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.

人类肌球蛋白VIIA（MYO7A）突变可引发多种累及内耳的病症，包括显性及隐性非综合征性听力损失，以及尤塞尔综合征（Usher syndrome）等综合征性疾病。耳聋小鼠模型有助于我们探究正常与异常听觉过程所涉及的功能通路。本研究报道两种携带Myo7a基因突变且具有独特表型的新型小鼠模型：其中Myo7aI487N/I487N ewaso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；而Myo7aF947I/F947I dumbo的突变位点位于该蛋白卷曲螺旋与首个MyTH4结构域之间的连接区域，其听力损失程度轻于Myo7aI487N/I487N ewaso：该品系小鼠在4周龄时听力阈值便已升高，且随年龄增长呈进行性加重。尽管扫描电子显微镜（scanning electron microscopy）可观察到其前庭静纤毛束存在轻度表型异常，但该小鼠未表现出明显的前庭功能障碍体征。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型耳聋的潜在研究模型。阐明这些新发现突变的分子机制，将有助于解析听觉维持过程中涉及的复杂遗传通路，同时为人类隐性遗传性感音神经性听力损失的研究提供新的见解。