Epilepsy-Associated Dysfunction in the Voltage-Gated Neuronal Sodium Channel SCN1A

Christoph Lossin, Thomas H. Rhodes, Reshma R. Desai, Carlos G. Vanoye, Dao Wang, Sanda Carniciu, Orrin Devinsky, Alfred L. George*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

159 Scopus citations

Abstract

Mutations in SCN1A, the gene encoding the brain voltage-gated sodium channel α1 subunit (Nav1.1), are associated with at least two forms of epilepsy, generalized epilepsy with febrile seizures plus (GEFS+) and severe myoclonic epilepsy of infancy (SMEI). We examined the functional properties of four GEFS+ alleles and one SMEI allele using whole-cell patch-clamp analysis of heterologously expressed recombinant human SCN1A. One previously reported GEFS+ mutation (I1656M) and an additional novel allele (R1657C), both affecting residues in a voltage-sensing S4 segment, exhibited a similar depolarizing shift in the voltage dependence of activation. Additionally, R1657C showed a 50% reduction in current density and accelerated recovery from slow inactivation. Unlike three other GEFS+ alleles that we recently characterized, neither R1657C nor I1656M gave rise to a persistent, noninactivating current. In contrast, two other GEFS+ mutations (A1685V and V1353L) and L986F, an SMEI-associated allele, exhibited complete loss of function. In conclusion, our data provide evidence for a wide spectrum of sodium channel dysfunction in familial epilepsy and demonstrate that both GEFS+ and SMEI can be associated with nonfunctional SCN1A alleles.

Original languageEnglish (US)
Pages (from-to)11289-11295
Number of pages7
JournalJournal of Neuroscience
Volume23
Issue number36
DOIs
StatePublished - Dec 10 2003

Keywords

  • Electrophysiology
  • Epilepsy
  • SCN1A
  • SMEI
  • Sodium channel

ASJC Scopus subject areas

  • Neuroscience(all)

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