The Jackson Laboratory, Bar Harbor, ME 04609, USA.
Hear Res. 2010 Sep 1;268(1-2):85-92. doi: 10.1016/j.heares.2010.05.002. Epub 2010 May 12.
Both the ahl allele of Cdh23 and the null mutation of Sod1 have been shown to contribute to age-related hearing loss (AHL) in mice, but mixed strain backgrounds have confounded analyses of their individual and combined effects. To test for the effects of Sod1 deficiency independently from those of Cdh23(ahl), we produced mice with four digenic genotypes: Sod1(+/+)Cdh23(ahl)(/ahl), Sod1(+/+)Cdh23(+/+), Sod1(-/-)Cdh23(ahl)(/ahl), and Sod1(-/-)Cdh23(+/+), all on a uniform C57BL(/)6J strain background. We assessed hearing loss by ABR threshold measurements and evaluated cochlear pathologies in age-matched mice of each digenic combination. ABR analysis showed that Sod1(+/+)Cdh23(+/+) mice retain normal hearing up to 15 months of age and that hearing loss of Sod1(+/+)Cdh23(ahl)(/ahl) mice is more age and frequency dependent than that of Sod1(-/-)Cdh23(+/+) mice. ABR results also showed that mice with both gene mutations (Sod1(-/-)Cdh23(ahl)(/ahl)) exhibit the earliest onset and most severe hearing loss, greater than predicted for strictly additive effects. Histological analysis of cochleas showed that hair cell lesions are most severe in Sod1(-)(/-)Cdh23(ahl)(/ahl) mice followed closely by Sod1(+)(/+)Cdh23(ahl)(/ahl) mice and much smaller in Sod1(-)(/-)Cdh23(+)(/+) and Sod1(+)(/+)Cdh23(+)(/+) mice. Despite extensive damage to cochlear hair cells, vestibular hair cells appeared remarkably normal in all strains. Although both Sod1(-/-) and Cdh23(ahl)(/ahl) genotypes had strong effects on hearing loss, the Cdh23(ahl/ahl) genotype was primarily responsible for the increase in hair cell loss, suggesting that the two mutations have different underlying mechanisms of pathology.
Cdh23 的 ahl 等位基因和 Sod1 的 null 突变都被证明会导致小鼠的年龄相关性听力损失 (AHL)，但混合的品系背景使对它们各自和共同作用的分析变得复杂。为了独立于 Cdh23(ahl)测试 Sod1 缺乏的影响，我们生成了具有四种双基因基因型的小鼠：Sod1(+/+)Cdh23(ahl)(/ahl)、Sod1(+/+)Cdh23(+/+)、Sod1(-/-)Cdh23(ahl)(/ahl)和 Sod1(-/-)Cdh23(+/+)，所有这些都在均匀的 C57BL(/)6J 品系背景上。我们通过 ABR 阈值测量评估听力损失，并评估每个双基因组合中年龄匹配的小鼠的耳蜗病理学。ABR 分析表明，Sod1(+/+)Cdh23(+/+)小鼠在 15 个月之前保持正常听力，并且 Sod1(+/+)Cdh23(ahl)(/ahl)小鼠的听力损失比 Sod1(-/-)Cdh23(+/+)小鼠更依赖于年龄和频率。ABR 结果还表明，具有两种基因突变的小鼠 (Sod1(-/-)Cdh23(ahl)(/ahl)) 表现出最早和最严重的听力损失，超过了严格相加效应的预测。耳蜗的组织学分析表明，毛细胞病变在 Sod1(-/-)Cdh23(ahl)(/ahl)小鼠中最为严重，其次是 Sod1(+)(/+)Cdh23(ahl)(/ahl)小鼠，而 Sod1(-/-)Cdh23(+)(/+)和 Sod1(+)(/+)Cdh23(+)(/+)小鼠的病变则小得多。尽管耳蜗毛细胞受到广泛损害，但所有品系的前庭毛细胞看起来都非常正常。尽管 Sod1(-/-)和 Cdh23(ahl)(/ahl)基因型对听力损失都有很强的影响，但 Cdh23(ahl/ahl)基因型主要负责毛细胞丢失的增加，这表明这两种突变具有不同的病理机制。
