Hearing loss (HL) is the most common sensory disorder affecting more than 28 million Americans. Despite the significant role of genetic factors in the etiology of HL, and astonishing success that has been achieved in the identification of approximately 70 genes for non-syndromic hearing loss (NSHL), much remains to be known about genes involved in the hearing process and the molecular mechanisms of disorders due to defects of these genes. Our long-range goal is to better understand the genetic and molecular basis of hereditary deafness so that effective genetic counseling and successful treatment strategies can be developed. Given the facts that many deafness pedigrees still fail to show linkage to any of the known loci and that mutation frequencies in all the known genes in persons with NSHL remains to be determined, it is therefore important for us to continue identifying new human deafness genes and to complete mutation screening of all known genes for NSHL. The recent technological advances in "target- enrichment" methods and next generation sequencing (NGS) offers a unique opportunity to break through the barriers of limitations imposed by gene arrays and now allows for the complete analysis of all known deafness-causing genes. The application of NGS will greatly accelerate the pace of disease gene discovery and is now making molecular epidemiological studies of genetic deafness possible for the first time. Interestingly, as shown in our preliminary studies, we have collected a unique group of large families segregating autosomal dominant or recessive deafness, confirmed further heterogeneity of NSHL in these families, successfully identified two new genes using NGS, mapped new loci, and established mutation screening protocol for known NSHL genes. These interesting preliminary results have thus led us to continue identification of novel genes for NSHL and to fully investigate the molecular mechanisms underlying NSHL. Overall, completion of the proposed aims will not only increase our understanding of the biology of hearing and deafness, but will be highly translational by improving the clinical diagnosis of NSHL and patient care.
Our Specific Aims i n this competitive renewal are: 1. Identify new genes for NSHL. 1a. Identify new genes for autosomal dominant NSHL (ADNSHL) using traditional and innovative technologies;1b. Identify new genes for autosomal recessive NSHL (ARNSHL) using traditional and innovative technologies in the collected consanguineous families and in the selected probands from deaf x deaf mating families with extensive family histories of NSHL but known not to carry mutations in any known deafness gene. 2. Complete mutation screening of deafness-causing mutations in known NSHL genes. 2a. Determine the prevalence of deafness-causing mutations in known NSHL genes. 2b. Search for clinically relevant genotype- phenotype correlations in our large database.
The current studies will identify and characterize novel genes involved in hearing in an effort to enhance our understanding of the normal hearing and the genetic aberrations that result in hearing impairments. A more complete knowledge of genes involved in the auditory system will provide a foundation for better genetic counseling, clinical management and treatment options for HL.
|Qing, Jie; Yan, Denise; Zhou, Yuan et al. (2014) Whole-exome sequencing to decipher the genetic heterogeneity of hearing loss in a Chinese family with deaf by deaf mating. PLoS One 9:e109178|
|Mittal, Rahul; Grati, M'hamed; Gerring, Robert et al. (2014) In vitro interaction of Pseudomonas aeruginosa with human middle ear epithelial cells. PLoS One 9:e91885|
|Diaz-Horta, Oscar; Subasioglu-Uzak, Asli; Grati, M'hamed et al. (2014) FAM65B is a membrane-associated protein of hair cell stereocilia required for hearing. Proc Natl Acad Sci U S A 111:9864-8|
|Liu, Xue Zhong; Xie, Dinghua; Yuan, Hui Jun et al. (2013) Hearing loss and PRPS1 mutations: Wide spectrum of phenotypes and potential therapy. Int J Audiol 52:23-8|
|Yan, Denise; Zhu, Yan; Walsh, Tom et al. (2013) Mutation of the ATP-gated P2X(2) receptor leads to progressive hearing loss and increased susceptibility to noise. Proc Natl Acad Sci U S A 110:2228-33|
|Yan, Denise; Tekin, Mustafa; Blanton, Susan H et al. (2013) Next-generation sequencing in genetic hearing loss. Genet Test Mol Biomarkers 17:581-7|
|Yan, Denise; Kamiya, Kazusaku; Ouyang, Xiao Mei et al. (2011) Analysis of subcellular localization of Myo7a, Pcdh15 and Sans in Ush1c knockout mice. Int J Exp Pathol 92:66-71|
|Cheng, Jing; Zhu, Yuhua; He, Sudan et al. (2011) Functional mutation of SMAC/DIABLO, encoding a mitochondrial proapoptotic protein, causes human progressive hearing loss DFNA64. Am J Hum Genet 89:56-66|
|Ouyang, Xiao Mei; Yan, Denise; Aslan, Idil et al. (2011) Mutation screening of the GJA7 (Cx45) gene in a large international series of probands with nonsyndromic hearing impairment. Genet Test Mol Biomarkers 15:333-6|
|Lipan, Michael; Ouyang, Xiaomei; Yan, Denise et al. (2011) Clinical comparison of hearing-impaired patients with DFNB1 against heterozygote carriers of connexin 26 mutations. Laryngoscope 121:811-4|
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