Mutations in ASH1L confer susceptibility to Tourette syndrome

Liu, Shiguo; Tian, Miaomiao; He, Fan; Li, Jiani; Xie, Hong; Liu, Wenmiao; Zhang, Yeting; Zhang, Ru; Man, Yi; Che, Fengyuan; Ma, Xu; Zheng, Yi; Deng, Hao; Wang, Guiju; Chen, Lang; Sun, Xue; Xu, Yinglei; Wang, Jingli; Zang, Yali; Han, Mengmeng; Wang, Xiuhai; Guan, Hongzai; Ge, Yubin; Wu, Chunmei; Wang, Haiyan; Liang, Hui; Li, Hui; Ni, Ran; Yang, Zhaochuan; Huang, Huanhuan; Wei, Yanzhao; Zheng, Xueping; Sun, Xiangrong; Feng, Xia; Zheng, Lanlan; Zhu, Τao; Luo, Wenhan; Chen, Qinan; Yan, Yuze; Huang, Zuzhou; Jing, Zhongcui; Guo, Yongli; Zhang, Xuzhan; Schaaf, Christian P.; Xing, Jinchuan; Wang, Chuanyue; Yu, Fuli; Guan, Ji

doi:10.1038/s41380-019-0560-8

Cited by 48 publications

(42 citation statements)

References 76 publications

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“…The heterozygous mutations in Ash1l , previously identified by whole exome sequencing (WES), are strongly enriched for variants likely to increase nervous system disease risk (Faundes et al., 2018), including TS, ASD, ADHD, multiple congenital malformation (MCA)/intellectual disability (ID), and SCZ (Cravedi et al., 2017; Kern et al., 2015; Liu et al., 2020; Okamoto et al., 2017; Penzes et al., 2013; Reay & Cairns, 2020; Satterstrom et al., 2019; Toro et al., 2010; Wang et al., 2016). Ash1l is a methyltransferase that catalyzes H3K36me2 at specific locations on the histone tail and plays a critical role in maintaining active gene expression (Gregory et al., 2007).…”

Section: Mutations In Ash1l Confer Susceptibility To Tourette Syndromementioning

confidence: 99%

“…We conducted WES of 100 TS‐affected trios to perform a de novo mutation analysis and RV‐TDT and identified candidate genes that increase the risk for TS (Liu et al., 2020). Overall, we found that 76 genes were likely associated with TS ( p value ≤ .05), and further screened five promising candidate genes that are intolerant to variants and highly expressed in the brain.…”

Section: Mutations In Ash1l Confer Susceptibility To Tourette Syndromementioning

confidence: 99%

“…Activity‐dependent spine maintenance or elimination is the most important factor for the remodeling of established neuronal circuits during postnatal and adolescence periods, thus, placing the early brain in a susceptible context (Sahin & Sur, 2015). Our research group identified mutations (p.S74L and p.Y2077F) in Ash1l of TS patients, resulting in defects in enzymatic activity and conferring susceptibility to TS (Liu et al., 2020). Furthermore, an Ash1l +/− mouse line has been created which exhibits tics and repetitive grooming behaviors that are rescued by haloperidol.…”

Section: Ash1l‐knockout Mouse As a Pathophysiological Model Of Tsmentioning

confidence: 99%

“…We first reported that mutations in Ash1l confer susceptibility to TS, underlying the significance of this gene in the molecular mechanism underlying TS (Liu et al., 2020). In addition to TS, Ash1l has been assumed to play a pathogenic role in other, more common neuropsychiatric illnesses.…”

Section: Introductionmentioning

confidence: 99%

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Role of Ash1l in Tourette syndrome and other neurodevelopmental disorders

