The majority of inherited hearing loss (HL) is non-syndromic, and is often neuroepithelial in origin arising from defects in the function of the organ of Corti - the site of auditory transduction in the inner ear. Of these, up to 30% are autosomal dominant non-syndromic hearing loss (ADNSHL) (Liu and Xu, 1994). Although the past few years have witnessed a rapidly expanding list of HL genes using genomics based approaches, there is evidence that there are more HL genes and loci to be discovered. First, of the 65 mapped genes for ADSNHL, the gene has been identified for only 26. Second, many deaf pedigrees still fail to show linkage to any of these known loci, indicating that additional genes are involved. Third, despite recent progress in identifying genes underlying non syndromic HL (NSHL), there are still relatively few mouse models for progressive hearing loss. A large number of deaf mouse mutants also exist with no obvious human homologue, and human deafness genes localized or identified with no equivalent mouse model available, indicating that we still have much to learn about deafness from a genetic approach in humans. Therefore, there is an established need for mapping and identifying new genes for ADNSHL in order to provide accurate diagnosis of the genetic cause of deafness. Advances in DNA enrichment and Next Generation Sequencing (NGS) technology have made it possible to quickly and cost-effectively sequence all the genes of the genome, and then to rapidly identify variants responsible for Mendelian disorders. 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. We have recently identified several new genes and mapped several novel loci for ADNSHL. We have successfully generated the animal models for some of these genes. In addition, we have collected 15 large multi-generational families with ADNSHL not linked to known ADNSHL loci, providing the basis for the present proposal for gene identification (Short-term objective) (Specific Aims 1 and 2) and for in vitro and in vivo function studies on both newly identified ADNSHL genes in the current proposal (Specific Aims 2 and 3).
Our Specific Aims i n this grant are: 1. Map new loci for ADNSHL. 2. Identify new genes for ADNSHL using traditional and innovative technologies. 3. Characterize the structural and functional consequences of the human S71L mutation of the SMAC gene in the smac knock-in mice. 4. Complete in vitro and in vivo functional studies of the P2XR2_V60L mutation. Completion of the proposed aims will not only increase our understanding of the biology of hearing and deafness, but will be highly translational by increasing availability of genetic testin, improving molecular diagnosis and, consequently, genetic counseling.

Public Health Relevance

The current studies will identify and characterize novel genes involved in hearing and responsible for late onset hearing impairment using large multi-generational families and state-of-the-art genomic tools such as massively parallel sequencing technologies. This will enhance our understanding of the normal hearing and the genetic aberrations that result in age-related 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 hearing loss.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
1R01DC012546-01
Application #
8346327
Study Section
Genetics of Health and Disease Study Section (GHD)
Program Officer
Watson, Bracie
Project Start
2012-08-01
Project End
2017-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
1
Fiscal Year
2012
Total Cost
$325,125
Indirect Cost
$112,625
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
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Yao, Qi; DeSmidt, Alexandra A; Tekin, Mustafa et al. (2016) Hearing Assessment in Zebrafish During the First Week Postfertilization. Zebrafish 13:79-86
Knecht, Leslie D; O'Connor, Gregory; Mittal, Rahul et al. (2016) Serotonin Activates Bacterial Quorum Sensing and Enhances the Virulence of Pseudomonas aeruginosa in the Host. EBioMedicine 9:161-9
Grati, M'hamed; Chakchouk, Imen; Ma, Qi et al. (2015) A missense mutation in DCDC2 causes human recessive deafness DFNB66, likely by interfering with sensory hair cell and supporting cell cilia length regulation. Hum Mol Genet 24:2482-91
Zou, Bing; Mittal, Rahul; Grati, M'hamed et al. (2015) The application of genome editing in studying hearing loss. Hear Res 327:102-8
Wang, Honghan; Wang, Xinwei; He, Chufeng et al. (2015) Exome sequencing identifies a novel CEACAM16 mutation associated with autosomal dominant nonsyndromic hearing loss DFNA4B in a Chinese family. J Hum Genet 60:119-26

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