Abstract
Mutations of SCN5A, gene-encoding alpha-subunit of cardiac sodium channel, can cause mixed phenotypes of Brugada syndrome (BrS) and cardiac conduction diseases (CCD). We have identified a nucleotide change of SCN5A (4178T > G), which results in a nonsense mutation, L1393X, in a 36-year-old Caucasian man who presented with intraventricular conduction delays and BrS-type electrocardiogram change. To study biophysical characteristics of L1393X-SCN5A, electrophysiological and immuno-staining studies were performed using mammalian expression systems. While WT-SCN5A showed significant currents (93.3 +/- 10.6 pA/pF; 1 microg plasmid), L1393X (5 microg) did not generate any significant currents in NIH-3T3 cells. The cells cotransfected with WT (0.5 microg) and L1393X (0.5 microg) showed approximately 50% current amplitudes compared to the WT (1 microg). Voltage dependency of a steady-state activation and inactivation was not affected by the cotransfection of L1393X. Immuno-histochemical stainings demonstrated that L1393X proteins were expressed in the plasma membranes. Our study demonstrated that L1393X-SCN5A does not form functional channel proteins, which might account for the patient's mixed phenotypes of BrS and CCD.