FEBRILE SEIZURES AND GENERALIZED EPILEPSY ASSOCIATED WITH A MUTATION IN THE NA-CHANNEL BETA-1 SUBUNIT GENE SCN1B()

Febrile seizures affect approximately 3% of all children under six yea rs of age and are by far the most common seizure disorder(1). A small proportion of children with febrile seizures later develop ongoing epi lepsy with afebrile seizures(2). Segregation analysis suggests the maj ority of cases have complex inheritance(3) but rare families show appa rent autosomal dominant: inheritance. Two putative loci have been mapp ed (FEB1 and FEB2), but specific genes have not yet been identified(4, 5). We recently described a clinical subset, termed generalized epilep sy with febrile seizures plus (GEFS(+)), in which many family members have seizures with fever that may persist beyond six years of age or b e associated with afebrile generalized seizures(6). We now report link age, in another large GEFS(+) family, to chromosome region 19q13.1 and identification of a mutation in the voltage-gated sodium (Na+)-channe l beta 1 subunit gene (SCN1B). The mutation changes a conserved cystei ne residue disrupting a putative disulfide bridge which normally maint ains an extracellular immunoglobulin-like fold. Go-expression of the m utant pr subunit with a brain Na+-channel alpha subunit in Xenopus lae vis 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 idio pathic epilepsies are a family of channelopathies and raises the possi bility of involvement of other Na+-channel subunit genes in febrile se izures and generalized epilepsies with complex inheritance patterns.