Brugada Syndrome (BrS) is a rare, inherited cardiac arrhythmia often leading to syncope or cardiac arrest due to ventricular tachycardia or fibrillation. Primarily affecting young individuals without apparent heart structural issues, BrS can lead to fatal outcomes, often striking unexpectedly during rest or sleep. The hallmark of BrS is an abnormal ST segment elevation on the electrocardiogram, a signature that often leads to the syndrome’s diagnosis.

The syndrome’s complex pathophysiology defies simple categorization as a monogenic disease. Originally believed to be predominantly associated with mutations in SCN5A gene (encoding for the cardiac sodium channel Nav1.5), mutations in more than 20 genes have been implicated in the pathogenesis of BrS to date. Nevertheless, SCN5A mutations remain perhaps the most significant, responsible for 20-30% of genetically diagnosed cases. More than 300 SCN5A BrS-related mutations have been identified to date, associated with a wide range of disease severities.

In a recent study, Anthony Frosio et al. identified and functionally characterized three novel BrS-related mutations in SCN5A (namely c.1030 G>T (p.A344S), c.1041 C>A (p.N347K), and c.1045 G>A (p.D349N)). Automated patch clamp experiments conducted with Nanion’s Patchliner revealed that these mutations disrupt sodium currents: p.A344S reduced current density, while p.N347K and p.D349N completely abolished it, leading to altered voltage dependence and inactivation kinetics when co-expressed with WT channels. The current reduction observed in all three mutations apparently was not caused by trafficking impairments.

The three mutations were found to be located in the P-loop of domain I, in the region where five more mutations have been described previously, suggesting its relevant role in the protein’s function and a possible mutational hot spot.

Interestingly, the study also explored the potential therapeutic intervention with mexiletine, an antiarrhythmic drug known to block late Nav1.5 current. The responses to mexiletine treatment varied among the mutations. For p.N347K and p.D349N mutations, mexiletine modestly rescued the current density, possibly indicating its potential to stabilize the selectivity filter’s position within the protein and counteract mutation-induced conformational alterations. In contrast, the p.A344S channel was negatively influenced by mexiletine treatment, showing an 85% current reduction.

Overall, this study enhances our understanding of the potential impact of novel mutations on Nav1.5 channel function and once again underscores the complexity of the genetic background of Brugada Syndrome.

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