基于iPS技术的AUTS2基因缺陷细胞模型的建立及机制研究

孤独症是具有高度遗传异质性的神经发育障碍性疾病，已成为严重影响儿童健康的常见病。因病因和发病机制不明，迄今仍缺乏有效治疗措施。我们前期在1例孤独症患儿中检测到孤独症易感候选基因2（AUTS2）缺失突变，收集患儿尿液，将尿液细胞（UCs）重编程为iPSCs，并进一步诱导为神经前体细胞（NPCs），发现与健康儿童的iPSCs/NPCs相比，AUTS2表达降低，Rac1表达也下调；我们尝试将NPCs分化为神经元，发现其电生理功能异常。动物实验显示Auts2缺陷可抑制Rac1活性导致神经元迁移及神经突形成缺陷，因此我们推测人AUTS2可以通过调控Rac1的表达影响神经细胞电生理功能。为证实本假说，本研究拟建立AUTS2缺陷患儿iPSCs/NPCs模型，以此探讨AUTS2和Rac1对神经细胞表型及电生理功能的影响，揭示AUTS2缺陷所致孤独症的分子机制，为寻找孤独症个体化治疗药物靶点提供依据。

Autism, a complex neurodevelopmental disorder with high genetic heterogeneity, has become a serious common disorder to children’s health. As the etiology and pathogenesis are unclear, no effective treatments available. In our previous study, an exonic deletion of autism susceptibility candidate 2 (AUTS2) was identified in a patient with autism. His urinary cells (UCs) were cultured and reprogrammed to non-integrating induced pluripotent stem cells (iPSCs), and then differentiated to neural progenitor cells (NPCs). Compared with UCs-derived iPSCs/NPCs obtained from a healthy child, the expression of AUTS2 from the patient’s iPSCs/NPCs was decreased and Rac1 was also showed down-regulated. We tried to induce NPCs to mature neurons and found that electrophysiological function of the neuron from the patient was impaired. Given that Auts2 deletion could result in abnormal neuronal migration and neurite formation via repressing Rac1 activity in mice, we speculate that AUTS2 may affect electrophysiological function of neuron by binding Rac1. To confirm this hypothesis, the patient’s UCs-derived iPSCs/NPCs/neurocytes were established to explore the role of AUTS2 and pathogenesis of autism in order to provide a scientific and experimental basis for discovery of new pharmacological targets and individualized treatment.