Age-related hearing loss (presbycusis) is the most common sensory deficit in human populations; about 1 in 3 adults older than 60 suffer from a significant hearing loss. The genetic basis of presbycusis is poorly understood because of the extreme difficulty in studying such a late-onset genetically complex disorder. The laboratory mouse provides promising models for studying human presbycusis because age-related hearing loss (AHL) is common in inbred mouse strains and mice are more amenable to genetic analyses. We have shown that a gene on Chromosome 10 (Ahl) is a major susceptibility factor for AHL in more than 10 inbred strains of mice and that a mitochondrial mutation in A/J mice exacerbates this hearing loss. We hypothesize that the genetic predisposition and the pathophysiological pathways involved in the mouse are also involved in humans and that further genetic studies of AHL in mice will add significantly to our understanding of presbycusis in humans.
Our specific aims are (1) to identify the Chr 10 Ahl gene, first analyzing Cdh23, a co-localized gene that is mutated in deaf waltzer mice, by genetic complementation tests for allelism and by gene rescue experiments; (2) to refine the map position of a newly discovered AHL locus on Chr 5 (Ahl2) and test candidate genes in the region; (3) to map additional loci that contribute to AHL and analyze defined locus combinations on uniform strain backgrounds; and (4) to test homologs of mouse AHL loci for their potential role in human presbycusis by analyses of linkage disequilibrium and DNA alterations in patients and matched controls. The long-term objectives of this research are to provide a better understanding of the molecular mechanisms and pathophysiology of AHL that could contribute to the development of diagnostics, preventive interventions, and therapies for human presbycusis.

National Institute of Health (NIH)
National Institute on Deafness and Other Communication Disorders (NIDCD)
Research Project (R01)
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Special Emphasis Panel (ZRG1-IFCN-6 (01))
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Watson, Bracie
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Jackson Laboratory
Bar Harbor
United States
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Johnson, Kenneth R; Tian, Cong; Gagnon, Leona H et al. (2017) Effects of Cdh23 single nucleotide substitutions on age-related hearing loss in C57BL/6 and 129S1/Sv mice and comparisons with congenic strains. Sci Rep 7:44450
Ding, Dalian; Jiang, Haiyan; Chen, Guang-Di et al. (2016) N-acetyl-cysteine prevents age-related hearing loss and the progressive loss of inner hair cells in ?-glutamyl transferase 1 deficient mice. Aging (Albany NY) 8:730-50
Johnson, Kenneth R; Longo-Guess, Chantal M; Gagnon, Leona H (2015) A QTL on Chr 5 modifies hearing loss associated with the fascin-2 variant of DBA/2J mice. Mamm Genome 26:338-47
Perrin, Benjamin J; Strandjord, Dana M; Narayanan, Praveena et al. (2013) ýý-Actin and fascin-2 cooperate to maintain stereocilia length. J Neurosci 33:8114-21
Johnson, Kenneth R; Gagnon, Leona H; Longo-Guess, Chantal et al. (2012) Association of a citrate synthase missense mutation with age-related hearing loss in A/J mice. Neurobiol Aging 33:1720-9
Kane, Kelly L; Longo-Guess, Chantal M; Gagnon, Leona H et al. (2012) Genetic background effects on age-related hearing loss associated with Cdh23 variants in mice. Hear Res 283:80-8
Johnson, Kenneth R; Yu, Heping; Ding, Dalian et al. (2010) Separate and combined effects of Sod1 and Cdh23 mutations on age-related hearing loss and cochlear pathology in C57BL/6J mice. Hear Res 268:85-92
Shin, Jung-Bum; Longo-Guess, Chantal M; Gagnon, Leona H et al. (2010) The R109H variant of fascin-2, a developmentally regulated actin crosslinker in hair-cell stereocilia, underlies early-onset hearing loss of DBA/2J mice. J Neurosci 30:9683-94
Zheng, Qing Yin; Ding, Dalian; Yu, Heping et al. (2009) A locus on distal chromosome 10 (ahl4) affecting age-related hearing loss in A/J mice. Neurobiol Aging 30:1693-705
Noben-Trauth, Konrad; Johnson, Kenneth R (2009) Inheritance patterns of progressive hearing loss in laboratory strains of mice. Brain Res 1277:42-51

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