Monoallelic loss-of-function variants in GSK3B lead to autism and developmental delay

IF 9.6 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Senwei Tan, Qiumeng Zhang, Rui Zhan, Si Luo, Yaoling Han, Bin Yu, Candace Muss, Veronique Pingault, Sandrine Marlin, Andrée Delahaye, Sophia Peters, Claudia Perne, Martina Kreiß, Nino Spataro, Juan Pablo Trujillo-Quintero, Caroline Racine, Frederic Tran-Mau-Them, Chanika Phornphutkul, Aaron D. Besterman, Julian Martinez, Xiuxia Wang, Xiaoyu Tian, Siddharth Srivastava, David K. Urion, Jill A. Madden, Hind Al Saif, Michelle M. Morrow, Amber Begtrup, Xing Li, Sarah Jurgensmeyer, Peter Leahy, Shimin Zhou, Faxiang Li, Zhengmao Hu, Jieqiong Tan, Kun Xia, Hui Guo
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Abstract

De novo variants adjacent to the canonical splicing sites or in the well-defined splicing-related regions are more likely to impair splicing but remain under-investigated in autism spectrum disorder (ASD). By analyzing large, recent ASD genome sequencing cohorts, we find a significant burden of de novo potential splicing-disrupting variants (PSDVs) in 5048 probands compared to 4090 unaffected siblings. We identified 55 genes with recurrent de novo PSDVs that were highly intolerant to variation. Forty-six of these genes have not been strongly implicated in ASD or other neurodevelopmental disorders previously, including GSK3B. Through international, multicenter collaborations, we assembled genotype and phenotype data for 15 individuals with GSK3B variants and identified common phenotypes including developmental delay, ASD, sleeping disturbance, and aggressive behavior. Using available single-cell transcriptomic data, we show that GSK3B is enriched in dorsal progenitors and intermediate forms of excitatory neurons in the developing brain. We showed that Gsk3b knockdown in mouse excitatory neurons interferes with dendrite arborization and spine maturation which could not be rescued by de novo missense variants identified from affected individuals. In summary, our findings suggest that PSDVs may play an important role in the genetic etiology of ASD and allow for the prioritization of new ASD candidate genes. Importantly, we show that genetic variation resulting in GSK3B loss-of-function can lead to a neurodevelopmental disorder with core features of ASD and developmental delay.

Abstract Image

GSK3B 单倍功能缺失变异导致自闭症和发育迟缓
邻近规范剪接位点或明确剪接相关区域的从头变异更有可能损害剪接,但在自闭症谱系障碍(ASD)中,对这些变异的研究仍然不足。通过分析最近的大型 ASD 基因组测序队列,我们发现,与 4090 个未受影响的兄弟姐妹相比,5048 个疑似患者中存在大量从头产生的潜在剪接干扰变异(PSDVs)。我们发现 55 个基因反复出现新的 PSDV,这些基因对变异的耐受性很差。其中 46 个基因以前与 ASD 或其他神经发育障碍没有密切联系,包括 GSK3B。通过国际多中心合作,我们收集了 15 个 GSK3B 变异个体的基因型和表型数据,并确定了包括发育迟缓、ASD、睡眠障碍和攻击行为在内的常见表型。利用现有的单细胞转录组数据,我们发现 GSK3B 在发育中的大脑背侧祖细胞和中间形式的兴奋神经元中富集。我们发现,在小鼠兴奋性神经元中敲除 Gsk3b 会干扰树突分枝和棘突成熟,而从受影响个体中发现的从头错义变体无法挽救这一点。总之,我们的研究结果表明,PSDVs 可能在 ASD 的遗传病因学中扮演重要角色,并允许优先选择新的 ASD 候选基因。重要的是,我们发现导致 GSK3B 功能缺失的遗传变异可导致具有 ASD 核心特征和发育迟缓的神经发育障碍。
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来源期刊
Molecular Psychiatry
Molecular Psychiatry 医学-精神病学
CiteScore
20.50
自引率
4.50%
发文量
459
审稿时长
4-8 weeks
期刊介绍: Molecular Psychiatry focuses on publishing research that aims to uncover the biological mechanisms behind psychiatric disorders and their treatment. The journal emphasizes studies that bridge pre-clinical and clinical research, covering cellular, molecular, integrative, clinical, imaging, and psychopharmacology levels.
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