iPSC-derived cardiomyocytes with the MYPN p.N989I variant showed no significant biophysical changes but demonstrated transcriptomic dysregulation of sarcomeric, cytoskeletal, and metabolic genes.
Does the p.N989I variant of MYPN alter biophysical characteristics and transcriptomic profiles in iPSC-derived cardiomyocytes?
The novel p.N989I variant of MYPN disrupts sarcomeric organization and muscle gene regulation at the transcriptomic level in iPSC-derived cardiomyocytes without significantly altering basic electrophysiological parameters.
Background/Objectives: Variants of MYPN, encoding a sarcomeric protein myopalladin, are associated with different types of cardiomyopathies and myopathies. However, the molecular mechanisms of MYPN-associated pathologies are still poorly understood. Methods: In this study, we generated induced pluripotent stem cells (iPSCs) from a hypertrophic cardiomyopathy patient carrying a novel p.N989I (c.2966A>T) variant of MYPN and used iPSC-derived cardiomyocytes to examine the impact of the variant on biophysical characteristics and transcriptomic profile. Results: No significant changes in parameters of calcium transients, sodium current and action potential were found in iPSC-derived cardiomyocytes with the p.N989I (c.2966A>T) variant of MYPN compared to non-isogenic cells from an unrelated healthy donor. At the transcriptomic level, MYPN-N989I cardiomyocytes demonstrated an upregulation of genes linked to cell cycle, mitotic spindle, microtubule cytoskeleton organization, and myogenic program genes. Downregulation of sarcomeric, Z-disc- and cell junction-associated genes, as well as genes involved in ATP synthesis, oxidative phosphorylation, and the SRF-signaling pathway, was also revealed. Conclusions: Our data suggest that the p.N989I (c.2966A>T) variant of MYPN plays a dual role in hypertrophic cardiomyopathy pathogenesis, disrupting not only sarcomeric and cytoskeletal organization but also the regulation of the muscle gene program.
Dementyeva et al. (Tue,) conducted a other in Hypertrophic cardiomyopathy. iPSC-derived cardiomyocytes with MYPN p.N989I variant vs. Non-isogenic cells from an unrelated healthy donor was evaluated on Biophysical characteristics and transcriptomic profile. iPSC-derived cardiomyocytes with the MYPN p.N989I variant showed no significant biophysical changes but demonstrated transcriptomic dysregulation of sarcomeric, cytoskeletal, and metabolic genes.