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

Hawkins NA, Martin MS, Frankel WN, Kearney JA, Escayg A
Neurobiol Dis. 2011 41 (3): 655-60

PMID: 21156207 · PMCID: PMC3035952 · DOI:10.1016/j.nbd.2010.11.016

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 (Scn1a(RH/+)) have decreased thresholds to induced seizures and infrequent spontaneous seizures, whereas homozygotes display spontaneous seizures and premature lethality. Scn2a(Q54) 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 Scn2a(Q54) or Kcnq2(V182M/+) 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 Scn1a(RH/+) heterozygotes and improved survival of Scn1a(RH/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.

Copyright © 2010 Elsevier Inc. All rights reserved.

MeSH Terms (22)

Alleles Animals Epilepsy, Generalized Female Genetic Predisposition to Disease Genetic Variation Humans KCNQ2 Potassium Channel Male Mice Mice, 129 Strain Mice, Inbred C57BL Mice, Transgenic Mutation NAV1.1 Voltage-Gated Sodium Channel NAV1.2 Voltage-Gated Sodium Channel NAV1.6 Voltage-Gated Sodium Channel Nerve Tissue Proteins Neurons Phenotype Seizures, Febrile Sodium Channels

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