IQSEC2 mutation associated with epilepsy, intellectual disability, and autism results in hyperexcitability of patient-derived neurons and deficient synaptic transmission

Abstract

Mutations in the IQSEC2 gene are associated with drug-resistant, multifocal infantile and childhood epilepsy; autism; and severe intellectual disability (ID). We used induced pluripotent stem cell (iPSC) technology to obtain hippocampal neurons to investigate the neuropathology of IQSEC2-mediated disease. The neurons were characterized at three-time points during differentiation to assess developmental progression. We showed that immature IQSEC2 mutant dentate gyrus (DG) granule neurons were extremely hyperexcitable, exhibiting increased sodium and potassium currents compared to those of CRISPR-Cas9-corrected isogenic controls, and displayed dysregulation of genes involved in differentiation and development. Immature IQSEC2 mutant cultured neurons exhibited a marked reduction in the number of inhibitory neurons, which contributed further to hyperexcitability. As the mutant neurons aged, they became hypoexcitable, exhibiting reduced sodium and potassium currents and a reduction in the rate of synaptic and network activity, and showed dysregulation of genes involved in synaptic transmission and neuronal differentiation. Mature IQSEC2 mutant neurons were less viable than wild-type mature neurons and had reduced expression of surface AMPA receptors. Our studies provide mechanistic insights into severe infantile epilepsy and neurodevelopmental delay associated with this mutation and present a human model for studying IQSEC2 mutations in vitro.

The Role of Microtubule Associated Serine/Threonine Kinase 3 Variants in Neurodevelopmental Diseases: Genotype-Phenotype Association

“…From the co-expression analysis, nine DEE/NDD genes ( SYNGAP1, SYN1, IQSEC2, DNM1, PACS1, STXBP1, GRIN1, STX1B, and KIF1A ) were highly correlated with MAST3 . Known NDD and/or EE genes, such as IQSEC2, DNM1 , and STX1B , have all been proved to play a role in vital synaptic functions, such as synaptic vesicle recycling, excitatory synaptic transmission, and calcium-dependent synaptic vesicle release in neurodevelopment ( Smirnova et al, 1996 ; Boumil et al, 2010 ; Brant et al, 2021 ). The mutants of these genes could cause synaptic deficit and be associated with NDD and/or EE.…”

Current progress in understanding Schizophrenia using genomics and pluripotent stem cells: A Meta-analytical overview

“…Since its discovery in the previous decade (Takahashi and Yamanaka 2006), iPSC technology has been utilized to model a variety of diseases, including neurodegenerative and neuropsychiatric disorders(Stern, Sarkar, Galor, et al 2020; Stern, Sarkar, Stern, et al 2020; Stern, Zhang, et al 2022; Brant et al 2021; Quraishi et al 2019; Stern, Lau, et al 2022; Rowe and Daley 2019). It has a considerable advantage in the research of fundamental mechanisms and pathways affecting neuropsychiatric illnesses such as SCZ, BD, and ASD that are otherwise difficult to model due to a lack of causative genes (Soliman et al 2017; Stern, Sarkar, Stern, et al 2020; De Los Angeles et al 2021).…”

Monozygotic twins discordant for schizophrenia differ in maturation and synaptic transmission

“…iPSC reprogramming and neuron differentiation iPSCs were derived from fibroblasts for control and schizophrenia patients using the Cyto-Tune Sendai reprogramming kit (Invitrogen) according to the manufacturer's instructions. iPSCs were characterized for a normal karyotype as well as for pluripotency markers as previously described 37 . iPSC colonies were cultured on Matrigel-coated plates using mTeSR medium (StemCell Technologies).…”