Mutations in ASH1L confer susceptibility to Tourette syndrome.,Molecular Psychiatry

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Mutations in ASH1L confer susceptibility to Tourette syndrome.
Molecular Psychiatry ( IF 9.6 ) Pub Date : 2019-10-31 , DOI: 10.1038/s41380-019-0560-8
Shiguo Liu _{1,

2} , Miaomiao Tian _{3,

4} , Fan He ₅ , Jiani Li ₆ , Hong Xie _{4,

7} , Wenmiao Liu _{1,

2} , Yeting Zhang ₈ , Ru Zhang _{1,

2} , Mingji Yi ₉ , Fengyuan Che ₁₀ , Xu Ma ₁₁ , Yi Zheng ₅ , Hao Deng ₁₂ , Guiju Wang ₁₃ , Lang Chen ₁₄ , Xue Sun ₁₅ , Yinglei Xu _{1,

2} , Jingli Wang _{1,

2} , Yucui Zang _{1,

2} , Mengmeng Han _{1,

2} , Xiuhai Wang ₁₆ , Hongzai Guan ₁₇ , Yinlin Ge ₁₈ , Chunmei Wu ₁₇ , Haiyan Wang ₁₉ , Hui Liang ₂₀ , Hui Li ₂₁ , Ni Ran ₉ , Zhaochuan Yang ₉ , Huanhuan Huang ₅ , Yanzhao Wei ₅ , Xueping Zheng ₂₂ , Xiangrong Sun _{1,

2} , Xueying Feng ₉ , Lanlan Zheng ₂₃ , Tao Zhu _{3,

24} , Wenhan Luo _{3,

4} , Qinan Chen ₄ , Yuze Yan _{3,

4} , Zuzhou Huang ₁₉ , Zhongcui Jing ₁₉ , Yixia Guo ₉ , Xuzhan Zhang ₂₁ , Christian P Schaaf ₂₅ , Jinchuan Xing ₈ , Chuanyue Wang ₅ , Fuli Yu ₆ , Ji-Song Guan _{4,

26}

Affiliation

Medical Genetic Department, The Affiliated Hospital of Qingdao University, Qingdao, China.
The Prenatal Diagnosis Center, The Affiliated Hospital of Qingdao University, Qingdao, China.
School of Life Sciences, IDG/McGovern Institute for Brain Research, Tsinghua University, Beijing, China.
School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China.
The National Clinical Research Center for Mental Disorders & Beijing Key Laboratory of Mental Disorders & Beijing Institute for Brain Disorders Center of Schizophrenia, Beijing Anding Hospital, Capital Medical University, Beijing, China.
Human Genome Sequencing Center, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
Institute of Brain-Intelligence Technology, Zhangjiang Laboratory & Shanghai Research Center for Brain Science and Brain-Inspired Intelligence, Shanghai, 201210, China.
Department of Genetics, Human Genetics Institute of New Jersey, Rutgers, The State University of New Jersey, Piscataway, NJ, USA.
Developmental Behavioral Pediatric Department, The Affiliated Hospital of Qingdao University, Qingdao, China.
Department of Neurology, Linyi People's Hospital, Linyi, China.
National Research Institute for Family Planning, Beijing, China.
Center for Experimental Medicine & Department of Neurology, The Third Xiangya Hospital, Central South University, Changsha, China.
Child Healthcare Department, Rizhao people's Hospital, Rizhao, China.
Department of Pediatrics, Fujian Provincial Hospital, Provincial Clinical Medical College Affiliated to Fujian Medical University, Fuzhou, China.
Department of Medical Record, The Affiliated Hospital of Qingdao University, Qingdao, China.
Department of Biology, Qingdao University, Qingdao, China.
Department of Clinical Laboratory Diagnosis, Qingdao University, Qingdao, China.
Department of Biochemistry and Molecular Biology, Qingdao University, Qingdao, China.
Department of Blood Transfusion, The Affiliated Hospital of Qingdao University, Qingdao, China.
Department of Public Health, Qingdao University, Qingdao, China.
Physical Examination Center, The Affiliated Hospital of Qingdao University, Qingdao, China.
Department of Neurology, The Affiliated Hospital of Qingdao University, Qingdao, China.
Department of Psychiatry, The Third Hospital of Chaoyang District of Beijing, Beijing, China.
Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Comparative Medical Center, Peking Union Medical College, Beijing, China.
Department of Molecular and Human Genetics, Baylor College of Medicine, Department of Genetics; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA.
CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, 200031, China.

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.

中文翻译：

ASH1L 中的突变赋予了对图雷特综合征的易感性。

Tourette 综合征 (TS) 是一种儿童期发病的神经精神疾病，其特征是重复性运动和发声抽动。TS的临床表现复杂，常与其他神经精神疾病重叠。TS具有高度遗传性；然而，TS 的潜在遗传基础以及分子和神经元机制仍然很大程度上未知。我们对一百个三人组（先证者及其父母）进行了全外显子组测序，并详细记录了他们的临床表现，并根据传播不平衡测试确定了一个风险基因 ASH1L，该基因既是从头突变又与 TS 相关。作为复制，我们在另外 524 个不相关的 TS 样本中对 ASH1L 进行了后续靶向测序，并复制了关联（P 值 = 0.001）。ASH1L 中的点突变导致其酶活性缺陷。因此，我们建立了一个转基因小鼠系，并进行了一系列解剖学、行为学和功能分析来研究 ASH1L 的功能。Ash1l+/- 小鼠表现出类似抽动的行为和强迫行为，可以通过缓解抽动的药物氟哌啶醇来挽救。我们还发现，Ash1l 破坏导致背侧纹状体过度激活和多巴胺释放事件增加，所有这些都可以解释小鼠行为异常的神经机制。总之，我们的结果提供了令人信服的证据，表明 ASH1L 是 TS 风险基因。Ash1l+/- 小鼠表现出类似抽动的行为和强迫行为，可以通过缓解抽动的药物氟哌啶醇来挽救。我们还发现 Ash1l 破坏导致背侧纹状体过度激活和多巴胺释放事件增加，所有这些都可以解释小鼠行为异常的神经机制。总之，我们的结果提供了令人信服的证据，表明 ASH1L 是 TS 风险基因。Ash1l+/- 小鼠表现出类似抽动的行为和强迫行为，可以通过缓解抽动的药物氟哌啶醇来挽救。我们还发现 Ash1l 破坏导致背侧纹状体过度激活和多巴胺释放事件增加，所有这些都可以解释小鼠行为异常的神经机制。总之，我们的结果提供了令人信服的证据，表明 ASH1L 是 TS 风险基因。

更新日期：2019-11-01

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