Functional and Expression Studies of iPSC-Derived Cardiomyocytes Carrying a Novel HCM-Associated MYPN Genetic Variant

Variants in MYPN encoding a sarcomeric protein, myopalladin, are associated with different types of cardiomyopathies and myopathies. However, molecular mechanisms of MYPN-associated pathologies are still poorly understood. In this study, we generated induced pluripotent stem cells (iPSCs) from a hypertrophic cardiomyopathy patient carried a novel p.N989I (c.2966A>T) variant in MYPN and used iPSC-derived cardiomyocytes to examine the impact of the variant on biophysical characteristics and transcriptomic profile. No significant changes in parameters of calcium transient, sodium current and action potential were found in iPSC-derived cardiomyocytes with p.N989I (c.2966A>T) variant in MYPN compared to control cells from a healthy donor. At the transcriptomic level, MYPN-N989I cardiomyocytes demonstrated an upregulation of genes linked to cell cycle, division springle, microtubule cytoskeleton organization and myogenic program genes. A downregulation of sarcomeric, Z-disc- and cell junction-associated genes and genes involved in ATP synthesis, oxidative phosphorylation and SRF-signaling pathway was also revealed. Our data suggest that the p.N989I (c.2966A>T) variant in MYPN plays a dual role in hypertrophic cardiomyopathy pathogenesis, disrupting not only sarcomeric and cytoskeletal organization but also muscle gene program regulation.