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Disruption of the autism-associated gene SCN2A alters synaptic development and neuronal signaling in patient iPSC-glutamatergic neurons

By Chad O. Brown, Jarryll Uy, Nadeem Murtaza, Elyse Rosa, Alexandria Afonso, Sansi Xing, Biren M. Dave, Savannah Kilpatrick, Annie A. Cheng, Sean H White, Jennifer Howe, Stephen W. Scherer, Yu Lu, Karun K Singh

Posted 15 Sep 2021
bioRxiv DOI: 10.1101/2021.09.14.460368

SCN2A is an autism spectrum disorder (ASD) risk gene and encodes a voltage-gated sodium channel. However, the impact of autism-associated SCN2A de novo variants on human neuron development is unknown. We studied SCN2A using isogenic SCN2A-/- induced pluripotent stem cells (iPSCs), and patient-derived iPSCs harboring a p.R607* or a C-terminal p.G1744* de novo truncating variant. We used Neurogenin2 to generate excitatory glutamatergic neurons and found that SCN2A+/p.R607* and SCN2A-/- neurons displayed a reduction in synapse formation and excitatory synaptic activity using multielectrode arrays and electrophysiology. However, the p.G1744* variant, which leads to early-onset seizures in addition to ASD, altered action-potential dynamics but not synaptic activity. Proteomic and functional analysis of SCN2A+/p.R607* neurons revealed defects in neuronal morphology and bioenergetic pathways, which were not present in SCN2A+/p.G1744* neurons. Our study reveals that SCN2A de novo variants can have differential impact on human neuron function and signaling.

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