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Mutations at position 634 in the RS-domain cause DCM\n                    <jats:italic>with<\/jats:italic>\n                    (R634L) or\n                    <jats:italic>without<\/jats:italic>\n                    (R634W) left ventricular non-compaction (LVNC). However, the mechanisms underlying phenotype variability and personalized therapy beyond HFrEF remain unclear. We generated induced pluripotent stem cell-derived cardiomyocytes (iPSC-CM), 3D-cardiospheres and engineered myocardial tissues from patients with RBM20 mutations R634L (LVNC) or R634W (DCM). Using CRISPR\/Cas9, we created isogenic rescue and mutation-insertion lines, identifying RBM20 mis-localization, splicing errors in\n                    <jats:italic>TTN<\/jats:italic>\n                    and\n                    <jats:italic>RYR2<\/jats:italic>\n                    , and sarcomere irregularities in both. DCM-CM showed increased resting Ca\n                    <jats:sup>2+<\/jats:sup>\n                    leak and reduced Ca\n                    <jats:sup>2+<\/jats:sup>\n                    transient amplitude, typical of HFrEF, and spatial disorganization of sarcoplasmic reticulum and mitochondria. In contrast, LVNC-CM exhibited elevated Ca\n                    <jats:sup>2+<\/jats:sup>\n                    transient amplitude with faster kinetics, driven by elevated cAMP and mis-spliced, hyperactive CAMK2D, leading to PLN-hyperphosphorylation and increased metabolic respiration. Further, LVNC showed desmosomal derangement potentially from mis-splicing of\n                    <jats:italic>Junction plakoglobin<\/jats:italic>\n                    and reduced 3D cardiosphere compaction. Despite distinct mechanisms, contractile force was reduced in both. Isogenic controls confirm mutation causality. Drug intervention with verapamil partially improved selected abnormal Ca\n                    <jats:sup>2+<\/jats:sup>\n                    handling and contractile phenotypes in LVNC- and DCM-CM, whereas the CAMK2D inhibitor AIP improved systolic Ca\n                    <jats:sup>2+<\/jats:sup>\n                    handling predominantly in LVNC-CM. In conclusion, different amino acid substitutions at the same RBM20-residue induce opposing Ca\n                    <jats:sup>2+<\/jats:sup>\n                    -handling and structural phenotypes. While DCM features impaired Ca\n                    <jats:sup>2+<\/jats:sup>\n                    handling, LVNC shows defective cell-cell coupling and activated Ca\n                    <jats:sup>2+<\/jats:sup>\n                    handling and metabolism, yet insufficient to compensate for organ-level dysfunction. This supports personalized pharmacological therapies in early HF, and potential CRISPR\/Cas9 repair for RBM20 cardiomyopathy.\n                  <\/jats:p>","DOI":"10.1038\/s41392-026-02838-7","type":"journal-article","created":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T23:01:35Z","timestamp":1783983695000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["RBM20 variants disrupt Ca2+ handling and metabolism in dilated and non-compaction cardiomyopathy stem cell 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