Functional effects of two voltage-gated sodium channel mutations that cause generalized epilepsy with febrile seizures plus type 2

Two mutations that cause generalized epilepsy with febrile seizures plus (G EFS+) have been identified previously in the SCN1A gene encoding the alpha subunit of the Na(v)1.1 voltage-gated sodium channel (Escayg et al., 2000). Both mutations change conserved residues in putative voltage-sensing S4 se gments, T875M in domain II and R1648H in domain IV. Each mutation was clone d into the orthologous rat channel rNa(v)1.1, and the properties of the mut ant channels were determined in the absence and presence of the beta1 subun it in Xenopus oocytes. Neither mutation significantly altered the voltage d ependence of either activation or inactivation in the presence of the beta1 subunit. The most prominent effect of the T875M mutation was to enhance sl ow inactivation in the presence of beta1, with small effects on the kinetic s of recovery from inactivation and use-dependent activity of the channel i n both the presence and absence of the beta1 subunit. The most prominent ef fects of the R1648H mutation were to accelerate recovery from inactivation and decrease the use dependence of channel activity with and without the be ta1 subunit. The DIV mutation would cause a phenotype of sodium channel hyp erexcitability, 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.