The goal of the Section on Human Genetics is to identify and study the function of mutated genes for human hereditary deafness. This work begins with the ascertainment of large families in which deafness appears to be inherited either as a dominant or a recessive trait. We then search for linkage of the deafness to genetic markers for the known (already reported) syndromic, DFNA (dominant) and DFNB (recessive) loci. If linkage to the known deafness loci can be excluded, we initiate a genome-wide screen to search for novel deafness loci followed by work to identify the causative gene. During the past we ascertained several large families segregating deafness, mapped a novel deafness locus, and identified a novel gene for nonsyndromic deafness. Specifically, we 1. Genetically mapped DFNB79, a novel locus for nonsyndromic deafness (Khan et al., 2010). 2. Revealed that mutations of C9orf75 (renamed TPRN) are responsible for nonsyndromic deafness DFNB79 (Rehman et al., 2010). TPRN encodes taperin. This paper is one of the first to use the combination of enriched genomic DNA from the DFNB79 locus and next generations sequencing to identify a human disease gene. In inner ear hair cells, taperin is localized to the taper region at the base of stereocilia. The exact function taperin is being pursued using geneic, biochemical, molecular biological and cell biological techniques. 3. This past year we identified the function of TRIOBP-4 and TRIOBP-5, two proteins necessary for inner ear function as mutations of TRIOPBP are responsible for nonsyndromic deafness DFNB28 (Kitajiri et al., 2010). We demonstrated that TRIOBP-4 is a novel actin bundlin protein necessary for durable flexibility of hair cell stereocilia. In the absence of TRIOBP-4, the rootlets of stereocilia fail to form. An image from this study is featured on the cover of the May 28, 2010 issue of CELL. 4. In a large number of families we identified regulator mutations of HGF encoding hepatocyte growth factor as the cause of DFNB39 deafness. We also provide data from two mouse models that reduced or extra expression of HGF disrupt the normal development of the inner ear (Schultz et al., 2009). The precise role of HGF in auditory function is being explored. 5. Mutations of BSND were previously reported by other rsearchers to be associated with Bartter suyndrome, a progressive loss of kidney function and congenital deafness. BSND encodes the beta subunit of two chloride channels. In Riazuddin et al., 2009, we demonstrate that a missense mutation of BSND results only in nonsyndromic deafness and is responsible for DFNB73 deafness. 6. We mapped a novel locus of nonsyndromic deafness to chromosome 12q14.2-q15, which is designated DFNB74 Waryah et al., 2010). Positional cloning of the mutated gene responsible for DFNB74 deafness is ongoing. 7. As collaborations with extramural investigators we participated in studies of Grxcr1 (Odeh et al., 2010) and CD44 (Hertzano et al., 2010).
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