Mexiletine rescues a mixed biophysical phenotype of the cardiac sodium channel arising from the SCN5A mutation, N406K, found in LQT3 patients.

Introduction: Individual mutations in the SCN5A-encoding cardiac sodium channel -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 530ms. Mutational analysis identified a N406K mutation in SCN5A. The mutation was engineered by site-directed mutagenesis and heterologously expressed in HEK293 cells. After 48hours 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.