A novel mutation in the SCN5A gene is associated with Brugada syndrome

Brugada syndrome (BS) is an inherited cardiac disorder associated with a high risk of sudden cardiac death and is caused by mutations in the SCN5A gene encoding the cardiac sodium channel α-subunit (Nav1.5). The aim of this study was to identify the genetic cause of familial BS and characterize the electrophysiological properties of a novel SCN5A mutation (W1191X). Four families and one patient with BS were screened for SCN5A mutations by PCR and direct sequencing. Wild-type (WT) and mutant Nav1.5 channels were expressed in tsA201 cells, and the sodium currents (INa) were analyzed using the whole-cell patch-clamp technique. A novel mutation, W1191X, was identified in a family with BS. Expression of the WT or the mutant channel (Nav1.5/W1191X) co-transfected with the β1-subunit in tsA201 cells resulted in a loss of function of Nav1.5 channels. While voltage-clamp recordings of the WT channel showed a distinct acceleration of Nav1.5 activation and fast inactivation kinetics, the Nav1.5/W1191X mutant failed to generate any currents. Co-expression of the WT channel and the mutant channel resulted in a 50% reduction in INa. No effect on activation and inactivation were observed with this heterozygous expression. The W1191X mutation is associated with BS and resulted in the loss of function of the cardiac sodium channel.