Zhang

Zheng

et al. 2020

Developmental Neurobiology

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Ash1l potentially contributes to neurodevelopmental diseases. Although specific Ash1l mutations are rare, they have led to informative studies in animal models that may bring therapeutic advances. Ash1l is highly expressed in the brain and correlates with the neuropathology of Tourette syndrome (TS), autism spectrum disorder, and intellectual disability during development, implicating shared epigenetic factors and overlapping neuropathological mechanisms. Functional convergence of Ash1l generated several significant signaling pathways: chromatin remodeling and transcriptional regulation, protein synthesis and cellular metabolism, and synapse development and function. Here, we systematically review the literature on Ash1l, including its discovery, expression, function, regulation, implication in the nervous system, signaling pathway, mutations, and putative involvement in TS and other neurodevelopmental traits. Such findings highlight Ash1l pleiotropy and the necessity of transcending a single gene to complicated mechanisms of network convergence underlying these diseases. With the progress in functional genomic analysis (highlighted in this review), and although the importance and necessity of Ash1l becomes increasingly apparent in the medical field, further research is required to discover the precise function and molecular regulatory mechanisms related to Ash1l. Thus, a new perspective is proposed for basic scientific research and clinical interventions for cross‐disorder diseases.

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Section: Mutations In Ash1l Confer Susceptibility To Tourette Syndromementioning

confidence: 99%

Section: Mutations In Ash1l Confer Susceptibility To Tourette Syndromementioning

confidence: 99%

Section: Ash1l‐knockout Mouse As a Pathophysiological Model Of Tsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Role of Ash1l in Tourette syndrome and other neurodevelopmental disorders

Zhang

Zheng

et al. 2020

Developmental Neurobiology

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“…After whole exome sequencing of 100 trios (TS patients and their parents), point mutations in ASH1 Like Histone Lysine Methyltransferase (ASH1L) causing defects in its enzymatic activity were identified as a susceptibility gene for TS 9 , previously associated with mental retardation and autism. A transgenic mouse line (Ash1l heterozygous mice) indeed displayed tic-like motor and compulsive behaviors, and dopaminergic hyperinnervation was observed in the dorsal striatum, demonstrating good construct validity for this model.…”

Section: Etiologymentioning

confidence: 99%

Tourette syndrome research highlights from 2019

Hartmann¹,

Worbe²,

Black³

2020

F1000Res

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This is the sixth yearly article in the Tourette Syndrome Research Highlights series, summarizing research from 2019 relevant to Tourette syndrome and other tic disorders. The highlights from 2020 is being drafted on the Authorea online authoring platform; readers are encouraged to add references or give feedback on our selections comments feature on this page. After the calendar year ends, this article is submitted as the annual update for the Tics collection F1000Research.

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Rare variants in the outcome of social skills group training for autism

Olsson

Becker

et al. 2021

Autism Research

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Exome sequencing has been proposed as the first-tier genetic testing in autism spectrum disorder (ASD). Here, we performed exome sequencing in autistic individuals with average to high intellectual abilities (N = 207) to identify molecular diagnoses and genetic modifiers of intervention outcomes of social skills group training (SSGT) or standard care. We prioritized variants of clinical significance (VCS), variants of uncertain significance (VUS) and generated a pilot scheme to calculate genetic scores of rare and common variants in ASD-related gene pathways. Mixed linear models were used to test the association between the carrier status of VCS/VUS or the genetic scores with intervention outcomes measured by the social responsiveness scale. Additionally, we combined behavioral and genetic features using a machine learning (ML) model to predict the individual response. We showed a rate of 4.4% and 11.3% of VCS and VUS in the cohort, respectively. Individuals with VCS or VUS had improved significantly less after standard care than non-carriers at post-intervention (β = 9.35; p = 0.036), while no such association was observed for SSGT (β = À2.50; p = 0.65). Higher rare variant genetic scores for synaptic transmission and regulation of transcription from RNA polymerase II were separately associated with less beneficial (β = 8.30, p = 0.0044) or more beneficial (β = À6.79, p = 0.014) effects after SSGT compared with standard care at follow-up, respectively. Our ML model showed the importance of rare variants for outcome prediction. Further studies are needed to understand genetic predisposition to intervention outcomes in ASD. Lay SummarySocial skills group training is one of the most common behavior interventions aiming at autistic children and adolescents, but the outcome varies between Sven Bölte and Kristiina Tammimies contributed equally to this study.

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Mutations in ASH1L confer susceptibility to Tourette syndrome

Cited by 48 publications

References 76 publications

Role of Ash1l in Tourette syndrome and other neurodevelopmental disorders

Role of Ash1l in Tourette syndrome and other neurodevelopmental disorders

Tourette syndrome research highlights from 2019

Rare variants in the outcome of social skills group training for autism

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