Abstract
INTRODUCTION: Individual mutations in the SCN5A-encoding cardiac sodium channel α-subunit usually cause a single cardiac arrhythmia disorder, some cause mixed biophysical or clinical phenotypes. Here we report an infant, female patient harboring a N406K mutation in SCN5A with a marked and mixed biophysical phenotype and assess pathogenic mechanisms. METHODS AND RESULTS: A patient suffered from recurrent seizures during sleep and torsades de pointes with a QTc of 530 ms. Mutational analysis identified a N406K mutation in SCN5A. The mutation was engineered by site-directed mutagenesis and heterologously expressed in HEK293 cells. After 48 hours incubation with and without mexiletine, macroscopic voltage-gated sodium current (I(Na)) was measured with standard whole-cell patch clamp techniques. SCN5A-N406K elicited both a significantly decreased peak I(Na) and a significantly increased late I(Na) compared to wide-type (WT) channels. Furthermore, mexiletine both restored the decreased peak I(Na) of the mutant channel and inhibited the increased late I(Na) of the mutant channel. CONCLUSION: SCN5A-N406K channel displays both "gain-of-function" in late I(Na) and "loss-of-function" in peak I(Na) density contributing to a mixed biophysical phenotype. Moreover, our finding may provide the first example that mexiletine exerts a dual rescue of both "gain-of-function" and "loss-of-function" of the mutant sodium channel.