Functional and pharmacological evaluation of a novel SCN2A variant linked to early‐onset epilepsy

Abstract

Objective We identified a novel de novo SCN2A variant (M1879T) associated with infantile‐onset epilepsy that responded dramatically to sodium channel blocker antiepileptic drugs. We analyzed the functional and pharmacological consequences of this variant to establish pathogenicity, and to correlate genotype with phenotype and clinical drug response. Methods The clinical and genetic features of an infant boy with epilepsy are presented. We investigated the effect of the variant using heterologously expressed recombinant human NaV1.2 channels. We performed whole‐cell patch clamp recording to determine the functional consequences and response to carbamazepine. Results The M1879T variant caused disturbances in channel inactivation including substantially depolarized voltage dependence of inactivation, slower time course of inactivation, and enhanced resurgent current that collectively represent a gain‐of‐function. Carbamazepine partially normalized the voltage dependence of inactivation and produced use‐dependent block of the variant channel at high pulsing frequencies. Carbamazepine also suppresses resurgent current conducted by M1879T channels, but this effect was explained primarily by reducing the peak transient current. Molecular modeling suggests that the M1879T variant disrupts contacts with nearby residues in the C‐terminal domain of the channel. Interpretation Our study demonstrates the value of conducting functional analyses of SCN2A variants of unknown significance to establish pathogenicity and genotype–phenotype correlations. We also show concordance of in vitro pharmacology using heterologous cells with the drug response observed clinically in a case of SCN2A‐associated epilepsy.

Cellular and behavioral effects of altered NaV1.2 sodium channel ion permeability in Scn2a K1422E mice

“…To our knowledge, K1422E is the only variant within the existing SCN2A patient population that affects ion selectivity, contrasting markedly with other variants that commonly alter voltage dependence, kinetics or trafficking ( 1 , 4 , 5 , 7 , 16 ). Given the unique properties of K1422E in heterologous expression systems, it is difficult to understand how it might affect the intrinsic properties of neurons.…”

Epilepsy-associated SCN2A (NaV1.2) variants exhibit diverse and complex functional properties

“…S3 ). Population variants were chosen based on minor allele frequency >0.0001 in the gnomAD database ( Karczewski et al, 2020 ), while pathogenic variants were chosen to represent either GoF or LoF effects based on previously published data ( Ben-Shalom et al, 2017 ; Berecki et al, 2018 ; Lauxmann et al, 2018 ; Begemann et al, 2019 ; Mason et al, 2019 ; Adney et al, 2020 ; Ganguly et al, 2021 ).…”

Functional analysis of a novel de novo SCN2A variant in a patient with seizures refractory to oxcarbazepine

“…For infants with epileptic seizures within 3 months after birth, SCBs, such as OXC, PHT, and CBZ are more effective, as the function of the variation of SCN2A is considered to be more likely to be GOF ( Adney et al, 2020 ). Therefore, we selected OXC for treatment based on the genetic test results, but the result was contrary to our expectation.…”