The mouse is an excellent model for studying human hearing disorders because of the similarities in inner ear anatomy, function, and pathology. Our research program seeks to identify molecules and pathways that are important in the normal development and physiology of the ear by discovering and studying gene mutations in mice that disrupt these processes. To achieve this goal, our research includes both discovery and hypothesis driven components. We identified five new hearing-related genes by the positional cloning of spontaneous, deafness-causing mutations named hurry-scurry (hscy), jitterbug (jbg), roundabout (rda), hyperspin (hspn), and deaf wanderer (dwnd). None of these five genes was previously known to be associated with hearing or deafness in humans or mice.
The first aim of this renewal application is to determine the specific roles of these genes in inner ear development and auditory function. Inner ears of mutant mice at various ages will be examined by light and electron microscopy for structural anomalies, and temporal and spatial distributions of gene transcripts and proteins will be determined by in situ hybridization and immunohistochemistry. Potential interactions among the proteins encoded by these newly identified genes and other inner ear-expressing genes will be analyzed by subcellular co-localizations, GST pull-down assays and co-immunoprecipitation experiments. Other experiments will test specific hypotheses about the proposed functions of each gene, as they relate to such processes as inner ear development, endolymph homeostasis, hair cell morphogenesis, and mechanotransduction.
The second aim of this application is to identify, by high resolution mapping and candidate gene analysis, the genes underlying six newly mapped deafness mutations: tilt-a-whirl (tow), variable circling (Varc), propeller (pir), figure eight (fgt), windmill (wdml), and helter-skelter (hsk). These new mutations were mapped to chromosome regions that are devoid of known deafness-causing mutations and therefore are likely to identify genes not previously known to be involved in the hearing process. Inner ear pathologies associated with the new mutations will be characterized to provide clues to gene identity and function. When the responsible genes are identified, gene expression patterns will be determined in mutant and control mice.
The third aim of this proposal is to continue our screening program to discover new mouse deafness mutations and determine their inheritance and chromosomal locations. Since the last grant application, we have discovered 26 new heritable mutations with associated hearing impairment. We propose to genetically map each of these mutations to a resolution of less than 5 cM. The mutations that map to the same chromosome locations as known deafness mutations or hearing-related genes will be tested for potential allelism by functional complementation and DNA sequence analysis, and those that map to new locations will become subjects for future positional cloning efforts to identify their underlying genes.

Public Health Relevance

Impairment of hearing is the most common sensory deficit in human populations and affects about one of every 1,000 children. We use the mouse as a model for studying human hearing disorders because of the anatomical, functional, and pathological similarities between mouse and human inner ears. Accomplishment of the goals stated in this grant application will (1) improve our understanding of the molecular mechanisms that underlie the hearing process and pathologies that cause deafness and (2) provide the scientific community with new mouse models that could contribute to the development of diagnostics, treatments and therapies for human hereditary hearing impairment.

National Institute of Health (NIH)
National Institute on Deafness and Other Communication Disorders (NIDCD)
Research Project (R01)
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Auditory System Study Section (AUD)
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Watson, Bracie
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Jackson Laboratory
Bar Harbor
United States
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Tarchini, Basile; Longo-Guess, Chantal; Tian, Cong et al. (2018) A spontaneous mouse deletion in Mctp1 uncovers a long-range cis-regulatory region crucial for NR2F1 function during inner ear development. Dev Biol 443:153-164
Johnson, Kenneth R; Gagnon, Leona H; Tian, Cong et al. (2018) Deletion of a Long-Range Dlx5 Enhancer Disrupts Inner Ear Development in Mice. Genetics 208:1165-1179
Tian, Cong; Gagnon, Leona H; Longo-Guess, Chantal et al. (2017) Hearing loss without overt metabolic acidosis in ATP6V1B1 deficient MRL mice, a new genetic model for non-syndromic deafness with enlarged vestibular aqueducts. Hum Mol Genet 26:3722-3735
Ohlemiller, Kevin K; Jones, Sherri M; Johnson, Kenneth R (2016) Application of Mouse Models to Research in Hearing and Balance. J Assoc Res Otolaryngol 17:493-523
Tian, Cong; Harris, Belinda S; Johnson, Kenneth R (2016) Ectopic Mineralization and Conductive Hearing Loss in Enpp1asj Mutant Mice, a New Model for Otitis Media and Tympanosclerosis. PLoS One 11:e0168159
Johnson, Kenneth R; Gagnon, Leona H; Chang, Bo (2016) A hypomorphic mutation of the gamma-1 adaptin gene (Ap1g1) causes inner ear, retina, thyroid, and testes abnormalities in mice. Mamm Genome 27:200-12
Calton, Melissa A; Lee, Dasom; Sundaresan, Srividya et al. (2014) A lack of immune system genes causes loss in high frequency hearing but does not disrupt cochlear synapse maturation in mice. PLoS One 9:e94549
Salles, Felipe T; Andrade, Leonardo R; Tanda, Soichi et al. (2014) CLIC5 stabilizes membrane-actin filament linkages at the base of hair cell stereocilia in a molecular complex with radixin, taperin, and myosin VI. Cytoskeleton (Hoboken) 71:61-78
Johnson, Kenneth R; Gagnon, Leona H; Longo-Guess, Chantal M et al. (2014) Hearing impairment in hypothyroid dwarf mice caused by mutations of the thyroid peroxidase gene. J Assoc Res Otolaryngol 15:45-55
Xiong, Wei; Grillet, Nicolas; Elledge, Heather M et al. (2012) TMHS is an integral component of the mechanotransduction machinery of cochlear hair cells. Cell 151:1283-95

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