Department of Communication Sciences and Disorders, East Carolina University, Greenville, NC, USA.
Hear Res. 2011 Feb;272(1-2):42-8. doi: 10.1016/j.heares.2010.11.002. Epub 2010 Nov 10.
Two mouse models, the Coch(G88E/G88E) or "knock-in" and the Coch(-/-) or "knock-out" (Coch null), have been developed to study the human late-onset, progressive, sensorineural hearing loss and vestibular dysfunction known as DFNA9. This disorder results from missense and in-frame deletion mutations in COCH (coagulation factor C homology), encoding cochlin, the most abundantly detected protein in the inner ear. We have performed hearing and vestibular analyses by auditory brainstem response (ABR) and vestibular evoked potential (VsEP) testing of the Coch(-/-) and Coch(G88E/G88E) mouse models. Both Coch(-/-) and Coch(G88E/G88E) mice show substantially elevated ABRs at 21 months of age, but only at the highest frequency tested for the former and all frequencies for the latter. At 21 months, 9 of 11 Coch(-/-) mice and 4 of 8 Coch(G88E/G88E) mice have absent ABRs. Interestingly Coch(-/+) mice do not show hearing deficits, in contrast to Coch(G88E/+), which demonstrate elevated ABR thresholds similar to homozyotes. These results corroborate the DFNA9 autosomal dominant mode of inheritance, in addition to the observation that haploinsufficiency of Coch does not result in impaired hearing. Vestibular evoked potential (VsEP) thresholds were analyzed using a two factor ANOVA (Age X Genotype). Elevated VsEP thresholds are detected in Coch(-/-) mice at 13 and 21 months, the two ages tested, and as early as seven months in the Coch(G88E/G88E) mice. These results indicate that in both mouse models, vestibular function is compromised before cochlear function. Analysis and comparison of hearing and vestibular function in these two DFNA9 mouse models, where deficits occur at such an advanced age, provide insight into the pathology of DFNA9 and age-related hearing loss and vestibular dysfunction as well as an opportunity to investigate potential interventional therapies.
已经开发出两种小鼠模型，即 Coch(G88E/G88E)或“敲入”和 Coch(-/-)或“敲除”(Coch 缺失)，用于研究已知为 DFNA9 的人类迟发性、进行性、感觉神经性听力损失和前庭功能障碍。这种疾病是由 COCH(凝血因子 C 同源物)中的错义和框内缺失突变引起的，COCH 编码 cochlin，这是内耳中检测到的最丰富的蛋白质。我们通过听觉脑干反应(ABR)和前庭诱发电位(VsEP)测试对 Coch(-/-)和 Coch(G88E/G88E)小鼠模型进行了听力和前庭分析。Coch(-/-)和 Coch(G88E/G88E)小鼠在 21 个月大时的 ABR 显著升高，但前者仅在测试的最高频率下升高，而后者则在所有频率下升高。在 21 个月时，11 只 Coch(-/-)小鼠中有 9 只和 8 只 Coch(G88E/G88E)小鼠的 ABR 消失。有趣的是，Coch(-/+)小鼠没有听力缺陷，而 Coch(G88E/+)则显示出与纯合子相似的 ABR 阈值升高。这些结果证实了 DFNA9 的常染色体显性遗传模式，此外还观察到 Coch 的单倍不足不会导致听力受损。使用双因素方差分析(年龄 X 基因型)分析前庭诱发电位(VsEP)阈值。在 13 个月和 21 个月测试的两个年龄以及 Coch(G88E/G88E)小鼠的 7 个月龄时，检测到 Coch(-/-)小鼠的 VsEP 阈值升高。这些结果表明，在这两种小鼠模型中，前庭功能在耳蜗功能之前受到损害。在这两种 DFNA9 小鼠模型中分析和比较听力和前庭功能，其中缺陷发生在如此高龄时，可以深入了解 DFNA9 和年龄相关性听力损失和前庭功能障碍的病理学，并为研究潜在的干预治疗提供机会。
