Thesis defense Thomas Stervinou

Equipe

Team II - Ion channels and cardiopathies

Directrice de thèse 

Nathalie Gaborit

Co-directeur 

Guillaume Lamirault

Rapporteurs

Jean Pierre Benitah, PhD, Directeur de Recherche, Université Paris-Saclay, Inserm UMR1180, Paris
Sonia Stefanovic, PhD, Chargée de Recherche, C2VN, Inserm, Marseille

Examinateurs

Abstract : 

Keywords :  Brugada syndrome, Transcriptomics, Cardiac development, hiPSC, Organoids, Electrophysiology

Brugada syndrome (BrS) is a rare inherited cardiac arrhythmia characterized by espisodes of ventricular fibrillation that may lead to sudden cardiac death. Genetic studies have identified SCN5A, encoding the cardiac sodium channel NaV1.5, as the major disease-causing gene in approximately 20% of cases, while also highlighting numerous genes involved in cardiac development, suggesting a developmental contribution to BrS pathophysiology. Human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs) provide a valuable model for recapitulating the early stages of cardiac development. Transcriptomic profiling throughout hiPS-CMs differentiation revealed early alterations in the cardiac developmental program at the cardiac progenitor stage in patients lacking rare SCN5A variants. These alterations were associated with dysregulation of the transcription factor IRX5. Single-cell transcriptomic analysis of a hiPSC line carrying an SCN5A variant identified a BrS-specific cardiomyocyte population, suggesting altered cardiac cell identity. Finally, the investigation of cardiac developmental factors genetically associated with BrS identified ZFPM2 and WT1 as regulators of SCN5A expression. Collectively, these findings provide the first evidence linking early cardiac developmental abnormalities to the molecular remodeling observed in BrS.