Febrile seizures and generalized epilepsy associated with a mutation in the Na+-channel β1 subunit gene SCN1B

Robyn H. Wallace, Dao W. Wang, Rita Singh, Ingrid E. Scheffer, Alfred L. George, Hilary A. Phillips, Kathrin Saar, Andre Reis, Eric W.johnson, Grant R. Sutherland, Samuel F. Berkovic, John C. Mulley*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

918 Scopus citations

Abstract

Febrile seizures affect approximately 3% of all children under six years of age and are by far the most common seizure disorder. A small proportion of children with febrile seizures later develop ongoing epilepsy with afebrile seizures. Segregation analysis suggests the majority of cases have complex inheritance 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. 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 seizures. 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 β1 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 β1 subunit with a brain Na+-channel α 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.

Original languageEnglish (US)
Pages (from-to)366-370
Number of pages5
JournalNature Genetics
Volume19
Issue number4
DOIs
StatePublished - 1998

ASJC Scopus subject areas

  • Genetics

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