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. 

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

JOURNAL=Frontiers in Cellular Neuroscience

VOLUME=17

YEAR=2024

URL=https://www.frontiersin.org/journals/cellular-neuroscience/articles/10.3389/fncel.2023.1239069

DOI=10.3389/fncel.2023.1239069

ISSN=1662-5102

ABSTRACT=<p><italic>SCN2A</italic> is an autism spectrum disorder (ASD) risk gene and encodes a voltage-gated sodium channel. However, the impact of ASD-associated SCN2A <italic>de novo</italic> variants on human neuron development is unknown. We studied SCN2A using isogenic <italic>SCN2A</italic><sup>–/–</sup> induced pluripotent stem cells (iPSCs), and patient-derived iPSCs harboring a <italic>de novo</italic> R607* truncating variant. We used Neurogenin2 to generate excitatory (glutamatergic) neurons and found that <italic>SCN2A</italic><sup>+/<italic>R</italic>607*</sup> and <italic>SCN2A</italic><sup>–/–</sup> 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 <italic>de novo</italic> truncating <italic>SCN2A</italic> variant impairs the development of human neuronal function.</p>