Nontruncating SCN1A mutations associated with severe myoclonic epilepsy of infancy impair cell surface expression

Christopher H. Thompson, J. Christopher Porter, Kristopher M. Kahlig, Melissa A. Daniels, Alfred L. George*

*Corresponding author for this work

Research output: Contribution to journalArticle

24 Scopus citations

Abstract

Mutations in SCN1A, encoding the voltage-gated sodium channel Na V1.1, are the most common cause of severe myoclonic epilepsy of infancy (SMEI) or Dravet syndrome. SMEI is most often associated with premature truncations of NaV1.1 that cause loss of function, but nontruncating mutations also occur. We hypothesized that some nontruncating mutations might impair trafficking of NaV1.1 to the plasma membrane. Here we demonstrated that seven nontruncating missense or in-frame deletion mutations (L986F, delF1289, R1648C, F1661S, G1674R, and G1979E) exhibited reduced cell surface expression relative to wild type (WT) NaV1.1 consistent with impaired trafficking. We tested whether two commonly prescribed antiepileptic drugs (phenytoin, lamotrigine), as well as the cystic fibrosis transmembrane conductance regulator (CFTR) trafficking corrector VRT-325, could rescue cell surface and functional expression of two representative NaV1.1 mutants (R1648C, G1674R). Treatment of cells with phenytoin increased cell surface expression of WT-NaV1.1 and both mutant channels, whereas lamotrigine only increased surface expression of R1648C. VRT-325 did not alter surface expression of WT-NaV1.1 or mutant channels. Although phenytoin increased surface expression of G1674R, channel function was not restored, suggesting that this mutation also causes an intrinsic loss of function. Both phenytoin and lamotrigine increased functional expression of R1648C, but lamotrigine also increased persistent sodium current evoked by this mutation. Our findings indicate that certain nontruncating SCN1A mutations associated with SMEI have impaired cell surface expression and that some alleles may be amenable to pharmacological rescue of this defect. However, rescue of dysfunctional NaV1.1 channels to the plasma membrane could contribute to exacerbating rather than ameliorating the disease.

Original languageEnglish (US)
Pages (from-to)42001-42008
Number of pages8
JournalJournal of Biological Chemistry
Volume287
Issue number50
DOIs
StatePublished - Dec 7 2012

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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