Numerous SCN5A mutations affect the cardiac sodium channel Na_v1.5 α-subunit and cause several types of arrhythmias. By expressing N- and C-terminal SCN5A mutations (R104W and R1860GfsX12) with wild-type (WT) channels in HEK cells to mimic the heterozygous state of the patients, we showed that interactions between α-subunits could modulate the channel function, location and potentially the disease phenotypes.

When expressed alone, the N- and C-terminal mutants were mostly degraded and showed either reduced or no I_Na density. When co-expressed with WT channels, the N-terminal mutant exerted a dominant-negative effect on WT channels by retaining them in the endoplasmic reticulum. In contrast, co-transfection of WT channels with C-terminal mutants almost restored the I_Na density to the level of WT and increased total and cell surface protein expression of mutant channels, suggesting that WT allow mutant proteins to escape proteasomal degradation. Co-immunoprecipitation studies showed that the WT α-subunits interacted with each other, as well as with the N- and C-terminal mutants. In addition, altered biophysical properties of I_Na current were found at the heterozygous state for both mutants.

In conclusion, interaction between Na_v1.5 α-subunits could explain the variable phenotypes observed in SCN5A-mutation carriers. The N-terminal variant associated with a loss-of-function due to its dominant-negative effect on WT channels lead to a Brugada type-I ECG pattern. In contrast, the partial rescue of the I_Na current of the C-terminal variant and its altered biophysical properties could explain the complex clinical picture of sick sinus syndrome and atrial fibrillation without Brugada ECG pattern.

Conference Title

24èmes Journées Européennes de la Société Française de cardiologie

Conference Country

France

Conference Date

Jan. 15, 2014 - Jan. 18, 2014

Conference Sponsor

Société Française de cardiologie

Additional Info

Conference Website