Impairment of hearing is the most common sensory deficit in human populations and affects about one of every 1,000 children. The mouse is an excellent model for studying human hearing disorders because of the anatomical and functional similarities between the mouse and human inner ears. In mice, mutations affecting the vestibular system of the inner ear often result in a characteristic circling or head bobbing phenotype; many of these mutations also affect the cochlea and cause deafness. Two independent spontaneous mutations responsible for such abnormal behavior were discovered at The Jackson Laboratory and mapped to Chromosomes (Chr) 9 and 17, at positions where no other mouse mutations or deafness genes have been located. Both mutations when homozygous cause deafness, as assessed by the absence of auditory brainstem responses to stimuli greater than 99 dB SPL. Preliminary light microscopic analysis of cross-sections from cochleas indicate that both mutations cause neuroepithelial defects. Mouse mutations with similar defects have been shown to be models for human nonsyndromic hearing loss. On the basis of known human-mouse genetic map relationships, the new mouse mutations may be homologous to the human nonsyndromic deafness genes DFNB16 and DFNA13. The object of this proposal is to clone both of the mouse mutations by the positional-candidate gene approach. Preliminary mapping results have localized each mutation to within a 5 cM interval. These intervals will be further refined to less than 0.2 cM by recombinational analysis of extended linkage crosses. Physical maps will then be constructed and candidate genes within these regions will be screened for mutations. The human homologues of the genes shown to be mutated in mice will be identified for evaluation as candidates for human deafness. Mouse mutations enable studies of inner ear anatomy and development that are not possible in humans; such studies help elucidate pathways critical for the normal development and physiology of the ear. Another objective of this proposal is to establish a time course of pathology and gene expression in inner ears from mutant and control mice. The molecular identification and pathological characterization of these two new mouse mutations causing deafness will provide valuable models for understanding causes of hearing impairment in humans and for developing possible treatments and therapies.
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