{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T10:33:00Z","timestamp":1789468380880,"version":"build-2803163510"},"reference-count":104,"publisher":"Ovid Technologies (Wolters Kluwer Health)","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>\n                      Pathogenic variants in\n                      <jats:italic toggle=\"yes\">RBM20<\/jats:italic>\n                      cause severe dilated cardiomyopathy. Loss-of-function variants disrupt splicing; neomorphic gain-of-function (GoF) variants also mislocalize RBM20 to cytoplasmic ribonucleoprotein granules and are associated with more aggressive disease. The mechanism by which RBM20 mislocalization drives cardiac dysfunction remains unknown.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>\n                      We investigated the effects of\n                      <jats:italic toggle=\"yes\">Rbm20<\/jats:italic>\n                      GoF and loss-of-function (LoF) variants using proteomic profiling, protein solubility assays, mitochondrial respiration and calcium flux analyses, and ultrastructural imaging in mouse models. Human induced pluripotent stem cell\u2013derived cardioids were used to validate variant-specific phenotypes.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>\n                      <jats:italic toggle=\"yes\">Rbm20<\/jats:italic>\n                      GoF, but not LoF, variants caused posttranscriptional downregulation of soluble mitochondrial proteins, including the calcium efflux regulator TMEM65 (transmembrane protein 65), and reduced solubility of mitochondrial membrane proteins. Electron microscopy revealed enlarged mitochondria with cristae disorganization. Functional assays confirmed impaired oxidative phosphorylation, reduced mitochondrial membrane potential, and abnormal calcium handling in\n                      <jats:italic toggle=\"yes\">Rbm20<\/jats:italic>\n                      GoF models. Human cardioids reproduced these findings, demonstrating that cytoplasmic mislocalization, rather than splicing deficiency, drives mitochondrial dysfunction.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>\n                      Cytoplasmic mislocalization of RBM20 disrupts mitochondrial function by reducing mitochondrial protein abundance, leading to oxidative phosphorylation failure and abnormal mitochondrial calcium handling. This mechanism distinguishes\n                      <jats:italic toggle=\"yes\">RBM20<\/jats:italic>\n                      GoF from LoF variants and may explain the more severe heart failure phenotype observed in patients with\n                      <jats:italic toggle=\"yes\">RBM20<\/jats:italic>\n                      GoF variants. These insights advance the mechanistic understanding of\n                      <jats:italic toggle=\"yes\">RBM20<\/jats:italic>\n                      -related cardiomyopathy and identify mitochondrial mRNA\/protein regulation as a key node in cardiac energetics.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circulationaha.125.077061","type":"journal-article","created":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T09:00:17Z","timestamp":1789462817000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["Dysregulated Ribonucleoprotein Granules Impair Mitochondrial Function in\n                    <i>RBM20<\/i>\n                    -Related Dilated Cardiomyopathy"],"prefix":"10.1161","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7876-230X","authenticated-orcid":true,"given":"Julia","family":"Kornienko","sequence":"first","affiliation":[{"name":"DZHK (German Center for Cardiovascular Research), partner site Heidelberg\/Mannheim, Heidelberg, Germany (J. Kornienko, D.L., K.F., L.K., M.M.G.v.d.H., L.M.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9250-0541","authenticated-orcid":true,"given":"Linda H.","family":"M\u00fcller","sequence":"additional","affiliation":[{"name":"Faculty of Biosciences, Heidelberg University, Germany (L.H.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7761-0769","authenticated-orcid":true,"given":"Alexander","family":"Nickel","sequence":"additional","affiliation":[{"name":"Department of Translational Research, Comprehensive Heart Failure Center (A.N., M.K., M.F., S.L., J. Kees, J.M., C.M.), University Hospital W\u00fcrzburg, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6132-6037","authenticated-orcid":true,"given":"Michael","family":"Kohlhaas","sequence":"additional","affiliation":[{"name":"Department of Translational Research, Comprehensive Heart Failure Center (A.N., M.K., M.F., S.L., J. Kees, J.M., C.M.), University Hospital W\u00fcrzburg, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4354-891X","authenticated-orcid":true,"given":"Mandy","family":"B\u00f6rmel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-4307-3352","authenticated-orcid":true,"given":"Carlos","family":"Alfonso-Gonzalez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8122-8271","authenticated-orcid":true,"given":"Viola M.J.","family":"Oorschot","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michel","family":"Fungate","sequence":"additional","affiliation":[{"name":"Department of Translational Research, Comprehensive Heart Failure Center (A.N., M.K., M.F., S.L., J. Kees, J.M., C.M.), University Hospital W\u00fcrzburg, Germany."},{"name":"Department of Anaesthesiology, Intensive Care, Emergency and Pain Medicine (M.F.), University Hospital W\u00fcrzburg, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susanne","family":"Lewey","sequence":"additional","affiliation":[{"name":"Department of Translational Research, Comprehensive Heart Failure Center (A.N., M.K., M.F., S.L., J. Kees, J.M., C.M.), University Hospital W\u00fcrzburg, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacob","family":"Kees","sequence":"additional","affiliation":[{"name":"Department of Translational Research, Comprehensive Heart Failure Center (A.N., M.K., M.F., S.L., J. Kees, J.M., C.M.), University Hospital W\u00fcrzburg, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johanna","family":"M\u00fcller","sequence":"additional","affiliation":[{"name":"Department of Translational Research, Comprehensive Heart Failure Center (A.N., M.K., M.F., S.L., J. Kees, J.M., C.M.), University Hospital W\u00fcrzburg, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8838-7163","authenticated-orcid":true,"given":"Dominik","family":"Lindenhofer","sequence":"additional","affiliation":[{"name":"DZHK (German Center for Cardiovascular Research), partner site Heidelberg\/Mannheim, Heidelberg, Germany (J. Kornienko, D.L., K.F., L.K., M.M.G.v.d.H., L.M.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8097-7740","authenticated-orcid":true,"given":"Kai","family":"Fenzl","sequence":"additional","affiliation":[{"name":"DZHK (German Center for Cardiovascular Research), partner site Heidelberg\/Mannheim, Heidelberg, Germany (J. Kornienko, D.L., K.F., L.K., M.M.G.v.d.H., L.M.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-4504-8926","authenticated-orcid":true,"given":"Laura","family":"Schraft","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9530-2938","authenticated-orcid":true,"given":"Sandra","family":"Clauder-M\u00fcnster","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-4700-7433","authenticated-orcid":true,"given":"Laura","family":"Konrad","sequence":"additional","affiliation":[{"name":"DZHK (German Center for Cardiovascular Research), partner site Heidelberg\/Mannheim, Heidelberg, Germany (J. 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