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Epilepsia. 2008 Sep;49(9):1535-45. doi: 10.1111/j.1528-1167.2008.01619.x. Epub 2008 Apr 21.

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

Author information

1
Department of Pharmacology, Division of GeneticMedicine, Vanderbilt University, Nashville, Tennessee 37232-0275, USA.

Abstract

PURPOSE:

Mutations in SCN2A, the gene encoding the brain voltage-gated sodium channel alpha-subunit Na(V)1.2, 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 Na(V)1.2. Membrane biotinylation was employed to examine the cell surface protein expression of the four Na(V)1.2 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) Na(V)1.2. 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.

PMID:
18479388
PMCID:
PMC3647030
DOI:
10.1111/j.1528-1167.2008.01619.x
[Indexed for MEDLINE]
Free PMC Article

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