An SCN2A mutation in a family with infantile seizures from Madagascar reveals an increased subthreshold Na⁺ current

Abstract

SUMMARYMissense mutations in SCN2A, encoding the brain sodium channel Na V 1.2, have been described in benign familial neonatal-infantile seizures (BFNIS), a self-limiting disorder, whereas several SCN2A de novo nonsense mutations have been found in patients with more severe phenotypes including epileptic encephalopathy. We report a family with BFNIS originating from Madagascar. Onset extended from 3 to 9 months of age. Interictal EEGs were normal. In two patients, ictal electroencephalography (EEG) studies showed partial seizure patterns with secondary generalization in one. Seizures remitted before 18 months of age, with or without medication. Intellectual development was normal. A novel missense mutation of SCN2A, c.4766A>G/p.Tyr1589Cys, was found in a highly conserved region of Na V 1.2 (D4/S2-S3). Functional studies using heterologous expression in tsA201 cells and whole-cell patch clamping revealed a depolarizing shift of steady-state inactivation, increased persistent Na + current, a slowing of fast inactivation and an acceleration of its recovery, thus a gain-of-function. Using an action potential waveform in a voltage-clamp experiment we indicated an increased inward Na + current at subthreshold voltages, which can explain a neuronal hyperexcitability. Our results suggest that this mutation induces neuronal hyperexcitability, resulting in infantile epilepsy with favorable outcome.

Relationship of electrophysiological dysfunction and clinical severity inSCN2A-related epilepsies

“…For the p.(Lys908Glu) variant, we found a significantly increased sodium inward current, which occurred only in the critical subthreshold depolarizing phase of an action potential ( I NaS ). This phenomenon was first observed in Na V 1.2 channels for the BFNIE‐causing variant p.(Tyr1589Cys), which additionally showed a depolarizing shift of steady‐state inactivation, an increased I NaP , a slowing of fast inactivation and an acceleration of its recovery (Lauxmann et al., ). The nature of this subthreshold current is still unclear.…”

“…So far, more than 140 different SCN2A variants and more than 7 chromosomal aberrations have been identified with a broad range of the phenotypic spectrum. Within those, only 25 different variants (including the three here studied variants) in the adult and neonatal splice variants have been electrophysiologically characterized until now (Table ), four of which were classified as LoF variants (Kamiya et al., ; Liao, Anttonen, et al., ; Liao, Deprez, et al., ; Ogiwara et al., ; Scalmani et al., ; Schwarz et al., ; Sugawara et al., ; Sugawara et al., ; Wolff et al., ), 15 as GoF variants (Lauxmann et al., ; Wolff et al., ; Xu et al., ), and as a combination of LoF and GoF variants (Ogiwara et al., ). Three variants (p.(Arg1319Gln), p.(Leu1330Phe) and p.(Leu1563Val)) exhibited a significant reduction in cell surface expression (Misra et al., ) predicting a net decrease in channel activity.…”

Opposing Effects on Na V 1.2 Function Underlie Differences Between SCN2A Variants Observed in Individuals With Autism Spectrum Disorder or Infantile Seizures

“…If this hypothesis were correct, we would expect the missense variants observed in ASD to reduce Na V 1.2 channel function and decrease neuron excitability. We therefore performed functional analyses of all 12 de novo SCN2A mutations observed in the 4,109 ASD cases from the Simons Simplex Collection (SSC; 2,508 families with a single affected child) and Autism Sequencing Consortium (ASC; 1,601 families with one or more affected children), as these cases were identified as representing idiopathic ASD in clearly defined cohorts (4, 9, 22). …”

Structure-based assessment of disease-related mutations in human voltage-gated sodium channels

“…More than 30 Na v 1.2 mutations have been discovered and some of them are now functionally characterized. Interestingly, electrophysiological studies showed that Na v 1.2 mutations can either be loss-of-function (R1319Q and L1330F) or gain-of-function (M252V, V261M, L1563V, and Y1579C) (Misra et al, 2008; Liao et al, 2010; Lauxmann et al, 2013). It is noted that BFIS3 mutations in Na v 1.2 create less pronounced changes in the activation and inactivation potentials than the EIEE11 mutations (Shi et al, 2012).…”