PubMed 18479388

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

Authors: Sunita N Misra, Kristopher M Kahlig, Alfred L George

Journal, date & volume: Epilepsia, 2008 Sep , 49, 1535-45

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SUMMARY 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.