Neuronal voltage-gated ion channels are genetic modifiers of generalized epilepsy with febrile seizures plus

Mutations in the neuronal voltage-gated sodium channel genes SCN1A and SCN2A are associated with inherited epilepsies, including genetic epilepsy with febrile seizures plus (GEFS+) and Dravet syndrome (severe myoclonic epilepsy of infancy). The clinical presentation and severity of these epilepsies vary widely, even in people with the same mutation, suggesting the action of environmental or genetic modifiers. To gain support for the hypothesis that genetic modifiers can influence clinical presentation in patients with SCN1A-derived GEFS+, we used mouse models to study the effect of combining the human GEFS+ mutation SCN1A-R1648H with SCN2A, KCNQ2, and SCN8A mutations. Knock-in mice heterozygous for the R1648H mutation (Scn1aRH/+) have decreased thresholds to induced seizures and infrequent spontaneous seizures, whereas homozygotes display spontaneous seizures and premature lethality. Scn2aQ54 transgenic mice have a mutation in Scn2a that results in spontaneous, adult-onset partial motor seizures, and mice carrying the Kcnq2-V182M mutation exhibit increased susceptibility to induced seizures, and rare spontaneous seizures as adults. Combining the Scn1a-R1648H allele with either Scn2aQ54 or Kcnq2V182M/+ results in early-onset, generalized tonic–clonic seizures and juvenile lethality in double heterozygous mice. In contrast, Scn8a mutants exhibit increased resistance to induced seizures. Combining the Scn1a-R1648H and Scn8a-med-jo alleles restores normal thresholds to flurothyl-induced seizures in Scn1aRH/+ heterozygotes and improved survival of Scn1aRH/RH homozygotes. Our results demonstrate that variants in Scn2a, Kcnq2, and Scn8a can dramatically influence the phenotype of mice carrying the Scn1a-R1648H mutation and suggest that ion channel variants may contribute to the clinical variation seen in patients with monogenic epilepsy.

Research Highlights
► Scn1aR1648H mice carry a human GEFS+ epilepsy mutation and have a mild phenotype.
► A Scn2a mutation results in severe epilepsy and early lethality in Scn1aR1648H mice.
► A subclinical Kcnq2 mutation exacerbates the phenotype of Scn1aR1648H mice.
► A seizure-resistant Scn8a mutation improves the phenotype of Scn1aR1648H mice.
► Ion channel variants may contribute to clinical variability in monogenic epilepsy.