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 year we ascertained several large families segregating deafness, mapped a novel deafness locus, and identified a novel gene for nonsyndromic deafness. The following projects were completed in the past year. 1. We identified MSRB3 as the causative gene for DFNB74 nonsyndromci deafness(Riazuddin et al., 2011). MSRB3 encodes a methionine sulfoxide reductase. This protein reduces methionine (amino acid) that has been damaged by oxidation. It is not clear why the inner ear is so sensitive to the loss of this enzyme which is expressed in a great variety of cell types in the body. The precise role of this enzyme in the auditory system is not known (Ahmed et al., 2011). 2. We identified mutations of ILDR1 as the underlying cause of DFNB42 nonsyndromic deafness (Borck et al., 2011). Identification of the DFNB42 gene was a multi-lab international collaboration with Drs. Leal (Texas), Smith (Iowa), Gillespie (California), Riazuddin (Pakistan), Muller (California), Kubisch (Germany), and Borck (Germany;communicating and first author). Twelve different mutations of ILDR1 segregating in eleven families are described. Eight of these recessive mutations are nonsense, frameshift or splice site variants that introduce premature stop codons, and are predicted null alleles of ILDR1. ILDR1 is a member of a highly conserved Ig domain-containing family, but its function in the auditory system is entirely unknown at this time (Borck et al., 2011). 3. Three families segregating deafness linked to genetic markers on chromosome 11q were discovered to have mutations in the FGF3 gene. FGF3 encodes fibroblast growth factor 3. Mutations of FGF3 were known to cause LAMM syndrome that is characterized by inner ear a failure of the inner to develop, small outer ears (microtia) and small malformed teeth (microdontia). In one of the three families inner ear development was partially developed and there are near-normal-appearing outer ears and teeth. A partially developed inner ear means that some FGF3-affected individuals are candidates for a cochlear implant that should help restore some level of hearing to an otherwise deaf person (Riazuddin et al., 2011). 4. We mapped a novel nonsyndromic deafness locus (DFNB81) to chromosome 19p, which is distinct from the closely linked DFNB72 locus. Mutations of GIPC3 are responsible for DFNB72 deafness. We are presently working to identify the mutated gene underlying DFNB81 deafness using next-generation sequencing technology. 5. We mapped a novel locus for nonsyndromic deafness to chromosome 16p. The locus is designated DFNB86 (Ali et al., 2011). We are also working to identify the mutated gene underlying this chromosome 16p deafness gene using advanced sequencing methodologies. 6. We reported that a compound heterozygote for a nonsyndromic deafness (DFNB12) allele of CDH23 (encoding cadherin 23) in trans to a type 1 Usher syndrome allele (USH1D) is deaf but has normal vision. These data indicate that a DFNB12 allele is dominant to an USH1D allele (Schultz et al., Journal of Medical Genetics, in press). Our observations are crucial to proper genetic counselling of deaf subjects requesting information about their liklihood of vision loss. Our observations also provide reason to be optimistic about the possibility of developing a therapy to retard progressive vision loss in USH since it appears that imperfect cadherin 23 protein in the retina can prevent the loss of vision due to retinitis pigmentosa in some DFNB12 patients. This project is part of an ongoing NIH clinical research protocol to study the natural history of progressive loss of vision in Usher syndrome.
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