GENETIC MODEL FOR CONGENITAL DEAFNESS

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Congenital, perinatal, or early onset hearing loss occurs in approximately 7 out of 1000 neonates in the United States. Especially in young people, noise-induced hearing loss is increasingly common. In the adult population, more than 50% of U.S. males age >65 years have a 53dB loss at 4 kHz, substantially impairing perception of normal speech. The primary pathohistological defect in each of these hearing impaired groups is the loss of outer (and inner) hair cells near the base of the cochlea, where high frequency sounds are transduced. We have recently identified a mutant mouse strain, called deafwaddler (dfw), in which hearing is most severely affected in the high frequency range. Anatomical studies show that outer hair cells (OHC) are absent from the basal region of the cochlea in dfw, becoming more frequent near the apex where low frequencies are heard. Inner hair cells (IHC) are sometimes missing at the base of dfw cochlea but appear intact in the mid- and apical regions. Other physiological measures (e.g. endocochlear potentials, 8th nerve conduction, and anatomical structures appear intact in dfw. Thus, the dfw mutant provides a unique genetic model for understanding the physiological changes leading to sensorineural deafness and loss of functional hair cells in the cochlea. Here we propose to identify the dfw gene by positional cloning techniques. We will: 1.) Refine dfw 's chromosomal location by analyzing inbred backcross (IB) panels between M. musculus (dfw) and M. castaneus, scoring the mutant phenotype relative to molecular microsatellite markers. This panel will provide the high resolution pedigree required for successful positional cloning of dfw. 2.) Clone the dfw region in YACs, establishing a physical map and developing new polymorphic markers that will be scored in IB panel for yet more accurate localization of dfw. 3.) Screen candidate genes from the region for the mutation causing dfw. 4.) Analyze the structure and function of the dfw gene product in parallel with, 5.) Further analyze the developmental and spatial changes in hair cell loss in the dfw model. These studies should provide new insight into the molecular basis of congenital auditory hair cell loss, and relate directly to hair cell loss in aging and due to noise exposure.