Journal
MOLECULAR PSYCHIATRY
Volume 25, Issue 2, Pages 476-490Publisher
SPRINGERNATURE
DOI: 10.1038/s41380-019-0560-8
Keywords
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Funding
- National Natural Science Foundation (NSFC) [81371499, 31671104, 81471365, 31970903, 31371059]
- National Key Research and Development Program of China [2016YFC1000307]
- National Basic Research Program of China [2013CB835100]
- Beijing Municipal Education Commission [BIBD-PXM2013_014226_07_000084]
- Beijing Natural Science Foundation [7132083]
- Shandong Provincial Natural Science Foundation of China [ZR2019PH072]
- NSFC [61621136008]
- German Research Foundation (DFG) [TRR-169]
- National Institutes of Health [R01HG008115]
- National Human Genome Research Institute [R01HG008115]
- Joan and Stanford Alexander Family
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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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