A novel epilepsy mutation in the sodium channel SCN1A identifies a cytoplasmic domain for β subunit interaction

J. Spampanato, J. A. Kearney, G. De Haan, D. P. McEwen, A. Escayg, I. Aradi, B. T. MacDonald, S. I. Levin, I. Soltesz, P. Benna, E. Montalenti, L. L. Isom, A. L. Goldin, M. H. Meisler*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

130 Scopus citations


A mutation in the sodium channel SCN1A was identified in a small Italian family with dominantly inherited generalized epilepsy with febrile seizures plus (GEFS+). The mutation, D1866Y, alters an evolutionary conserved aspartate residue in the C-terminal cytoplasmic domain of the sodium channel α subunit. The mutation decreased modulation of the α subunit by β1, which normally causes a negative shift in the voltage dependence of inactivation in oocytes. There was less of a shift with the mutant channel, resultingin a 10 mV difference between the wild-type and mutant channels in the presence of β1. This shift increased the magnitude of the window current, which resulted in more persistent current during a voltage ramp. Computational analysis suggests that neurons expressing the mutant channels will fire an action potential with a shorter onset delay in response to a threshold current injection, and that they will fire multiple action potentials with a shorter interspike interval at a higher input stimulus. These results suggest a causal relationship between a positive shift in the voltage dependence of sodium channel inactivation and spontaneous seizure activity. Direct interaction between the cytoplasmic C-terminal domain of the wild-type α subunit with the β1 or β3 subunit was first demonstrated by yeast two-hybrid analysis. The SCN1A peptide K1846-R1886 is sufficient for β subunit interaction. Coimmunoprecipitation from transfected mammalian cells confirmed the interaction between the C-terminal domains of the α and β1 subunits. The D1866Y mutation weakens this interaction, demonstrating a novel molecular mechanism leading to seizure susceptibility.

Original languageEnglish (US)
Pages (from-to)10022-10034
Number of pages13
JournalJournal of Neuroscience
Issue number44
StatePublished - Nov 3 2004


  • Channel
  • Epilepsy
  • Genetics
  • Kinetic (kinetics)
  • Mutant
  • Sodium (Na)

ASJC Scopus subject areas

  • Neuroscience(all)

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