0441 : Electrophysiological characterization of a novel SCN5A mutation causing Brugada syndrome, using cardiomyocytes differentiated from hiPSCs

Rationale Brugada syndrome is a human hereditary cardiac disease known to cause ventricular tachyarrhythmias (torsade de pointes) that can lead to sudden death. In about 20% of the Brugada affected patients, mutations have been identified in the gene encoding the Na+ ion channel, SCN5A. Up to now, genotype-phenotype studies have been performed using heterologous expression systems that lack the correct cellular context of a cardiomyocyte. Human Induced Pluripotent stem cells (hiPSCs) offer a now new paradigm for gene mutation characterization. Objective In this study, using cardiomyocytes differentiated from hiPSCs, we have electrophysiologically characterized a previously undescribed mutation in SCN5A gene, carried by a Brugada affected patient. Methods and results hiPSCs from a Brugada affected patient carrying the N1722D mutation in SCN5A have been generated and validated. hiPSCs from a healthy subject were used as control. Using patch clamp techniques, the biophysical properties of the Na+ channel and action potential characteristics were evaluated in both cardiomyocytes differentiated from these hiPSCs and in a mammalian expression system expressing the mutant channel. Preliminary data from both cellular models suggest a three-times reduction in Na+ current. The hiPSCs-derived cardiomyocytes revealed a specific action potential phenotype which is still under investigation Conclusion Brugada syndrome modeling using hiPSCs-derived cardiomyocytes suggests that this cellular model recapitulates the characteristics of a loss-of-function Na+ channel mutation and that hiPSCs-derived cardiomyocytes can be used as an accurate model for cardiac Na+ channel disease.