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Liu, Shiguo; Tian, Miaomiao; He, Fan; Li, Jiani; Xie, Hong; Liu, Wenmiao; Zhang, Yeting; Zhang, Ru; Yi, Mingji; Che, Fengyuan; Ma, Xu; Zheng, Yi; Deng, Hao; Wang, Guiju; Chen, Lang; Sun, Xue; Xu, Yinglei; Wang, Jingli; Zang, Yucui; Han, Mengmeng; Wang, Xiuhai; Guan, Hongzai; Ge, Yinlin; Wu, Chunmei; Wang, Haiyan; Liang, Hui; Li, Hui; Ran, Ni; Yang, Zhaochuan; Huang, Huanhuan; Wei, Yanzhao; Zheng, Xueping; Sun, Xiangrong; Feng, Xueying; Zheng, Lanlan; Zhu, Tao; Luo, Wenhan; Chen, Qinan; Yan, Yuze; Huang, Zuzhou; Jing, Zhongcui; Guo, Yixia; Zhang, Xuzhan; Schaaf, Christian P; Xing, Jinchuan; Wang, Chuanyue; Yu, Fuli; Guan, Ji-Song
Molecular psychiatry, 02/2020, Volume: 25, Issue: 2Journal Article
Tourette syndrome (TS) is a childhood-onset neuropsychiatric disorder characterized by repetitive motor movements and vocal tics. The clinical manifestations of TS are complex and often overlap with other neuropsychiatric disorders. TS is highly heritable; however, the underlying genetic basis and molecular and neuronal mechanisms of TS remain largely unknown. We performed whole-exome sequencing of a hundred trios (probands and their parents) with detailed records of their clinical presentations and identified a risk gene, ASH1L, that was both de novo mutated and associated with TS based on a transmission disequilibrium test. As a replication, we performed follow-up targeted sequencing of ASH1L in additional 524 unrelated TS samples and replicated the association (P value = 0.001). The point mutations in ASH1L cause defects in its enzymatic activity. Therefore, we established a transgenic mouse line and performed an array of anatomical, behavioral, and functional assays to investigate ASH1L function. The Ash1l mice manifested tic-like behaviors and compulsive behaviors that could be rescued by the tic-relieving drug haloperidol. We also found that Ash1l disruption leads to hyper-activation and elevated dopamine-releasing events in the dorsal striatum, all of which could explain the neural mechanisms for the behavioral abnormalities in mice. Taken together, our results provide compelling evidence that ASH1L is a TS risk gene.
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