The sodium channel α and β subunits are transmembrane proteins. The 4 homologous domains of the α subunit are represented in different colors. The transmembrane segments associate in the membrane to form an Na⁺-permeable pore lined by the re-entrant S5–S6 pore-loop segments (inset).

More than 150 mutations in the sodium channel protein have been identified in patients with GEFS+ and SMEI. (A) Missense mutations of SCN1A identified in families with GEFS+ (14, 16, 17, 19, 21–25). (B) Truncation mutations of SCN1A identified in SMEI patients (18, 26, 27, 44, 47, 50, 53, 54, 79–84). (C) Missense mutations of SCN1A in patients with SMEI (red), intractable childhood epilepsy with generalized tonic-clonic seizures (ICEGTC) (orange), and infantile spasms (purple) (18, 26, 27, 44, 47, 50, 53, 79–84). (D) Mutations of SCN2A in patients with benign familial neonatal-infantile seizures (BFNIS) (blue), GEFS+ (yellow), and SMEI (red) (29–32).

The effects of GEFS+ mutations on SCN1A channel properties have been studied in the Xenopus oocyte system and in transfected mammalian cells. (A) Whole-cell recordings from HEK tsA201 cells transfected with the indicated mutant SCN1A cDNAs demonstrate increased persistent current from the mutant channels (39). (B) Mean normalized amplitudes of sodium currents elicited by 80-Hz pulse trains in HEK cells expressing SCN2A cDNA containing the GEFS+ mutation D188V demonstrate reduced cumulative inactivation of the mutant channel during high-frequency trains of channel activation (40). (C) Voltage-dependent gating of SCN1A cDNA constructs in Xenopus oocytes expressed in the absence (left) or presence (right) of the β1 cDNA (85). See text for discussion.

An SCN2A mutation with persistent current causes seizures in the Q54 transgenic mouse. (A) Focal motor seizure in a Q54 mouse. (B) The GAL879–881QQQ mutation is located in the D2S4–S5 linker. (C) The mutant channel generates persistent current in Xenopus oocytes. (D) Whole-cell sodium currents recorded from CA1 hippocampal neurons from presymptomatic Q54 mice demonstrate increased persistent current. (E) Nissl-stained sections of hippocampus area CA3 reveal extensive neuronal cell loss in a Q54 mouse compared with a wild-type littermate. Adapted with permission from Neuroscience (48).