Presbycusis or age-related hearing loss (AHL) is the most common sensory deficit in aging human populations and a major factor in reducing the quality of life of the elderly. Genetic studies in humans are difficult because of the late onset of the condition and because non-genetic factors such as noise trauma, disease, and ototoxic drugs confound interpretations. The laboratory mouse provides promising models for human presbycusis because AHL is common in inbred mouse strains and mice are more amenable to detailed genetic and pathological analyses. Mice and humans often share the same genes and inner ear pathologies underlying monogenic hearing disorders, so genetic studies of AHL in mice are likely to add significantly to our understanding of human presbycusis.
Aim 1 of this proposal is to complete the analysis of genetically engineered knock-in mice to verify that a splice variant of the cadherin 23 gene (Cdh23) underlies ahl, a variant conferring AHL susceptibility to multiple inbred strains, and to genetically analyze strain-specific influences on its manifestation. Cdh23 encodes a component of the stereocilia tip link, which is essential to hair cell mechanotransduction, but it is unclear how the Cdh23ahl variant influences AHL. We previously showed that a missense mutation of fascin 2 (FSCN2), an actin bundling protein of hair cell stereocilia, underlies ahl8, a locus on distal Chr 11 that contributes to the early onset hearing loss of DBA/2J mice.
Aim 2 of this proposal is to further elucidate the role of FSCN2 in auditory function by examining hair bundle morphology and hearing loss progression in Fscn2 knockout mice, and by genetically mapping strain-specific loci that modify the effect of Fscn2ahl8 on hearing loss. The chromosomal location and strain distribution of a citrate synthase (Cs) missense mutation strongly supports it as a candidate for the ahl4-related hearing loss of A/J mice.
Aim 3 is to determine the causative nature of this mutation on AHL by a BAC rescue approach, in which a wild-type Cs transgene is integrated into the genome of A/J mice. Another aspect of this aim is to investigate the effects of the A/J ahl4 (Cs) variant and a previously described mt-Tr variant on mitochondrial function and oxidative stress in cochlear tissues. We recently discovered that mice with a null mutation of gamma-glutamyltransferase 1(Ggt1), which are glutathione deficient, exhibit a progressive hearing loss that is associated with a selective loss of cochlear inner hair cells.
Aim 4 is to examine in detail the progression of inner ear pathologies and to measure glutathione-related oxidative stress parameters related to the hearing loss of Ggt1 mutant mice.
Aim 5 of this proposal is to refine the chromosomal locations and test candidate genes for three newly mapped loci that contribute to AHL in A/J mice (ahl9 on Chr 11) and NOD/ShiLtJ mice (ahl10 on Chr 1 and ahl11 on Chr 6).
Presbycusis or age-related hearing loss (AHL) is the most common sensory deficit in aging human populations and a major factor in reducing the quality of life of the elderly. Genetic studies in humans are difficult because of the late onset of the condition and because non-genetic factors such as noise trauma, disease, and ototoxic drugs confound interpretations. AHL is common in inbred mouse strains, and mice are more amenable to detailed genetic and pathological analyses, which could add significantly to our understanding of presbycusis in humans.
|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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