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A new mouse mutant of the Cdh23 gene with early-onset hearing loss facilitates evaluation of otoprotection drugs.

ABSTRACT: We report a novel mutation (erlong, erl) of the cadherin 23 (Cdh23) gene in a mouse model for DFNB12 characterized by progressive hearing loss beginning from postnatal day 27 (P27). Genetic and sequencing analysis revealed a 208?T >C transition causing an amino-acid substitution (70S-P). Caspase expression was upregulated in mutant inner ears. Hearing was preserved (up to 35-dB improvement) in pan-caspase inhibitor Z-VAD-FMK-treated mutants compared with untreated mutants (P<0.05). Outer hair cell (OHC) loss in the cochleae of Z-VAD-FMK-treated mutants was significantly reduced compared with those of untreated mice. Thus, the erl mutation can lead to hearing loss through apoptosis. This is the first genetic mouse model of hearing loss shown to respond to otoprotective drug therapy. The short interval from initial hearing loss to deafness (P27-P90) makes this model ideal for screening and validating otoprotective drugs.

SUBMITTER: Han F

PROVIDER: S-EPMC3000876 | biostudies-literature | 2012 Feb

REPOSITORIES: biostudies-literature

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A new mouse mutant of the Cdh23 gene with early-onset hearing loss facilitates evaluation of otoprotection drugs.

Han F F Yu H H Tian C C Chen H E HE Benedict-Alderfer C C Zheng Y Y Wang Q Q Han X X Zheng Q Y QY

The pharmacogenomics journal 20100720 1

We report a novel mutation (erlong, erl) of the cadherin 23 (Cdh23) gene in a mouse model for DFNB12 characterized by progressive hearing loss beginning from postnatal day 27 (P27). Genetic and sequencing analysis revealed a 208 T >C transition causing an amino-acid substitution (70S-P). Caspase expression was upregulated in mutant inner ears. Hearing was preserved (up to 35-dB improvement) in pan-caspase inhibitor Z-VAD-FMK-treated mutants compared with untreated mutants (P<0.05). Outer hair ce ...[more]

PMID: 20644563

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Project description:Alzheimer's disease (AD) is the most common type of dementia and is characterized by cognitive and behavioral impairment that significantly interferes with social functioning. Over the last decade, there has been an increased interest in whether sensory deficiency may be associated with the development of AD. Notably, the relationship between hearing impairment and AD is of great relevance, but still poorly understood. In this study, we found an early-onset hearing loss in 3xTgAD and 3xTgAD/Polβ+/− mouse models. The hearing assessment was measured by auditory brainstem response (ABR) and distortion product otoacoustic emission (DPOAE) recordings. Herein, we report that both 3xTgAD and 3xTgAD/Polβ+/− mice showed increased ABR thresholds between at 16 and 32 kHz at 4 weeks of age, much earlier than any AD behavioral changes. The ABR thresholds were significantly higher in 3xTgAD/Polβ+/− mice than in 3xTgAD mice at 16 kHz, and DPOAE signals were also reduced, indicating that DNA damage may affect hearing impairment in AD. Poly ADP-ribosylation levels and protein expression of DNA damage markers increased significantly and NAD+ levels were reduced in the cochlea of 3xTgAD and 3xTgAD/Polβ+/− mice. Remarkably, we observed the downregulation of phosphoglycerate mutase 2 (PGAM2) in cochlea and a decrease in the number of synaptic ribbons in the presynaptic zones of inner hair cells in 3xTgAD/Polβ+/− mice. We also find that the activity of sirtuin 3 (SIRT3) is downregulated in cochlea, indicative of impaired mitochondrial function. Taken together, hearing impairment may be a potential early marker of AD. In addition, these findings provide new insights into the mechanism of the relationship between hearing dysfunction and AD and suggest that DNA damage in the cochlea can contributes to the development of early hearing loss of AD. The hearing assessment was measured by auditory brainstem response (ABR) and distortion product otoacoustic emission (DPOAE) at 4 weeks of age, thereafter whole cochlea and auditory cortex tissue were collected from each mouse (WT, Polβ+/−, 3xTgAD, and 3xTgAD/Polβ+/−) and subjected to total RNA isolation to understand what metabolism-related gene expression changes in cochlea and auditory cortex.

Project description:Inbred strain variants of the Cdh23 gene have been shown to influence the onset and progression of age-related hearing loss (AHL) in mice. In linkage backcrosses, the recessive Cdh23 allele (ahl) of the C57BL/6J strain, when homozygous, confers increased susceptibility to AHL, while the dominant allele (Ahl+) of the CBA/CaJ strain confers resistance. To determine the isolated effects of these alleles on different strain backgrounds, we produced the reciprocal congenic strains B6.CBACa-Cdh23(Ahl)(+) and CBACa.B6-Cdh23(ahl) and tested 15-30 mice from each for hearing loss progression. ABR thresholds for 8 kHz, 16 kHz, and 32 kHz pure-tone stimuli were measured at 3, 6, 9, 12, 15 and 18 months of age and compared with age-matched mice of the C57BL/6J and CBA/CaJ parental strains. Mice of the C57BL/6N strain, which is the source of embryonic stem cells for the large International Knockout Mouse Consortium, were also tested for comparisons with C57BL/6J mice. Mice of the C57BL/6J and C57BL/6N strains exhibited identical hearing loss profiles: their 32 kHz ABR thresholds were significantly higher than those of CBA/CaJ and congenic strain mice by 6 months of age, and their 16 kHz thresholds were significantly higher by 12 months. Thresholds of the CBA/CaJ, the B6.CBACa-Cdh23(Ahl)(+), and the CBACa.B6-Cdh23(ahl) strain mice differed little from one another and only slightly increased throughout the 18-month test period. Hearing loss, which corresponded well with cochlear hair cell loss, was most profound in the C57BL/6J and C57BL/6NJ strains. These results indicate that the CBA/CaJ-derived Cdh23(Ahl)(+) allele dramatically lessens hearing loss and hair cell death in an otherwise C57BL/6J genetic background, but that the C57BL/6J-derived Cdh23(ahl) allele has little effect on hearing loss in an otherwise CBA/CaJ background. We conclude that although Cdh23(ahl) homozygosity is necessary, it is not by itself sufficient to account for the accelerated hearing loss of C57BL/6J mice.

Dataset Information

A new mouse mutant of the Cdh23 gene with early-onset hearing loss facilitates evaluation of otoprotection drugs.

Publications

A new mouse mutant of the Cdh23 gene with early-onset hearing loss facilitates evaluation of otoprotection drugs.

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