A hypomorphic PIGA gene mutation causes severe defects in neuron development and susceptibility to complement-mediated toxicity in a human iPSC model.
A hypomorphic PIGA gene mutation causes severe defects in neuron development and susceptibility to complement-mediated toxicity in a human iPSC model.
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DOI：
10.1371/journal.pone.0174074
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Brodsky RA
中科院分区：
文献类型：
--
作者：
Yuan X;Li Z;Baines AC;Gavriilaki E;Ye Z;Wen Z;Braunstein EM;Biesecker LG;Cheng L;Dong X;Brodsky RA
参与糖基磷脂酰肌醇（GPI）锚生物合成的基因突变是一组以严重神经发育缺陷为特征的先天性综合征的基础。GPI锚定蛋白在细胞粘附、信号传导、代谢和补体调节中具有不同的作用。GPI锚生物合成需要超过30种酶，PIGA参与该过程的第一步。X连锁PIGA基因（c.1234C>T）的亚型突变导致多个先天性异常低张力癫痫综合征2（MCAHS 2），表明即使部分减少GPI锚定蛋白也会严重损害中枢神经系统发育，但机制尚不清楚。在这里，我们建立了一个人诱导多能干细胞（hiPSC）模型含有PIGAc.1234C>T突变，以研究的影响PIGA的亚型等位基因对神经元发育。在PIGAc.1234C>T中通过EB形成产生的神经祖细胞的神经元分化显著受损，具有降低的增殖、异常突触形成和异常膜去极化。这些结果为GPI锚蛋白在早期神经发育中的关键作用提供了直接证据。此外，来源于PIGAc.1234C>T hiPSC的神经祖细胞表现出对补体介导的细胞毒性的敏感性增加，表明补体调节缺陷可能导致神经发育障碍。
Mutations in genes involved in glycosylphosphatidylinositol (GPI) anchor biosynthesis underlie a group of congenital syndromes characterized by severe neurodevelopmental defects. GPI anchored proteins have diverse roles in cell adhesion, signaling, metabolism and complement regulation. Over 30 enzymes are required for GPI anchor biosynthesis and PIGA is involved in the first step of this process. A hypomorphic mutation in the X-linked PIGA gene (c.1234C>T) causes multiple congenital anomalies hypotonia seizure syndrome 2 (MCAHS2), indicating that even partial reduction of GPI anchored proteins dramatically impairs central nervous system development, but the mechanism is unclear. Here, we established a human induced pluripotent stem cell (hiPSC) model containing the PIGAc.1234C>T mutation to study the effects of a hypomorphic allele of PIGA on neuronal development. Neuronal differentiation from neural progenitor cells generated by EB formation in PIGAc.1234C>T is significantly impaired with decreased proliferation, aberrant synapse formation and abnormal membrane depolarization. The results provide direct evidence for a critical role of GPI anchor proteins in early neurodevelopment. Furthermore, neural progenitors derived from PIGAc.1234C>T hiPSCs demonstrate increased susceptibility to complement-mediated cytotoxicity, suggesting that defective complement regulation may contribute to neurodevelopmental disorders.