Sodium channel SCN1A and epilepsy: mutations and mechanisms

Abstract

Mutations in a number of genes encoding voltage-gated sodium channels cause a variety of epilepsy syndromes in humans, including genetic (generalized) epilepsy with febrile seizures plus (GEFS+) and Dravet syndrome (DS, severe myoclonic epilepsy of infancy). Most of these mutations are in the SCN1A gene, and all are dominantly inherited. Most of the mutations that cause DS result in loss of function, whereas all of the known mutations that cause GEFS+ are missense, presumably altering channel activity. Family members with the same GEFS+ mutation often display a wide range of seizure types and severities, and at least part of this variability likely results from variation in other genes. Many different biophysical effects of SCN1A-GEFS+ mutations have been observed in heterologous expression systems, consistent with both gain and loss of channel activity. However, results from mouse models suggest that the primary effect of both GEFS+ and DS mutations is to decrease the activity of GABAergic inhibitory neurons. Decreased activity of the inhibitory circuitry is thus likely to be a major factor contributing to seizure generation in patients with GEFS+ and DS, and may be a general consequence of SCN1A mutations.

Keywords: Dravet syndrome; GEFS; Genetics; Knock-in mice; Knockout mice.

Figure 1. Epilepsy-Causing Mutations in SCN1A

Schematic diagram of the Na_v1.1 sodium channel α subunit and associated β1 and β2 subunits. The Na_v1.1 α subunit is associated non-covalently with β1 or β3, and it is associated via a disulfide linkage with either β2 or β4. The α subunit consists of four homologous domains (I–IV), each containing six transmembrane segments (S1–S6). The voltage-sensing S4 segment has multiple positively charged amino acids (+), and the intracellular loop between domains III and IV functions as the inactivation gate, containing four residues (IFMT) that interact with the inactivation docking site. The GEFS+ mutations that are mentioned in this review are indicated by filled circles. A complete list of the epilepsy-causing mutations in SCN1A can be found at http://web.scn1a.info (Lossin, 2009) and http://www.molgen.ua.ac.be/SCN1AMutations/(Claes et al., 2009).