ARHGAP10, which encodes Rho GTPase-activating protein 10, is a novel gene for schizophrenia risk
ARHGAP10, which encodes Rho GTPase-activating protein 10, is a novel gene for schizophrenia risk
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DOI：
10.1038/s41398-020-00917-z
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发表时间：
2020-07-22
影响因子：
6.8
通讯作者：
Ozaki, Norio
中科院分区：
文献类型：
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作者：
Sekiguchi, Mariko;Sobue, Akira;Ozaki, Norio
众所周知，精神分裂症(SCZ)是一种可遗传的疾病；然而，它的多因素性质大大阻碍了确定其发病机制的尝试。因此，在这项研究中，我们对2940名SCZ患者和2402名对照受试者进行了全基因组拷贝数变异(CNV)分析，发现SCZ和ARHGAP10基因外显子CNV之间存在统计学意义上的关联。ARHGAP10编码RhoGAP超家族蛋白中的一个成员，参与小GTP酶信号转导。该信号通路是SCZ相关通路之一，可能与神经发育和功能有关。然而，ARHGAP10基因经常被混淆为ARHGAP21，因此，ARHGAP10在SCZ分子病理学中的意义，包括ARHGAP10蛋白的表达谱，仍然知之甚少。为了解决这个问题，我们重点研究了一名ARHGAP10中既有外显子缺失又有错义变异(p.S490P)的患者。错义变异体被发现位于RhoGAP结构域，并被确定与ARHGAP10与RhoA的活性形式之间的关联有关。我们评估了ARHGAP10蛋白在报告小鼠大脑中的表达，并建立了一个模拟患者病例的小鼠模型。该模型表现出异常的情绪行为，并伴有内侧前额叶皮质(MPFC)脊椎密度的降低。此外，从小鼠模型脑中制备的原代培养的神经元在体外显示出未成熟的轴突。此外，我们从该患者体内建立了诱导多能干细胞(IPSCs)，并将其分化为酪氨酸羟化酶(TH)阳性神经元，以分析其形态表型。从患者来源的IPSCs分化出的TH阳性神经元在轴突长度和分支数量方面都出现了严重的缺陷；这些缺陷可以通过添加Rho-Kinase抑制剂Y-27632来修复。总之，我们的发现表明，罕见的ARHGAP10变异可能在遗传和生物学上与SCZ相关，并表明Rho信号转导系统是治疗SCZ的一个有前途的药物发现靶点。
Schizophrenia (SCZ) is known to be a heritable disorder; however, its multifactorial nature has significantly hampered attempts to establish its pathogenesis. Therefore, in this study, we performed genome-wide copy-number variation (CNV) analysis of 2940 patients with SCZ and 2402 control subjects and identified a statistically significant association between SCZ and exonic CNVs in the ARHGAP10 gene. ARHGAP10 encodes a member of the RhoGAP superfamily of proteins that is involved in small GTPase signaling. This signaling pathway is one of the SCZ-associated pathways and may contribute to neural development and function. However, the ARHGAP10 gene is often confused with ARHGAP21, thus, the significance of ARHGAP10 in the molecular pathology of SCZ, including the expression profile of the ARHGAP10 protein, remains poorly understood. To address this issue, we focused on one patient identified to have both an exonic deletion and a missense variant (p.S490P) in ARHGAP10. The missense variant was found to be located in the RhoGAP domain and was determined to be relevant to the association between ARHGAP10 and the active form of RhoA. We evaluated ARHGAP10 protein expression in the brains of reporter mice and generated a mouse model to mimic the patient case. The model exhibited abnormal emotional behaviors, along with reduced spine density in the medial prefrontal cortex (mPFC). In addition, primary cultured neurons prepared from the mouse model brain exhibited immature neurites in vitro. Furthermore, we established induced pluripotent stem cells (iPSCs) from this patient, and differentiated them into tyrosine hydroxylase (TH)-positive neurons in order to analyze their morphological phenotypes. TH-positive neurons differentiated from the patient-derived iPSCs exhibited severe defects in both neurite length and branch number; these defects were restored by the addition of the Rho-kinase inhibitor, Y-27632. Collectively, our findings suggest that rare ARHGAP10 variants may be genetically and biologically associated with SCZ and indicate that Rho signaling represents a promising drug discovery target for SCZ treatment.