Department of Otolaryngology-HNS, Case Western Reserve University, Cleveland, OH 44106, USA.
Pharmacogenomics J. 2012 Feb;12(1):30-44. doi: 10.1038/tpj.2010.60. Epub 2010 Jul 20.
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.
我们报告了一种新型突变（erlong，erl）的钙黏蛋白 23（Cdh23）基因在一个以渐进性听力损失为特征的 DFNB12 小鼠模型中，这种听力损失始于出生后第 27 天（P27）。遗传和测序分析显示，208T>C 转换导致氨基酸取代（70S-P）。突变型内耳中的半胱天冬酶表达上调。与未治疗的突变体相比，用广谱半胱天冬酶抑制剂 Z-VAD-FMK 处理的突变体的听力得到了保留（高达 35dB 的改善）（P<0.05）。与未治疗的小鼠相比，用 Z-VAD-FMK 处理的突变体的耳蜗中的外毛细胞（OHC）损失明显减少。因此，erl 突变可通过细胞凋亡导致听力损失。这是第一个对听力保护药物治疗有反应的遗传性听力损失小鼠模型。从初始听力损失到耳聋的时间间隔很短（P27-P90），这使得该模型非常适合筛选和验证听力保护药物。
