Non-syndromic autism SCN2A variants selectively exert dominant-negative effects on Na v 1.2 channels

ABSTRACT The voltage-gated Na + channel Na v 1.2 has a key role for the initiation and propagation of action potentials and therefore in neuronal excitability in brain development and function. Genetic variants of the encoding gene SCN2A cause various neurodevelopmental phenotypes with infantile-childhood onset. Here, we investigated the functional impact on hNa v 1.2 function of 15 variants associated with pure non-syndromic ASD (nsASD), ASD with epileptic activity, developmental and epileptic encephalopathy or schizophrenia. Only nsASD variants caused a complete loss of function hNa v 1.2 channels when expressed alone in tsA-201 cells and cultured neocortical neurons. Co-expression of the WT and mutant channels mimicking heterozygosis revealed that ASD mutants induce a dominant negative effect. Using different strategies to impair the domains of the channels that have been suggested to be implicated in the interaction of two Na v α subunits, we reversed the dominant negative effect of ASD mutants on WT channels. These findings identify in heterologous systems a mechanistically distinct class of SCN2A variants implicated in nsASD, defined by dominant-negative loss of Nav1.2 function, with potential utility as a biomarker for genetic counseling, patient stratification, and the development of precision therapeutic strategies.