Mécanismes cellulaires conduisant aux myocardiopathies héréditaires : modélisation de deux variants de la lamine A/C et d'ALMS1 dans des cardiomyocytes dérivés d'iPSC humaines

Cardiomyopathies are a major cause of heart failure and cardiac transplantation, arising from diverse genetic variants that compromise cellular homeostasis. My thesis project investigates two independent rare mutations, LMNA p.L92F and ALMS1 p.G3334R, using human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes as a platform to dissect their molecular and cellular consequences. The LMNA p.L92F mutation, located within the α-helical rod domain of lamin A/C, was studied using patient-derived hiPSC-cardiomyocytes. Mutant cells exhibited enlarged and misshapen nuclei, nuclear envelope instability, and lamin A/C aggregation. These architectural defects were accompanied by enhanced nuclear accumulation of YAP1, indicating altered mechanotransduction. Functionally, LMNA-mutant cardiomyocytes displayed disrupted calcium handling, with elevated basal cytosolic calcium and reduced transient amplitude, as well as impaired mitochondrial respiration. Together, these findings reveal how structural defects at the nuclear lamina propagate to signalling, excitation-contraction coupling, and metabolism, providing mechanistic insight into the pathogenesis of dilated cardiomyopathy associated with LMNA mutations. In parallel, the ALMS1 p.G3334R variant, homologous to a residue associated to a feline cardiomyopathy, was modelled using CRISPR-Cas9 edited isogenic hiPSC lines. Mutant cells demonstrated a significant reduction in ventricular cardiomyocyte differentiation efficiency, suggesting an early vulnerability during cardiac lineage commitment or survival. However, cardiomyocytes that successfully differentiated exhibited preserved morphology, contractile activity, sarcomere structure, and nucleation state. These results suggest that ALMS1 p.G3334R functions as a modifier allele with stage-specific effects, influencing developmental efficiency without overtly disrupting the structural or functional properties of mature cardiomyocytes under baseline conditions. Taken together, these studies highlight two distinct cellular pathways, nuclear lamina mechanics in LMNA and centrosomal/ciliary biology in ALMS1, through which genetic variants shape cardiomyocyte biology. By integrating structural, signalling, and functional analyses, this thesis advances the mechanistic understanding of cardiomyopathy and highlights the value of hiPSC-based models in clarifying variant-specific effects and uncovering context-dependent vulnerabilities in cardiac disease.