Zou Junhuang, Mathur Pranav D, Zheng Tihua, Wang Yong, Almishaal Ali, Park Albert H, Yang Jun
Department of Ophthalmology and Visual Sciences, Moran Eye Center, University of Utah, 65 Mario Capecchi Drive, Salt Lake City, UT 84132, USA.
Department of Ophthalmology and Visual Sciences, Moran Eye Center, University of Utah, 65 Mario Capecchi Drive, Salt Lake City, UT 84132, USA, Department of Neurobiology and Anatomy, University of Utah, 20 North 1900 East, Salt Lake City, UT 84132, USA.
Hum Mol Genet. 2015 Dec 15;24(24):6944-57. doi: 10.1093/hmg/ddv398. Epub 2015 Sep 23.
Usher syndrome (USH) is the leading cause of inherited deaf-blindness, with type 2 (USH2) being the most common clinical form. Studies suggest that proteins encoded by USH2 causative genes assemble into the ankle link complex (ALC) at the hair cell stereociliary bundle; however, little is known about the in vivo assembly and function of this complex. Using various USH2 mutant mice, we showed by immunofluorescence that USH2 proteins play different roles in cochlear ALC assembly, with G protein-coupled receptor 98 being the most important protein. Complex assembly likely occurs at the stereociliary bundle but not along the protein transport route in the cell body. Stereociliary morphological defects in USH2 mutant mice suggest roles for the ALC in regulating inner hair cell stereociliary growth and differentiation as well as outer hair cell stereociliary rigidity and organization during development. These roles are unique from the bundle cohesion role of Usher syndrome type 1 protein complexes. Loss of individual USH2 gene expressions leads to variable morphological and functional consequences, correlating with the severity of ALC disruption. This finding suggests a potential genotype-phenotype correlation in USH2 patients. In summary, this study provides novel insights into the molecular mechanism underlying cochlear stereociliary bundle development and hearing loss pathogenesis of various USH2 subtypes. Our thorough phenotypical characterization of USH2 mouse models is essential for future use of these animal models in therapeutic development.
Usher综合征（USH）是遗传性聋哑的主要病因，其中2型（USH2）是最常见的临床类型。研究表明，USH2致病基因编码的蛋白质在毛细胞静纤毛束处组装成脚踝连接复合体（ALC）；然而，关于该复合体在体内的组装和功能知之甚少。利用各种USH2突变小鼠，我们通过免疫荧光显示USH2蛋白在耳蜗ALC组装中发挥不同作用，其中G蛋白偶联受体98是最重要的蛋白质。复合体组装可能发生在静纤毛束处，而不是沿着细胞体内的蛋白质运输路线。USH2突变小鼠的静纤毛形态缺陷表明ALC在发育过程中对内毛细胞静纤毛生长和分化以及外毛细胞静纤毛硬度和组织的调节作用。这些作用与1型Usher综合征蛋白复合体的束凝聚作用不同。单个USH2基因表达的缺失会导致不同的形态和功能后果，这与ALC破坏的严重程度相关。这一发现提示USH2患者可能存在基因型与表型的相关性。总之，本研究为耳蜗静纤毛束发育及各种USH2亚型听力损失发病机制的分子机制提供了新的见解。我们对USH2小鼠模型的全面表型特征分析对于这些动物模型未来在治疗开发中的应用至关重要。
