Functional and Expression Studies of iPSC-Derived Cardiomyocytes Carrying a Novel HCM-Associated MYPN Genetic Variant
Summary
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.
| Authors | Dementyeva EV, Klimenko ES, Sorokina MY, Zaytseva AK, Ri MT, Nikitina EG, Kudlay DA, Zlotina AM, Tarnovskaya SI, Vyatkin YV, Shtokalo DN, Zakian SM, Kostareva AA |
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| Journal | Genes |
| Publication Date | 2026 Apr 14;17(4) |
| PubMed | 42074575 |
| PubMed Central | PMC13116294 |
| DOI | 10.3390/genes17040456 |