MOLECULAR BASIS OF INHERITED DEAFNESS

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In this proposal we outline studies on three genes for inherited deafness: those encoding Norrie (Norrie disease), myosin-VIIa (Usher 1B and the shaker-1 mouse), and myosin-VIIb (a candidate for the twirler and shaker-2 mouse mutants). The Norrie studies continue work done in the first two years of t his grant, while the myosin studies initiate two new programs. Norrie disease is a rare X-linked syndromic deafness, with congenital blindness and progressive hearing loss. We have cloned the gene defective in this disease; it encodes a small, secreted protein (norrin) that my be a growth factor. The pathology in some vagrants of the disease suggest that a defective norrin allows excessive growth of blood vessels - that it isnorally an angiogenesis inhibitor. We propose several methods to test this hypothesis, and propose to initiate or continue audiometric and histological studies of both humans and mice with this defective gene. Usher 1B presents with congenial deafness and absence of vestibular function, and progressive loss of vision. It is the most common genetic deafness in humans. The gene defective encodes myosinVIIa, a protein that connects and moves other proteins on action. We have closed human myosin-VIIa, and have used antibodies to locate it in auditory receptor cells with electron microscopy. We will test a specific hypotheses that myosin-VIIA is involved in maintaining cohesion of the mechanosensitive cilia, by using a mutant mouse, shaker-1, that has defective myosin-VIIa and by using gene transfers to disrupt myosin-VIIa in normal mice. There is evidence that other myosin-VII isoforms exist in the cochlea, and that they may also cause deafness when defective. We have closed fragments of the genes and have compared their chromosomal location to genetic deafness in mice. We propose to clone these other isoforms, and to test them as candidate deafness genes.