title: 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.
authors.affiliation: Department of Otolaryngology-HNS, Case Western Reserve University, Cleveland, OH 44106, USA.
authors.forename: F
authors.initials: F
authors.lastname: Han
authors.forename: H
authors.initials: H
authors.lastname: Yu
authors.forename: C
authors.initials: C
authors.lastname: Tian
authors.forename: H E
authors.initials: HE
authors.lastname: Chen
authors.forename: C
authors.initials: C
authors.lastname: Benedict-Alderfer
authors.forename: Y
authors.initials: Y
authors.lastname: Zheng
authors.forename: Q
authors.initials: Q
authors.lastname: Wang
authors.forename: X
authors.initials: X
authors.lastname: Han
authors.forename: Q Y
authors.initials: QY
authors.lastname: Zheng
mesh_terms: D000367:Age Factors; D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology / Q000627:therapeutic use*; D000595:Amino Acid Sequence; D000818:Animals; D015820:Cadherins / Q000235:genetics*; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D005816:Genetic Complementation Test; D018072:Hair Cells, Auditory, Outer / Q000187:drug effects / Q000473:pathology; D034381:Hearing Loss / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017354:Point Mutation
chemical_list: D000590:Amino Acid Chloromethyl Ketones; D015820:Cadherins; C499091:Cdh23 protein, mouse; D018696:Neuroprotective Agents; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone