Impaired NaV1.2 function and reduced cell surface expression in benign familial neonatal-infantile seizures

Sunita N. Misra, Kristopher M. Kahlig, Alfred L. George

Research output: Contribution to journalArticlepeer-review

68 Scopus citations

Abstract

Purpose: Mutations in SCN2A, the gene encoding the brain voltage-gated sodium channel α-subunit NaV1.2, are associated with inherited epilepsies including benign familial neonatal-infantile seizures (BFNIS). Functional characterization of three BFNIS mutations was performed to identify defects in channel function that underlie this disease. Methods: We examined three BFNIS mutations (R1319Q, L1330F, and L1563V) using whole-cell patch-clamp recording of heterologously expressed human NaV1.2. Membrane biotinylation was employed to examine the cell surface protein expression of the four NaV1.2 alleles. Results: R1319Q displayed mixed effects on activation and fast inactivation gating, consistent with a net loss of channel function. L1563V exhibited impaired fast inactivation predicting a net gain of channel function. The L1330F mutation significantly decreased overall channel availability during repetitive stimulation. Patch-clamp analysis also revealed that cells expressing BFNIS mutants exhibited lower levels of sodium current compared to wild type (WT) NaV1.2. Biochemical experiments demonstrated that all three BFNIS mutations exhibited a significant reduction in cell surface expression compared to WT. Discussion: Our findings indicate that BFNIS is associated with a range of biophysical defects accompanied by reduced levels of channel protein at the plasma membrane.

Original languageEnglish (US)
Pages (from-to)1535-1545
Number of pages11
JournalEpilepsia
Volume49
Issue number9
DOIs
StatePublished - Sep 2008

Keywords

  • Basic electrophysiology
  • Inherited epilepsy
  • Na 1.2
  • SCN2A
  • Sodium channel

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

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