Functional Effects of Two Voltage-Gated Sodium Channel Mutations That Cause Generalized Epilepsy with Febrile Seizures Plus Type 2

Abstract

Two mutations that cause generalized epilepsy with febrile seizures plus (GEFS+) have been identified previously in theSCN1A gene encoding the α subunit of the Na_v1.1 voltage-gated sodium channel (Escayg et al., 2000). Both mutations change conserved residues in putative voltage-sensing S4 segments, T875M in domain II and R1648H in domain IV. Each mutation was cloned into the orthologous rat channel rNa_v1.1, and the properties of the mutant channels were determined in the absence and presence of the β1 subunit in Xenopus oocytes. Neither mutation significantly altered the voltage dependence of either activation or inactivation in the presence of the β1 subunit. The most prominent effect of the T875M mutation was to enhance slow inactivation in the presence of β1, with small effects on the kinetics of recovery from inactivation and use-dependent activity of the channel in both the presence and absence of the β1 subunit. The most prominent effects of the R1648H mutation were to accelerate recovery from inactivation and decrease the use dependence of channel activity with and without the β1 subunit. The DIV mutation would cause a phenotype of sodium channel hyperexcitability, whereas the DII mutation would cause a phenotype of sodium channel hypoexcitability, suggesting that either an increase or decrease in sodium channel activity can result in seizures.