Distinct Pathogenic Genes Causing Intellectual Disability and Autism Exhibit a Common Neuronal Network Hyperactivity Phenotype.,Cell Reports

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Distinct Pathogenic Genes Causing Intellectual Disability and Autism Exhibit a Common Neuronal Network Hyperactivity Phenotype.
Cell Reports ( IF 7.5 ) Pub Date : 2020-01-07 , DOI: 10.1016/j.celrep.2019.12.002
Monica Frega ₁ , Martijn Selten ₂ , Britt Mossink ₃ , Jason M Keller ₃ , Katrin Linda ₃ , Rebecca Moerschen ₃ , Jieqiong Qu ₄ , Pierre Koerner ₄ , Sophie Jansen ₂ , Astrid Oudakker ₁ , Tjitske Kleefstra ₃ , Hans van Bokhoven ₁ , Huiqing Zhou ₅ , Dirk Schubert ₂ , Nael Nadif Kasri ₁

Affiliation

Pathogenic mutations in either one of the epigenetic modifiers EHMT1, MBD5, MLL3, or SMARCB1 have been identified to be causative for Kleefstra syndrome spectrum (KSS), a neurodevelopmental disorder with clinical features of both intellectual disability (ID) and autism spectrum disorder (ASD). To understand how these variants lead to the phenotypic convergence in KSS, we employ a loss-of-function approach to assess neuronal network development at the molecular, single-cell, and network activity level. KSS-gene-deficient neuronal networks all develop into hyperactive networks with altered network organization and excitatory-inhibitory balance. Interestingly, even though transcriptional data reveal distinct regulatory mechanisms, KSS target genes share similar functions in regulating neuronal excitability and synaptic function, several of which are associated with ID and ASD. Our results show that KSS genes mainly converge at the level of neuronal network communication, providing insights into the pathophysiology of KSS and phenotypically congruent disorders.

中文翻译：

导致智力残疾和自闭症的独特致病基因表现出常见的神经元网络活动过度表型。

表观遗传修饰因子EHMT1，MBD5，MLL3或SMARCB1中的任何一种的致病突变已被确定是导致Kleefstra综合征谱（KSS）的病因，Kleefstra综合征谱是一种具有智力障碍（ID）和自闭症谱障碍（ASD）临床特征的神经发育障碍）。为了了解这些变体如何导致KSS的表型趋同，我们采用功能丧失方法在分子，单细胞和网络活动水平上评估神经元网络的发育。缺乏KSS基因的神经元网络都发展成为具有改变的网络组织和兴奋抑制平衡的活动过度网络。有趣的是，即使转录数据显示出不同的调节机制，KSS靶基因在调节神经元兴奋性和突触功能方面也具有相似的功能，其中一些与ID和ASD相关联。我们的结果表明，KSS基因主要集中在神经元网络交流的水平上，从而为了解KSS的病理生理学和表型一致的疾病提供了见识。

更新日期：2020-01-07

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