Distinct pathogenic genes causing intellectual disability and autism exhibit a common neuronal network hyperactivity phenotype

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 employed 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 developed into hyperactive networks with altered network organization and excitatory-inhibitory balance. Interestingly, even though transcriptional data revealed 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 new insights into the pathophysiology of KSS and phenotypically congruent disorders.

现已确认，表观遗传调控因子（epigenetic modifiers）EHMT1、MBD5、MLL3或SMARCB1中任意一个发生致病性突变，均可引发克莱夫斯特拉综合征谱系（Kleefstra syndrome spectrum, KSS）——一种兼具智力障碍（intellectual disability, ID）与孤独症谱系障碍（autism spectrum disorder, ASD）临床特征的神经发育障碍。为阐明此类变异如何导致KSS的表型趋同，本研究采用功能缺失（loss of function）策略，从分子、单细胞及网络活动层面评估神经元网络的发育进程。KSS基因缺陷型神经元网络均发育为网络结构异常、兴奋-抑制平衡失调的过度活跃网络。有趣的是，尽管转录数据（transcriptional data）显示不同基因的调控机制存在显著差异，但KSS靶基因在调控神经元兴奋性与突触功能方面具有相似的功能，其中多个基因与ID及ASD密切相关。本研究结果表明，KSS相关基因主要在神经元网络通信层面发生功能趋同，为KSS及其表型一致疾病的病理生理学机制提供了全新的研究视角。