Mutations in ASH1L confer susceptibility to Tourette syndrome.

Abstract

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.

• Authors: Shiguo Liu, Miaomiao Tian, Fan He, Jiani Li, Hong Xie, Wenmiao Liu, Yeting Zhang, Ru Zhang, Mingji Yi, Fengyuan Che, Xu Ma, Yi Zheng, Hao Deng, Guiju Wang, Lang Chen, Xue Sun, Yinglei Xu, Jingli Wang, Yucui Zang, Mengmeng Han, Xiuhai Wang, Hongzai Guan, Yinlin Ge, Chunmei Wu, Haiyan Wang, Hui Liang, Hui Li, Ni Ran, Zhaochuan Yang, Huanhuan Huang, Yanzhao Wei, Xueping Zheng, Xiangrong Sun, Xueying Feng, Lanlan Zheng, Tao Zhu, Wenhan Luo, Qinan Chen, Yuze Yan, Zuzhou Huang, Zhongcui Jing, Yixia Guo, Xuzhan Zhang, Christian P Schaaf, Jinchuan Xing, Chuanyue Wang, Fuli Yu, Ji-Song Guan
• Journal: Molecular psychiatry (Mol Psychiatry) Vol. 25 Issue 2 Pg. 476-490 (02 2020) ISSN: 1476-5578 [Electronic] England
• PMID: 31673123 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• DNA-Binding Proteins
• Transcription Factors
• ASH1L protein, human
• Ash1l protein, mouse
• Histone-Lysine N-Methyltransferase

Topics

• Adolescent
• Adult
• Animals
• Child
• Child, Preschool
• China
• DNA-Binding Proteins (genetics, metabolism)
• Family
• Female
• Genetic Predisposition to Disease (genetics)
• Histone-Lysine N-Methyltransferase (genetics, metabolism)
• Humans
• Male
• Mice
• Mice, Transgenic
• Middle Aged
• Mutation (genetics)
• Parents
• Tic Disorders (genetics)
• Tourette Syndrome (complications, genetics)
• Transcription Factors (genetics)
• Exome Sequencing (methods)