Author:
Brown Chad O.,Uy Jarryll A.,Murtaza Nadeem,Rosa Elyse,Alfonso Alexandria,Dave Biren M.,Kilpatrick Savannah,Cheng Annie A.,White Sean H.,Scherer Stephen W.,Singh Karun K.
Abstract
SCN2A is an autism spectrum disorder (ASD) risk gene and encodes a voltage-gated sodium channel. However, the impact of ASD-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 de novo R607* truncating variant. We used Neurogenin2 to generate excitatory (glutamatergic) neurons and found that SCN2A+/R607* and SCN2A–/– neurons displayed a reduction in synapse formation and excitatory synaptic activity. We found differential impact on actional potential dynamics and neuronal excitability that reveals a loss-of-function effect of the R607* variant. Our study reveals that a de novo truncating SCN2A variant impairs the development of human neuronal function.
Subject
Cellular and Molecular Neuroscience