Febrile seizures and generalized epilepsy associated with a mutation in the Na+-channel ß1 subunit gene SCN1B

Abstract

Febrile seizures affect approximately 3% of all children under six years of age and are by far the most common seizure disorder¹. A small proportion of children with febrile seizures later develop ongoing epilepsy with afebrile seizures². Segregation analysis suggests the majority of cases have complex inheritance³ but rare families show apparent autosomal dominant inheritance. Two putative loci have been mapped (FEB1 and FEB2), but specific genes have not yet been identified^4,5. We recently described a clinical subset, termed generalized epilepsy with febrile seizures plus (GEFS⁺), in which many family members have seizures with fever that may persist beyond six years of age or be associated with afebrile generalized seizures⁶. We now report linkage, in another large GEFS⁺ family, to chromosome region 19q13.1 and identification of a mutation in the voltage-gated sodium (Na⁺)-channel ß1 subunit gene (SCN1B). The mutation changes a conserved cysteine residue disrupting a putative disulfide bridge which normally maintains an extracellular immunoglobulin-like fold. Co-expression of the mutant ß1 subunit with a brain Na⁺-channel ß subunit in Xenopus laevis oocytes demonstrates that the mutation interferes with the ability of the subunit to modulate channel-gating kinetics consistent with a loss-of-function allele. This observation develops the theme that idiopathic epilepsies are a family of channelopathies and raises the possibility of involvement of other Na⁺-channel subunit genes in febrile seizures and generalized epilepsies with complex inheritance patterns.