The goal of the Section on Human Genetics is to identify genes for Usher syndrome and nonsyndromic forms of 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, we mapped novel deafness and Usher syndrome loci, and we identified novel genes for nonsyndromic deafness. 1. This year we mapped a new type 1 Usher syndrome referred to as USH1H (Ahmed et al., 2009). The defining clinical features of type 1 Usher syndrome are hearing loss and progressive loss of vision due to retinitis pigmentosa (degeneration of the retina). Identifying the genes for Usher syndrome is important not only for genetic counseling of families but also opens the door to therapeutic possibilities because the actual underlying biochemical defect has been identified. 2. As a collaboration with Drs. Hannie Kremer and Saber Masmoudi we identified mutations of a novel gene, referred to as LRTOMT, as the underlying cause of nonsyndromic deafness at the DFNB63 locus (Ahmed et al., 2008). LRTOMT appears to encode a methyl transferase which adds a methyl group to a donor molecule. This is the first example of a methyl transferase that is important for normal hearing in humans. The role of this enzyme in the normal hearing process is being investigated. 3. We reported that nonsyndromic deafness DFNB73 is due to mutations of BSND encoding barttin, a beta-subunit of two related calcium channels (Riazuddin et al., 2009). Mutations of BSND were previously reported to cause a syndrome characterized by kidney failure and deafness. We identified less severe mutations of BSND associated just with deafness (no kidney abnormality) and reported how this might happen. Mutations of BSND causing kidney failure and deafness destroy the function of BSND as a necessary subunit of two calcium channels. Mutations of BSND causing just nonsyndromic deafness retain many functions of BSND but have a reduction in the ability to chaperone one the channels to the membrane in the inner ear without affecting the kidney. 4. In a large number of families segregating deafness, we identified noncoding mutations of HGF encoding hepatocyte growth factor that are responsible for DFNB39 nonsyndromic deafness (Schultz et al., 2009). Hepatocyte growth factor is part of a complex signaling pathway involving the MET receptor. Previously, no researcher had even suspected that the MET signaling pathway had any importance for normal hearing. Moreover, this is a rare example of mutations that do not alter the protein coding portion of a gene as the cause of human deafness. Presumably the HGF mutations alter the regulation of this gene. Exactly how this occurs is under investigation. 5. In addition, this year we published the chromosomal map locations of two novel recessive deafness loci, DFNB74 and DFNB79 (Waryah et al., 2009;Khan et al., 2009). We are presently attempting to identify the causative genes and their importance for normal hearing in humans.
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