Our research is about the identificationa and characterization of genes critical for structure and function of inner ear hair cells. Spontaneous mutations that cause balance dysfunction and hearing loss are ideal tools to identify genes important for the functioning of the inner ear and to elucidate their role in these sensory systems. Towards this end we concentrate our efforts on three deafness mutations: jackson circler (jc), jerker (je) and Varitint-waddler (Va). By auditory-evoked brain stem response analyses we showed that in these strains hearing impairment is completely penetrant and fully expressed in three to four week old animals. The vestibular phenotype is also fully expressed in je and Va mutants, but seems to vary in jc. To search for hearing and balance modifiers we outcrossed each of the mutations onto different genetic backgrounds. To identify their molecular identity we analyzed large segregating intersubspecific intercrosses. We constructed physical BAC contigs for each of the mutated loci and we evaluated candidate genes. The molecular cloning of these mutations should give us new insights in the development and function of the mammalian cochlea. High-resulution genetic and physical mapping of varitint-waddler identified two new members of the mucolipin gene familiy Mcoln2 and Mcoln3 in the critical interval. We found missense mutations in Mcoln3 which are responsible for deafness and pigmentaton defects in Va. Mcoln3 shows sequence and motif similarities to the transient-receptor-potential (TRP) family of ion channels. Mcoln3 localizes to cytoplasmic compartments and stereocilia of outer and inner hair cells in the organ of Corti. Based upon its motif structure and expression domain, we suggest that Mcoln3 is involved in the regulation of ion homeostasis in hair cells and melanocyte. Our work identifies a new molecular link between deafness and pigmentation defects. Finally, Mcoln2 and Mcoln3 are candidate genes for hereditary and/or sporadic forms of neurosensory disorders. We recently reported on the identification of a new allele of the protocadherin 15 gene in the mouse. Mutations in this gene cause deafness and balancing defects. This mouse model might be valuable in studying cochlea and retinal pathalogy encountered in Usher syndrome type 1F.
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