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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
5R01DC005575-13
Application #
8609016
Study Section
Genetics of Health and Disease Study Section (GHD)
Program Officer
Watson, Bracie
Project Start
2001-09-15
Project End
2017-02-28
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
13
Fiscal Year
2014
Total Cost
$584,598
Indirect Cost
$202,508
Name
University of Miami School of Medicine
Department
Otolaryngology
Type
Schools of Medicine
DUNS #
052780918
City
Coral Gables
State
FL
Country
United States
Zip Code
33146
Ben Said, Mariem; Grati, M'hamed; Ishimoto, Takahiro et al. (2016) A mutation in SLC22A4 encoding an organic cation transporter expressed in the cochlea strial endothelium causes human recessive non-syndromic hearing loss DFNB60. Hum Genet 135:513-24
Diaz-Horta, Oscar; Abad, Clemer; Sennaroglu, Levent et al. (2016) ROR1 is essential for proper innervation of auditory hair cells and hearing in humans and mice. Proc Natl Acad Sci U S A 113:5993-8
Mittal, Rahul; Grati, M'hamed; Yan, Denise et al. (2016) Pseudomonas aeruginosa Activates PKC-Alpha to Invade Middle Ear Epithelial Cells. Front Microbiol 7:255
Mittal, Rahul; Grati, M'hamed; Yan, Denise et al. (2016) Otopathogenic Pseudomonas aeruginosa induces MyD88-dependent auditory hair cell damage. Cell Death Discov 2:16030
Gurumurthy, Channabasavaiah B; Grati, M'hamed; Ohtsuka, Masato et al. (2016) CRISPR: a versatile tool for both forward and reverse genetics research. Hum Genet 135:971-6
Grati, M'hamed; Yan, Denise; Raval, Manmeet H et al. (2016) MYO3A Causes Human Dominant Deafness and Interacts with Protocadherin 15-CD2 Isoform. Hum Mutat 37:481-7
Ma, Q; Grati, M; Bai, F et al. (2016) Rescue from early-onset hearing loss in a mouse model lacking the cyclin-dependent kinase inhibitor p19Ink4d. Cell Death Dis 7:e2131
Manzoli, Gabrielle N; Bademci, Guney; Acosta, Angelina X et al. (2016) Targeted Resequencing of Deafness Genes Reveals a Founder MYO15A Variant in Northeastern Brazil. Ann Hum Genet 80:327-331
Tekin, Demet; Yan, Denise; Bademci, Guney et al. (2016) A next-generation sequencing gene panel (MiamiOtoGenes) for comprehensive analysis of deafness genes. Hear Res 333:179-84
Kim, So Young; Kim, Ah Reum; Kim, Nayoung K D et al. (2016) Functional characterization of a novel loss-of-function mutation of PRPS1 related to early-onset progressive nonsyndromic hearing loss in Koreans (DFNX1): Potential implications on future therapeutic intervention. J Gene Med 18:353-358

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