TgN2742Rpw. This insertional mutation causes deafness and circling behavior in the affected animals and is allelic with av. Genomic clones flanking the transgene insertion site will be used to determine the structure of the mutant locus and the corresponding wild-type locus. Sequence analysis and/or exon trapping of the wild-type genomic clones will identify coding regions, which will be followed by the search for cDNAs. Full- length wild-type av cDNA sequences will be compared in the database to determine the relationship with any known genes. An important aspect of the proposal is to analyze the genetic defect in the existing av mutant alleles at the molecular level to establish a structure/function relationship between the av gene and deafness. Finally, the full length wild-type av cDNA will be used to identify the human homologue. The proposed study will elucidate the molecular basis of the inner ear defects in av.
