Cellular and behavioral effects of altered NaV1.2 sodium channel ion permeability in Scn2aK1422Emice

Dennis M. Echevarria-Cooper, Nicole A. Hawkins, Sunita N. Misra, Alexandra M. Huffman, Tyler Thaxton, Christopher H. Thompson, Roy Ben-Shalom, Andrew D. Nelson, Anna M. Lipkin, Alfred L. George, Kevin J. Bender, Jennifer A. Kearney

Research output: Contribution to journalArticlepeer-review

8 Scopus citations


Genetic variants in SCN2A, encoding the NaV1.2 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 NaV1.2, conferring Ca2+ 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 Scn2aK1422E mice and characterized effects on neurons and neurological/neurobehavioral phenotypes. Cultured cortical neurons from heterozygous Scn2aK1422E/+ mice exhibited lower current density with a TTX-resistant component and reversal potential consistent with mixed ion permeation. Recordings from Scn2aK1442E/+ cortical slices demonstrated impaired AP initiation and larger Ca2+ transients at the axon initial segment during the rising phase of the AP, suggesting complex effects on channel function. Scn2aK1422E/+ mice exhibited rare spontaneous seizures, interictal electroencephalogram abnormalities, altered induced seizure thresholds, reduced anxiety-like behavior and alterations in olfactory-guided social behavior. Overall, Scn2aK1422E/+ mice present with phenotypes similar yet distinct from other Scn2a models, consistent with complex effects of K1422E on NaV1.2 channel function.

Original languageEnglish (US)
Pages (from-to)2964-2988
Number of pages25
JournalHuman molecular genetics
Issue number17
StatePublished - Sep 1 2022

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics
  • Molecular Biology


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