A mouse model of a rare ASD-implicated patient-derived SCN2A variant

Unbiased exome sequencing and family studies have repeatedly identified the voltage-gated Na V 1.2 sodium channel gene SCN2A as a top affected ASD-associated locus. Most, but not all, SCN2A ASD-associated variants appear to cause Na V 1.2 loss-of-function, and animal models have almost exclusively examined haploinsufficiency and have been studied in the context of the single affected SCN2A locus. De novo single-nucleotide variants, even in loci with large effect sizes like SCN2A , are identified in < 10% of ASD subjects while polygenic variation is additive and contributes to almost all ASD cases. How to interpret SCN2A variants in ASD subjects when the variants do not cause clear loss-of-function, however, is a clinical and experimental challenge. Na V 1.2 channels with an R1902C variant in SCN2A previously linked to ASD show biophysical parameters distinct from wild type channels and have reduced interaction with and regulation by key auxiliary proteins, yet preserve significant Na V 1.2 function. We generated Scn2a mice with the murine R1903C equivalent and characterized them for ASD phenotypes. We characterized consequences of the variant at the channel, cellular, and circuit level. Homozygous, but not heterozygous, R1903C mice showed key ASD-associated endophenotypes, showing a dose-dependent effect and suggesting that this variant, although insufficient in the heterozygous state, could contribute to ASD in a polygenic background. Electrophysiological characterization showed perturbations at the channel, cellular, and circuit level, many of which were explained by altered interaction with auxiliary subunits due to the amino acid substitution. Our data expand an understanding of the functions of SCN2A in neurons, how auxiliary subunits regulate Na V 1.2 channels, and thus how dysregulation of Na V 1.2 function can contribute to resulting endophenotypes. Further, the dose-dependent effect of this variant suggests how specific ASD-implicated variants from a locus associated with a large effect size may contribute part of an ASD-associated risk.