Mutations in ASH1L confer susceptibility to Tourette syndrome

doi:10.1038/s41380-019-0560-8

	Mutations in ASH1L confer susceptibility to Tourette syndrome
	Liu, Shiguo 1,2; Tian, Miaomiao 3,4; He, Fan 5,6,7; Li, Jiani 8; Xie, Hong 4,9,10; Liu, Wenmiao 1,2; Zhang, Yeting 11; Zhang, Ru 1,2; Yi, Mingji 12; Che, Fengyuan 13; Ma, Xu 14; Zheng, Yi 5,6,7; Deng, Hao 15,16; Wang, Guiju 17; Chen, Lang 18; Sun, Xue 19; Xu, Yinglei 1,2; Wang, Jingli 1,2; Zang, Yucui 1,2; Han, Mengmeng 1,2; Wang, Xiuhai 20; Guan, Hongzai 21; Ge, Yinlin 22; Wu, Chunmei 21; Wang, Haiyan 23; Liang, Hui 24; Li, Hui 25; Ran, Ni 12; Yang, Zhaochuan 12; Huang, Huanhuan 5,6,7; Wei, Yanzhao 5,6,7; Zheng, Xueping 26; Sun, Xiangrong 1,2; Feng, Xueying 12; Zheng, Lanlan 27; Zhu, Tao 3,31,32; Luo, Wenhan3,4 ; Chen, Qinan4 ; Yan, Yuze3,4 ; Huang, Zuzhou 23; Jing, Zhongcui 23; Guo, Yixia 12; Zhang, Xuzhan 25; Schaaf, Christian P.28,29; Xing, Jinchuan 11; Wang, Chuanyue 5,6,7; Yu, Fuli 8; Guan, Ji-Song4,30
	2020-02
发表期刊	MOLECULAR PSYCHIATRY (IF:9.6[JCR-2023],11.1[5-Year])
ISSN	1359-4184
EISSN	1476-5578
卷号	25 期号:2 页码:476-490
发表状态	已发表
DOI	10.1038/s41380-019-0560-8
摘要	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.
收录类别	SCI ; SCIE ; SSCI
语种	英语
资助项目	National Human Genome Research Institute[R01HG008115]
WOS研究方向	Biochemistry & Molecular Biology ; Neurosciences & Neurology ; Psychiatry
WOS类目	Biochemistry & Molecular Biology ; Neurosciences ; Psychiatry
WOS记录号	WOS:000510855100018
出版者	NATURE PUBLISHING GROUP
WOS关键词	DE-NOVO MUTATIONS ; AUTISM ; PREVALENCE ; TICS ; RISK ; GENE ; RARE ; BEHAVIORS ; CHILDREN ; DOPAMINE
原始文献类型	Article
引用统计	正在获取...
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/105315
专题	生命科学与技术学院_博士生生命科学与技术学院_PI研究组_管吉松组
通讯作者	Wang, Chuanyue; Yu, Fuli; Guan, Ji-Song
作者单位	1.Qingdao Univ, Affiliated Hosp, Dept Med Genet, Qingdao, Peoples R China 2.Qingdao Univ, Affiliated Hosp, Prenatal Diag Ctr, Qingdao, Peoples R China 3.Tsinghua Univ, IDG McGovern Inst Brain Res, Sch Life Sci, Beijing, Peoples R China 4.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China 5.Capital Med Univ, Beijing Anding Hosp, Natl Clin Res Ctr Mental Disorders, Beijing, Peoples R China 6.Capital Med Univ, Beijing Anding Hosp, Beijing Key Lab Mental Disorders, Beijing, Peoples R China 7.Capital Med Univ, Beijing Anding Hosp, Beijing Inst Brain Disorders Ctr Schizophrenia, Beijing, Peoples R China 8.Baylor Coll Med, Dept Mol & Human Genet, Human Genome Sequencing Ctr, Houston, TX 77030 USA 9.Inst Brain Intelligence Technol, Zhangjiang Lab, Shanghai 201210, Peoples R China 10.Shanghai Res Ctr Brain Sci & Brain Inspired Intel, Shanghai 201210, Peoples R China 11.Rutgers State Univ, Human Genet Inst New Jersey, Dept Genet, Piscataway, NJ USA 12.Qingdao Univ, Affiliated Hosp, Dev Behav Pediat Dept, Qingdao, Peoples R China 13.Linyi Peoples Hosp, Dept Neurol, Linyi, Shandong, Peoples R China 14.Natl Res Inst Family Planning, Beijing, Peoples R China 15.Cent S Univ, Xiangya Hosp 3, Ctr Med Expt, Changsha, Peoples R China 16.Cent S Univ, Xiangya Hosp 3, Dept Neurol, Changsha, Peoples R China 17.Rizhao Peoples Hosp, Child Healthcare Dept, Rizhao, Peoples R China 18.Fujian Med Univ, Prov Clin Med Coll, Fujian Prov Hosp, Dept Pediat, Fuzhou, Peoples R China 19.Qingdao Univ, Dept Med Record, Affiliated Hosp, Qingdao, Peoples R China 20.Qingdao Univ, Dept Biol, Qingdao, Peoples R China 21.Qingdao Univ, Dept Clin Lab Diag, Qingdao, Peoples R China 22.Qingdao Univ, Dept Biochem & Mol Biol, Qingdao, Peoples R China 23.Qingdao Univ, Dept Blood Transfus, Affiliated Hosp, Qingdao, Peoples R China 24.Qingdao Univ, Dept Publ Hlth, Qingdao, Peoples R China 25.Qingdao Univ, Phys Examinat Ctr, Affiliated Hosp, Qingdao, Peoples R China 26.Qingdao Univ, Dept Neurol, Affiliated Hosp, Qingdao, Peoples R China 27.Third Hosp Chaoyang Dist Beijing, Dept Psychiat, Beijing, Peoples R China 28.Baylor Coll Med, Dept Mol & Human Genet, Dept Genet, Houston, TX 77030 USA 29.Texas Childrens Hosp, Jan & Dan Duncan Neurol Res Inst, Houston, TX 77030 USA 30.Chinese Acad Sci, CAS Ctr Excellence Brain Sci & Intelligence Techn, Shanghai 200031, Peoples R China 31.Chinese Acad Med Sci, Inst Lab Anim Sci, Beijing, Peoples R China 32.Peking Union Med Coll, Comparat Med Ctr, Beijing, Peoples R China
通讯作者单位	生命科学与技术学院
推荐引用方式 GB/T 7714	Liu, Shiguo,Tian, Miaomiao,He, Fan,et al. Mutations in ASH1L confer susceptibility to Tourette syndrome[J]. MOLECULAR PSYCHIATRY,2020,25(2):476-490.
APA	Liu, Shiguo.,Tian, Miaomiao.,He, Fan.,Li, Jiani.,Xie, Hong.,...&Guan, Ji-Song.(2020).Mutations in ASH1L confer susceptibility to Tourette syndrome.MOLECULAR PSYCHIATRY,25(2),476-490.
MLA	Liu, Shiguo,et al."Mutations in ASH1L confer susceptibility to Tourette syndrome".MOLECULAR PSYCHIATRY 25.2(2020):476-490.