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| Item Type: | Article |
|---|---|
| Title: | CAMK2D causes heart failure in mice with RBM20 cardiomyopathy |
| Creators Name: | van den Hoogenhof, Maarten M.G., Duran, Javier, Britto-Borges, Thiago, Sequeira, Vasco, Kemmling, Elena, Konrad, Laura, Schreiter, Friederike, Lennermann, David C., Hartmann, Joshua, Schraft, Laura, Kornienko, Julia, Bock, Theresa, Krüger, Marcus, Maack, Christoph, Dieterich, Christoph, Steinmetz, Lars M., Dewenter, Matthias and Backs, Johannes |
| Abstract: | Although heart disease arises from different etiologies, treatment remains largely one-size-fits-all, leaving many patients without optimal benefit, which highlights the need for cause-directed therapies. Pathogenic variants in RBM20, a cardiac splicing factor, lead to an aggressive form of dilated cardiomyopathy with high risk of ventricular arrhythmias. We hypothesized that the splicing target calcium/calmodulin-dependent kinase II delta (CAMK2D) is disease causing in RBM20 cardiomyopathy. Here we show that Rbm20/Camk2d double knockout mice are protected from heart failure and sudden cardiac death. In Rbm20-deficient hearts, phosphorylation of CAMK2D targets was increased, indicating that RBM20 loss results not only in mis-splicing of Camk2d transcripts but also in functional activation of CAMK2D signaling. Reexpression of individual CAMK2D splice variants in Rbm20/Camk2d double knockout mice reintroduced cardiac dysfunction, demonstrating that overactivation, rather than mis-splicing, drives disease. Treatment of Rbm20-p.Arg636Gln knockin mice with the ATP-competitive CAMK2 inhibitor hesperadin improved cardiac function. These findings identify CAMK2D overactivation as a central mechanism in RBM20 cardiomyopathy and support CAMK2D inhibition as a promising cause-directed therapy. |
| Source: | Nature Cardiovascular Research |
| ISSN: | 2731-0590 |
| Publisher: | Springer Nature |
| Date: | 4 May 2026 |
| Official Publication: | https://doi.org/10.1038/s44161-026-00818-2 |
| PubMed: | View item in PubMed |
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