PDF(Pubmed)
Abstract：
The vacuolar H+-ATPase is an enzymatic complex that functions in an ATP-dependent manner to pump protons across membranes and acidify organelles, thereby creating the proton/pH gradient required for membrane trafficking by several different types of transporters. We describe heterozygous point variants in ATP6V0C, encoding the c-subunit in the membrane bound integral domain of the vacuolar H+-ATPase, in 27 patients with neurodevelopmental abnormalities with or without epilepsy. Corpus callosum hypoplasia and cardiac abnormalities were also present in some patients. In silico modelling suggested that the patient variants interfere with the interactions between the ATP6V0C and ATP6V0A subunits during ATP hydrolysis. Consistent with decreased vacuolar H+-ATPase activity, functional analyses conducted in Saccharomyces cerevisiae revealed reduced LysoSensor fluorescence and reduced growth in media containing varying concentrations of CaCl2. Knockdown of ATP6V0C in Drosophila resulted in increased duration of seizure-like behaviour, and the expression of selected patient variants in Caenorhabditis elegans led to reduced growth, motor dysfunction and reduced lifespan. In summary, this study establishes ATP6V0C as an important disease gene, describes the clinical features of the associated neurodevelopmental disorder and provides insight into disease mechanisms.
摘要：
液泡H-ATPase（V-ATPase）是一种酶促复合物，以ATP依赖性方式起作用，可将质子泵送穿过膜并酸化细胞器，从而通过几种不同类型的转运蛋白产生膜运输所需的质子/pH梯度。我们描述了ATP6V0C中的杂合点变体，编码V-ATP酶的膜结合整合域中的c亚基，在27例有或没有癫痫的神经发育异常患者中。某些患者还存在call体发育不全和心脏异常。计算机建模表明患者变体在ATP水解期间干扰ATP6V0C和ATP6V0A亚基之间的相互作用。与V-ATPase活性降低一致，在酿酒酵母中进行的功能分析显示，LysoSensor荧光降低，并且在含有不同浓度CaCl2的培养基中生长降低。果蝇中ATP6V0C的击倒导致癫痫样行为的持续时间增加，秀丽隐杆线虫中选定患者变异体的表达导致生长减少，运动功能障碍,减少寿命。总之,本研究确立ATP6V0C为重要的疾病基因,描述了相关神经发育障碍的临床特征，并提供对疾病机制的见解。
