Distinct pathogenic genes causing intellectual disability and autism exhibit a common neuronal network hyperactivity phenotype
Description
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.
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Steps to reproduce
All the individual data points of the main figures are in the excel sheet: Main figures_raw data.xlsx All the individual data points of the supplementary figures are in the excel sheet: Supplementary figures_raw data.xlsx