Nonfunctional SCN1A is common in severe myoclonic epilepsy of infancy

Iori Ohmori, Kristopher M. Kahlig, Thomas H. Rhodes, Dao W. Wang, Alfred L. George

Research output: Contribution to journalArticlepeer-review

65 Citations (Scopus)


Purpose: Mutations in SCN1A, encoding the human NaV1.1 neuronal voltage-gated sodium channel, cause the syndrome of severe myoclonic epilepsy of infancy (SMEI). Most SMEI-associated mutations are predicted to truncate the SCN1A protein, likely causing a loss of sodium channel function. However, many missense or in-frame deletion SCN1A mutations have also been reported in this disorder, but their functional impact is largely unknown. Here we report the functional characterization of eight SCN1A mutations (G177E, I227S, R393H, Y426N, H939Q, C959R, delF1289, and T1909I) previously identified in SMEI probands. Methods: SCN1A mutants were constructed in a recombinant human SCN1A and then heterologously expressed in human tsA201 cells along with the human β1 and β2 sodium channel accessory subunits. Whole-cell patch-clamp recording was used to define biophysical properties of each mutant and for comparison with the wild-type (WT) channel. Results: Six of the mutants were nonfunctional, but Y426N and T1909I generated measurable sodium channel activity. Cells expressing Y426N and T1909I had significantly lower current densities compared with WT-SCN1A. In addition, other biophysical abnormalities were observed for the two functional mutants including decreased channel availability (Y426N) and increased persistent sodium current (T1909I). Conclusions: We conclude that SMEI is caused either by complete loss of SCN1A function, or by dysfunctional sodium channels exhibiting mixed biophysical properties. This wide spectrum of functional defects observed among SCN1A mutations suggests that SMEI may result from more than a single molecular or cellular mechanism, or require other factors for pathogenesis.

Original languageEnglish
Pages (from-to)1636-1642
Number of pages7
Issue number10
Publication statusPublished - Oct 2006
Externally publishedYes


  • Basic electrophysiology
  • Inherited epilepsy
  • SCN1A
  • SMEI
  • Sodium channel

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology


Dive into the research topics of 'Nonfunctional SCN1A is common in severe myoclonic epilepsy of infancy'. Together they form a unique fingerprint.

Cite this