A subunit of V-ATPases, ATP6V1B2, underlies the pathology of intellectual disability
A subunit of V-ATPases, ATP6V1B2, underlies the pathology of intellectual disability
复制标题
V-ATPase 的一个亚基 ATP6V1B2 是智力障碍病理学的基础
DOI：
10.1016/j.ebiom.2019.06.035
复制
发表时间：
2019-07-01
期刊：
影响因子：
11.1
通讯作者：
Yuan, Yongyi
中科院分区：
文献类型：
--
作者：
Zhao, Weihao;Gao, Xue;Yuan, Yongyi
背景：显性耳聋甲营养不良（DDOD）综合征是一种罕见疾病，主要特征为重度耳聋、甲营养不良和短指畸形。我们之前将 ATP6V1B2 中的 c.1516C > T (p.Arg506X) 确定为 DDOD 综合征的病因，解释了这种遗传性疾病的所有病例。 DDOD综合征患者植入人工耳蜗后的临床随访发现，虽然植入的耳蜗功能良好，但语言康复效果并不理想，这表明DDOD综合征患者可能存在学习记忆问题。但具体机制尚不清楚。方法：构建atp6v1b2敲除斑马鱼和Atp6v1b2 c.1516C>T敲入小鼠，探讨其表型及相关机制。在突变小鼠中，进行听觉脑干反应测试和耳蜗形态分析以评估听觉功能。行为测试用于调查各种行为和认知领域。静息态功能磁共振成像用于评估小鼠大脑的功能连接。采用免疫荧光、Western印迹和免疫共沉淀检测V-ATPase亚基之间的表达和相互作用。结果：敲除atp6v1b2的斑马鱼在多个器官和系统中表现出发育缺陷。然而，Atp6v1b2 c.1516C>T敲入小鼠表现出明显的认知缺陷，但听力和耳蜗形态正常。观察到 Atp6v1b2(Arg506X//Arg506X) 小鼠海马 CA1 区受损以及 V1E 和 B2 亚基之间的相互作用减弱。解释：我们的研究扩展了 DDOD 综合征的表型范围。海马CA1区受损可能是突变小鼠行为缺陷的病理基础。 V-ATP酶功能障碍的分子机制涉及亚基之间的弱相互作用，尽管V-ATP酶的组装仍然可以发生。 (C) 2019 年由 Elsevier B.V. 出版
Background: Dominant deafness-onychodystrophy (DDOD) syndrome is a rare disordermainly characterized by severe deafness, onychodystrophy and brachydactyly. We previously identified c.1516C > T (p.Arg506X) in ATP6V1B2 as cause of DDOD syndrome, accounting for all cases of this genetic disorder. Clinical follow-up of DDOD syndrome patients with cochlear implantation revealed the language rehabilitation was unsatisfactory although the implanted cochlea worked well, which indicates there might be learning and memory problems in DDOD syndrome patients. However, the underlying mechanisms were unknown.Methods: atp6v1b2 knockdown zebrafish and Atp6v1b2 c.1516C > T knockin mice were constructed to explore the phenotypes and related mechanism. In mutant mice, auditory brainstem response test and cochlear morphology analysis were performed to evaluate the auditory function. Behavioral tests were used to investigate various behavioral and cognitive domains. Resting-state functional magnetic resonance imaging was used to evaluate functional connectivity in the mouse brain. Immunofluorescence, Western blot, and co-immunoprecipitation were performed to examine the expression and interactions between the subunits of V-ATPases.Findings: atp6v1b2 knockdown zebrafish showed developmental defects in multiple organs and systems. However, Atp6v1b2 c.1516C > T knockin mice displayed obvious cognitive defects but normal hearing and cochlear morphology. Impaired hippocampal CA1 region and weaker interaction between the V1E and B2 subunits in Atp6v1b2(Arg506X//Arg506X) mice were observed.Interpretation: Our study extends the phenotypic range of DDOD syndrome. The impaired hippocampal CA1 region may be the pathological basis of the behavioral defects inmutantmice. The molecular mechanism underlying V-ATPases dysfunction involves a weak interaction between subunits, although the assembly of V-ATPases can still take place. (C) 2019 Published by Elsevier B.V.