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

The Pharmacogenomics Journal volume 12, pages 30–44 (2012)Cite this article

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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.

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Acknowledgements

This work was supported by NIH R01DC007392 and R01DC009246 to QYZ. The mutagenesis program at the Jackson Laboratory was funded by NIH (U01NS041215). We thank Shengli Li and Baiya Li for technical assistance, Louise Dionne for initial colony management and Lucy Rowe for her genotyping service. Hui E Chen is supported by CWRU Summer Program in Undergraduate Research (SPUR).

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Author notes

  1. Q Wang

    Present address: 5Current address: Department of Otolaryngology and HNS, Chinese PLA Institute of Otolaryngology, Chinese PLA General Hospital, 28 Fuxing Road, Beijing 100853 China.,

  2. F Han and H Yu: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Otolaryngology-HNS, Case Western Reserve University, Cleveland, OH, USA

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

  2. Department of Genetics, Case Western Reserve University, Cleveland, OH, USA

    Q Y Zheng

  3. Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, USA

    Q Y Zheng

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Correspondence to Q Y Zheng.

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Competing interests

QYZ, FH and HY have filed a patent covering the general approach of Z-VAD-FMK as a therapeutic approach for genetic hearing loss and using the erl mouse model for evaluating otoprotective drugs.

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Han, F., Yu, H., Tian, C. et al. A new mouse mutant of the Cdh23 gene with early-onset hearing loss facilitates evaluation of otoprotection drugs. Pharmacogenomics J 12, 30–44 (2012). https://doi.org/10.1038/tpj.2010.60

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