Hearing loss is a genetically heterogeneous disorder that can occur at any age, with any degree of severity, and in any population. Worldwide, 1.33 per 1000 individuals are affected by prelingual severe or profound deafness. Eighty-six distinct recessive genetic loci (DFNB) have been linked to nonsyndromic hearing impairment. To date, however, only 38 mutated genes have been identified from the 86 loci. Thus, despite the significant role of genetic factors in the etiology of recessive deafness and the dramatic progress in mapping of the DFNB loci, much remains to be uncovered regarding the identification of the genes involved in the hearing process as well as the molecular and cellular basis of hearing impairment. Gaining such knowledge is pivotal for the advancement of clinical interventions, including early diagnosis and novel treatments. The major goals of this application are to identify and characterize three deafness genes (DFNB74, DFNB85 and DFNB94) through comprehensive and systematic genetic and functional analyses. In our preliminary data we have already identified the DFNB74 mutant gene (MSRB3) and have developed a knockout mouse model for characterization studies. In addition, we have identified and mapped two new deafness loci (DFNB85 and DFNB94) segregating among 19 human families, and we are positioned to identify the specific gene variants on both of these loci. The proposed experimental design includes two overall aims:
In Aim 1 we will identify causative genes on two novel DFNB loci (DFNB85 and DFNB94) using next-generation sequencing. We will also determine the expression and localization of the proteins encoded by the newly identified genes in the inner ear.
In Aim 2, we will fully characterize the function of the known gene (MSRB3, locus DFNB74) in the inner ear, using a mouse model. Our experimental approach in Aim 2, based on extensive preliminary data, is to define the consequences of loss of MSRB3 on inner ear function, morphology, oxidative stress, and expression of genes involved in the apoptotic pathway. Our studies proposed through these two aims will employ state-of-the art genetic, molecular, and cell biological techniques. We anticipate that the completion of these studies will identify and provide information about two new genes responsible for nonsyndromic hearing loss in humans, and elucidate the function of the recently identified MSRB3 gene in the inner ear This work will advance the scientific understanding of deafness and it will have important clinical impact by enabling improved genetic diagnosis, counseling and the development of therapeutic interventions.

Public Health Relevance

Advancing our understanding of molecular mechanisms in the inner ear is a prerequisite to developing therapeutic strategies for hearing impairment. The studies outlined in this proposal seek to identify genes for two additonal recently identified deafness loci and to charcterize the function of the known DFNB74 gene by utilizing mouse models. The proposed reserch is directly relevant to the NIH's interest in developing fundamental knowledge that will help to reduce the burdens of human disability.

National Institute of Health (NIH)
National Institute on Deafness and Other Communication Disorders (NIDCD)
Research Project (R01)
Project #
Application #
Study Section
Molecular Neurogenetics Study Section (MNG)
Program Officer
Watson, Bracie
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Cincinnati Children's Hospital Medical Center
United States
Zip Code
Santos-Cortez, Regie Lyn P; Lee, Kwanghyuk; Giese, Arnaud P et al. (2014) Adenylate cyclase 1 (ADCY1) mutations cause recessive hearing impairment in humans and defects in hair cell function and hearing in zebrafish. Hum Mol Genet 23:3289-98
Rehman, Atteeq U; Santos-Cortez, Regie Lyn P; Morell, Robert J et al. (2014) Mutations in TBC1D24, a gene associated with epilepsy, also cause nonsyndromic deafness DFNB86. Am J Hum Genet 94:144-52
Bashir, Zil-e-Huma; Latief, Noreen; Belyantseva, Inna A et al. (2013) Phenotypic variability of CLDN14 mutations causing DFNB29 hearing loss in the Pakistani population. J Hum Genet 58:102-8
Jaworek, Thomas J; Richard, Elodie M; Ivanova, Anna A et al. (2013) An alteration in ELMOD3, an Arl2 GTPase-activating protein, is associated with hearing impairment in humans. PLoS Genet 9:e1003774
Ahmed, Zubair M; Frolenkov, Gregory I; Riazuddin, Saima (2013) Usher proteins in inner ear structure and function. Physiol Genomics 45:987-9
Shahzad, Mohsin; Sivakumaran, Theru A; Qaiser, Tanveer A et al. (2013) Genetic analysis through OtoSeq of Pakistani families segregating prelingual hearing loss. Otolaryngol Head Neck Surg 149:478-87
Nayak, Gowri; Lee, Sue I; Yousaf, Rizwan et al. (2013) Tricellulin deficiency affects tight junction architecture and cochlear hair cells. J Clin Invest 123:4036-49