Hearing loss (HL) is the most common sensory disorder affecting more than 28 million Americans. Clinically significant HL is present in at least 1 per 500 infants at birth. Nearly 70% of HL expressed at birth has a genetic etiology. At least 80% o f n o n s y n d r o m i c deafness is autosomal recessive (ARNSHL). The identification of these genes has dramatically improved the clinical diagnosis and management of deaf and hard-of-hearing families. However, there is a pressing need to continue identifying new human HL genes and to determine causative variants in known NSHL genes for completing a genomic and phenotypic database. This is critical as we and others have provided direct evidence of further genetic heterogeneity of HL with a number of genes/mutations yet to be identified: causative variants are found in less than 4 0 % of cases and recent studies suggest that over a thousand genes are involved in deafness suggesting there are many deafness-causative genes still remaining to be identified in both human and mouse. Identifying all of the HL genes and causative mutation is imperative to our understanding of the biology of normal hearing and the disease etiology/processes, provides immediate benefit to the families involved for counseling and diagnosis, and, at the molecular level, allows for the development of novel gene-specific and even mutation-specific therapies to treat HL. The latter by using genome editing that can have much wider use than just in the families with mutations in that gene. Importantly, as shown in our preliminary studies, we have already collected DNA samples and phenotype data from a large international cohort (Miami Otogenetic Repository) of families with NSHL, well established the Miami Otogenetic Clinic and pipelines for the genetic and functional analysis of variants, excluded all known HL genes in a large cohort of multiplex families, successfully identified many potential new candidate genes, and generated several animal models with deafness phenotype for these human deafness genes using the CRISPR/Cas9 system and traditional targeted mutagenesis approach. In this proposal, we will build on our previous accomplishments and preliminary data by proposing to complete the following specific aims: 1) to determine causative variants in known NSHL genes for expanding a combined genomic and phenotypic deafness database; 2) to identify novel ARNSHL genes using targeted sequence capture/ whole exome (WES)/genome (WGS) analysis using a customized local pipeline platform; 3) to determine functional consequences of deafness genes with in vitro and in vivo models using innovative approaches. We will perform one of the largest and most integrated clinical/genomic/functional studies on ARNSHL to date. This innovative study will not only increase our understanding of the biology of hearing and deafness, but will be highly translational leading to improvements in the etiological diagnosis of NSHL and patient care as well as pave the wave for gene/variant specific treatments with animal models generated in the proposal.

Public Health Relevance

We will expand our comprehensive genomic and phenotypic deafness database for clinical care of deaf individuals and will identify and characterize novel genes involved in hearing loss using state-of-the-art genomic tools. These include massively parallel sequencing technologies and CRISPR/Cas9 system. This will enhance our understanding of biology of the normal hearing and the genetic aberrations that result in hearing impairments.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
2R01DC005575-16A1
Application #
9378333
Study Section
Genetics of Health and Disease Study Section (GHD)
Program Officer
Watson, Bracie
Project Start
2001-09-15
Project End
2022-08-31
Budget Start
2017-09-01
Budget End
2018-08-31
Support Year
16
Fiscal Year
2017
Total Cost
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
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; Chan, Brandon; Grati, M'hamed et al. (2016) Molecular Structure and Regulation of P2X Receptors With a Special Emphasis on the Role of P2X2 in the Auditory System. J Cell Physiol 231:1656-70
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

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