Inner Ear Morphology Is Perturbed in Two Novel Mouse Models of Recessive Deafness

Human MYO7A mutations can cause a variety of conditions involving the inner ear. These include dominant and recessive non-syndromic hearing loss and syndromic conditions such as Usher syndrome. Mouse models of deafness allow us to investigate functional pathways involved in normal and abnormal hearing processes. We present two novel mouse models with mutations in the Myo7a gene with distinct phenotypes. The mutation in Myo7aI487N/I487N ewaso is located within the head motor domain of Myo7a. Mice exhibit a profound hearing loss and manifest behaviour associated with a vestibular defect. A mutation located in the linker region between the coiled-coil and the first MyTH4 domains of the protein is responsible in Myo7aF947I/F947I dumbo. These mice show a less severe hearing loss than in Myo7aI487N/I487N ewaso; their hearing loss threshold is elevated at 4 weeks old, and progressively worsens with age. These mice show no obvious signs of vestibular dysfunction, although scanning electron microscopy reveals a mild phenotype in vestibular stereocilia bundles. The Myo7aF947I/F947I dumbo strain is therefore the first reported Myo7a mouse model without an overt vestibular phenotype; a possible model for human DFNB2 deafness. Understanding the molecular basis of these newly identified mutations will provide knowledge into the complex genetic pathways involved in the maintenance of hearing, and will provide insight into recessively inherited sensorineural hearing loss in humans.

人类MYO7A基因突变可引发多种累及内耳的病症，此类病症包括显性及隐性非综合征性听力损失，以及尤塞综合征（Usher syndrome）等综合征性疾病。耳聋小鼠模型可为我们探究正常与异常听觉过程所涉及的功能通路提供研究手段。本研究报道两种携带Myo7a基因突变、具有显著表型差异的新型小鼠模型：Myo7aI487N/I487N ewaso品系的突变位点位于Myo7a的头部运动结构域内，该品系小鼠表现为重度听力损失，并出现与前庭功能缺陷相关的行为异常；Myo7aF947I/F947I dumbo品系的突变位点位于该蛋白卷曲螺旋结构域与首个MyTH4结构域之间的连接区域，其听力损失程度轻于Myo7aI487N/I487N ewaso品系：4周龄时其听力阈值即出现升高，并随年龄增长逐渐加重。尽管扫描电子显微镜观察发现其前庭静纤毛束存在轻度表型异常，但该品系小鼠未表现出明显的前庭功能障碍症状。因此，Myo7aF947I/F947I dumbo品系是首个被报道的无明显前庭表型的Myo7a小鼠模型，可作为人类DFNB2型耳聋（DFNB2 deafness）的潜在研究模型。解析这些新发现突变的分子机制，将有助于我们深入了解听觉维持过程中涉及的复杂遗传通路，同时为人类常染色体隐性遗传性感音神经性听力损失的研究提供新的见解。