Chuang Yang-An, Hu Tsung-Ming, Chen Chia-Hsiang, Hsu Shih-Hsin, Tsai Hsin-Yao, Cheng Min-Chih
Department of Psychiatry, Yuli Mental Health Research Center, Yuli Branch, Taipei Veterans General Hospital, Hualien, Taiwan.
Department of Psychiatry, Chang Gung Memorial Hospital at Linkou and Department and Graduate School of Biomedical Sciences Chang Gung University, Taoyuan, Taiwan.
Schizophr Res. 2016 Oct;176(2-3):106-113. doi: 10.1016/j.schres.2016.07.019. Epub 2016 Jul 25.
Activity-regulated cytoskeleton-associated protein (ARC), which interacts with the N-methyl-d-aspartate receptor (NMDAR) complex, is a critical effector molecule downstream of multiple neuronal signaling pathways. Dysregulation of the ARC/NMDAR complex can disrupt learning, memory, and normal brain functions. This study examined the role of ARC in susceptibility to schizophrenia. We used a resequencing strategy to identify the variants of ARC in 1078 subjects, including patients with schizophrenia and normal controls. We identified 16 known SNPs and 27 rare mutations. SNP-based analysis showed no association of ARC with schizophrenia. In addition, the rare mutations did not increase the burden in patients compared with controls. However, one patient-specific allele in the putative ARC promoter region and seven patient-specific mutants in ARC exon regions significantly reduced the reporter gene activity compared with ARC wild-type. Methylation of a putative ARC promoter attenuated reporter activity in vitro, suggesting that ARC expression is regulated by DNA methylation. Pyrosequencing revealed eight hypermethylated CpG sites in the putative ARC promoter region in 64 schizophrenic patients compared with 63 controls. Taken together, our results suggest that both rare variants and epigenetic regulation of ARC contribute to the pathogenesis of schizophrenia in some patients.
活性调节细胞骨架相关蛋白（ARC）与N-甲基-D-天冬氨酸受体（NMDAR）复合物相互作用，是多个神经元信号通路下游的关键效应分子。ARC/NMDAR复合物的失调会破坏学习、记忆和正常脑功能。本研究探讨了ARC在精神分裂症易感性中的作用。我们采用重测序策略，在1078名受试者（包括精神分裂症患者和正常对照）中鉴定ARC的变异。我们鉴定出16个已知单核苷酸多态性（SNP）和27个罕见突变。基于SNP的分析显示ARC与精神分裂症无关联。此外，与对照组相比，罕见突变并未增加患者的负担。然而，与ARC野生型相比，在假定的ARC启动子区域中的一个患者特异性等位基因和ARC外显子区域中的七个患者特异性突变体显著降低了报告基因活性。假定的ARC启动子的甲基化在体外减弱了报告活性，表明ARC表达受DNA甲基化调节。焦磷酸测序显示，与63名对照相比，64名精神分裂症患者假定的ARC启动子区域中有8个高甲基化的CpG位点。综上所述，我们的结果表明，ARC的罕见变异和表观遗传调控在一些患者的精神分裂症发病机制中起作用。
