| First Author | Liu S | Year | 2020 |
| Journal | Mol Psychiatry | Volume | 25 |
| Issue | 2 | Pages | 476-490 |
| PubMed ID | 31673123 | Mgi Jnum | J:351300 |
| Mgi Id | MGI:7660993 | Doi | 10.1038/s41380-019-0560-8 |
| Citation | Liu S, et al. (2020) Mutations in ASH1L confer susceptibility to Tourette syndrome. Mol Psychiatry 25(2):476-490 |
| abstractText | 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. |
