Cloning & Functional Studies of Mouse Deafness Mutations

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DESCRIPTION (provided by applicant): The mouse is an excellent model for studying human hearing disorders because inner ear anatomy and function are similar in both species. The overall goal of our research program is to discover and characterize new mouse deafness mutations to (1) improve understanding of the molecular mechanisms that underlie the normal hearing process and pathologies that lead to deafness, and (2) provide new mouse models to the scientific community. The genes underlying three new mouse deafness mutations, hurry-scurry (hscy), roundabout (rda), and jitterbug (jbg), were identified by positional cloning. None of the genes have been previously associated with hearing or deafness. The first aim of this renewal application is to determine the functions of these three genes as they relate to the development and maintenance of the auditory system. Inner ears of mutant mice will be examined by electron microscopy for ultrastructural anomalies, and temporal and spatial distributions of transcripts and proteins will be determined by in situ hybridization and immunohistochemistry. The second aim of this application is to identify the gene underlying a fourth new mouse deafness mutation (hyperspin, hspn), which causes a gross malformation of the inner ear. To monitor when and how normal development is disrupted, paint-filled membranous labyrinths of inner ears from mutant embryos will be examined at multiple time points. When the hspn gene is identified, its expression pattern will be assessed along with those of other genes that may act in the same developmental pathway. The third aim of this proposal is to continue our screening program to identify new mouse deafness mutations and determine their inheritance, genetic map locations, and associated inner ear pathologies. Heritability of hearing impairment already has been proven for 28 new mutations, and these will be genetically mapped to a resolution of 5 cM or less. Mutant inner ears will be examined for anatomical abnormalities that lead to deafness and that may provide clues to gene function.