Hearing loss is an economically and socially important cause of human morbidity. The genetic factors are one of the main etiologies causing hearing loss. While more than 100 genes for non-syndromic hearing loss [NSHL) have been mapped and a growing number have been cloned, little is known about the molecular mechanisms underlying hereditary inner ear defect. The long-term objective is to better understand the cellular and molecular basis of hereditary deafness so that effective genetic counseling and successful treatment strategies for hereditary deafness can be developed. During the previous grant period, we have identified several genes and mapped two novel loci for non-syndromic hearing loss, which opened new avenues to genes cloning and functional investigations. Given the facts that little is known about how mutations in these genes produce similar phenotypes and that many deafness pedigrees still fail to show linkage to any of these loci, it is therefore important for us to continue identifying human deafness genes and to investigate function of identified genes. Interestingly, as shown in our preliminary studies, we have confirmed further heterogeneity of NSHL, narrowed the critical regions of the DFNA41 and DFNA53 loci, successfully created the Ush1c knockout mouse model and double mutant mice for Cdh23 and Pcdh15, and identified positive ES cell clones for the Slc26a5 knockin mouse model. These interesting preliminary results have thus led us to continue cloning novel genes for NSHL and fully investigate the molecular mechanisms underlying NSHL (short-term objective) towards identifying potential therapeutic approaches for hereditary inner ear diseases.
Aim 1. Localize and clone additional genes for NSHL.
Aim 2. Clone DFNA41/DFNA53 genes.
Aim 3. Determine cellular and molecular mechanism underlying inner ear defects using the Ush1c knockout mice and functional interactions in vivo of Ush1c with other Ush1 genes.
Aim 4. Characterize the structural and functional consequences of the IVS2-2A>G mutation of the human prestin gene in the Slc26a5 knockin mice. Significance: The studies proposed in the current proposal together with the studies completed during the previous grant period will provide new insights into the pathological mechanisms underlying genetic hearing loss in humans, which can uncover new development of strategies for therapeutic intervention of hearing impairment in NSHL.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
3R01DC005575-08S1
Application #
7856831
Study Section
Genetics of Health and Disease Study Section (GHD)
Program Officer
Watson, Bracie
Project Start
2009-07-17
Project End
2011-06-30
Budget Start
2009-07-17
Budget End
2011-06-30
Support Year
8
Fiscal Year
2009
Total Cost
$119,998
Indirect Cost
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
Mittal, Rahul; Patel, Amit P; Nguyen, Desiree et al. (2018) Genetic basis of hearing loss in Spanish, Hispanic and Latino populations. Gene 647:297-305
Wang, Li; Yan, Denise; Qin, Litao et al. (2018) Amino acid 118 in the Deafness Causing (DFNA20/26) ACTG1 gene is a Mutational Hot Spot. Gene Rep 11:264-269
Mittal, Rahul; Bencie, Nicole; Parrish, James M et al. (2018) An Update on Phosphodiesterase Mutations Underlying Genetic Etiology of Hearing Loss and Retinitis Pigmentosa. Front Genet 9:9
Snapp, Hillary A; Hoffer, Michael E; Liu, Xuezhong et al. (2017) Effectiveness in Rehabilitation of Current Wireless CROS Technology in Experienced Bone-Anchored Implant Users. Otol Neurotol 38:1397-1404
Li, Jia-Nan; Chen, Si; Zhai, Lei et al. (2017) The Advances in Hearing Rehabilitation and Cochlear Implants in China. Ear Hear 38:647-652
Mittal, Rahul; Nguyen, Desiree; Patel, Amit P et al. (2017) Recent Advancements in the Regeneration of Auditory Hair Cells and Hearing Restoration. Front Mol Neurosci 10:236
Yao, Qi; DeSmidt, Alexandra A; Tekin, Mustafa et al. (2016) Hearing Assessment in Zebrafish During the First Week Postfertilization. Zebrafish 13:79-86
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
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
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

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