title: Nonfunctional SCN1A is common in severe myoclonic epilepsy of infancy.
abstract: OBJECTIVE
  Mutations in SCN1A, encoding the human Na(V)1.1 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 beta(1) and beta(2) 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.
authors.affiliation: Division of Genetic Medicine, Department of Medicine, Vanderbilt University, Nashville, Tennessee 37232-0275, USA.
authors.forename: Iori
authors.initials: I
authors.lastname: Ohmori
authors.forename: Kristopher M
authors.initials: KM
authors.lastname: Kahlig
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Rhodes
authors.forename: Dao W
authors.initials: DW
authors.lastname: Wang
authors.forename: Alfred L
authors.initials: AL
authors.lastname: George
mesh_terms: D004831:Epilepsies, Myoclonic / Q000235:genetics* / Q000503:physiopathology; D015870:Gene Expression / Q000235:genetics; D006801:Humans; D008564:Membrane Potentials / Q000235:genetics / Q000502:physiology; D009154:Mutation / Q000235:genetics*; D020125:Mutation, Missense / Q000235:genetics; D062550:NAV1.1 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000235:genetics*; D018408:Patch-Clamp Techniques; D010641:Phenotype; D015222:Sodium Channels / Q000235:genetics* / Q000502:physiology
chemical_list: D062550:NAV1.1 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; C568242:SCN1A protein, human; D015222:Sodium Channels