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Genetic variants in  SCN2A , encoding the Na V 1.2 voltage-gated sodium channel, are associated with a range of neurodevelopmental disorders with overlapping phenotypes. Some variants fit into a framework wherein gain-of-function missense variants that increase neuronal excitability lead to developmental and epileptic encephalopathy, while loss-of-function variants that reduce neuronal excitability lead to intellectual disability and/or autism spectrum disorder (ASD) with or without co-morbid seizures. One unique case less easily classified using this framework is the  de novo  missense variant  SCN2A -p.K1422E, associated with infant-onset developmental delay, infantile spasms and features of ASD. Prior structure–function studies demonstrated that K1422E substitution alters ion selectivity of Na V 1.2, conferring Ca 2+  permeability, lowering overall conductance and conferring resistance to tetrodotoxin (TTX). Based on heterologous expression of K1422E, we developed a compartmental neuron model incorporating variant channels that predicted reductions in peak action potential (AP) speed. We generated  Scn2a   K1422E   mice and characterized effects on neurons and neurological/neurobehavioral phenotypes. Cultured cortical neurons from heterozygous  Scn2a   K1422E/+   mice exhibited lower current density with a TTX-resistant component and reversal potential consistent with mixed ion permeation. Recordings from  Scn2a   K1442E/+   cortical slices demonstrated impaired AP initiation and larger Ca 2+  transients at the axon initial segment during the rising phase of the AP, suggesting complex effects on channel function.  Scn2a   K1422E/+   mice exhibited rare spontaneous seizures, interictal electroencephalogram abnormalities, altered induced seizure thresholds, reduced anxiety-like behavior and alterations in olfactory-guided social behavior. Overall,  Scn2a   K1422E/+   mice present with phenotypes similar yet distinct from other  Scn2a  models, consistent with complex effects of K1422E on Na V 1.2 channel function.

Cellular and behavioral effects of altered Na V 1.2 sodium channel ion permeability in Scn2a K1422E mice