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Phosphorylation of RS domain is important for splicing control and nucleocytoplasmic transport in the cell. RNA\u2010binding motif 20 (RBM20) is a splicing factor primarily expressed in the heart. A previous study using phospho\u2010antibody against RS domain showed that RS domain can be phosphorylated. However, its actual phosphorylation sites and function have not been characterized. Using middle\u2010down mass spectrometry, we identified 16 phosphorylation sites, two of which (S638 and S640 in rats, or S637 and S639 in mice) were located in the RSRSP stretch in the RS domain. Mutations on S638 and S640 regulated splicing, promoted nucleocytoplasmic transport and protein\u2010RNA condensates. Phosphomimetic mutations on S638 and S640 indicated that phosphorylation was not the major cause for RBM20 nucleocytoplasmic transport and condensation in vitro. We generated a S637A knock\u2010in (KI) mouse model (Rbm20\n                    <jats:sup>S637A<\/jats:sup>\n                    ) and observed the reduced RBM20 phosphorylation. The KI mice exhibited aberrant gene splicing, protein condensates, and a dilated cardiomyopathy (DCM)\u2010like phenotype. Transcriptomic profiling demonstrated that KI mice had altered expression and splicing of genes involving cardiac dysfunction, protein localization, and condensation. Our in vitro data showed that phosphorylation was not a direct cause for nucleocytoplasmic transport and protein condensation. Subsequently, the in vivo results reveal that RBM20\u00a0mutations led to cardiac pathogenesis. However, the role of phosphorylation in vivo needs further investigation.\n                  <\/jats:p>","DOI":"10.1096\/fj.202101811rr","type":"journal-article","created":{"date-parts":[[2022,4,8]],"date-time":"2022-04-08T09:59:44Z","timestamp":1649411984000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["RBM20 phosphorylation and its role in nucleocytoplasmic transport and cardiac pathogenesis"],"prefix":"10.1096","volume":"36","author":[{"given":"Yanghai","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Animal and Dairy Sciences University of Wisconsin\u2010Madison  Wisconsin USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunyan","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Animal and Dairy Sciences University of Wisconsin\u2010Madison  Wisconsin 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A.","family":"Hacker","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine Department of Medicine University of Wisconsin School of Medicine and Public Health  Madison Wisconsin USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Liss","sequence":"additional","affiliation":[{"name":"Neuromuscular and Cardiovascular Cell Biology Max Delbrueck Center for Molecular Medicine in the Helmholtz Association  Berlin Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Gotthardt","sequence":"additional","affiliation":[{"name":"Neuromuscular and Cardiovascular Cell Biology Max Delbrueck Center for Molecular Medicine in the Helmholtz Association  Berlin Germany"},{"name":"Charit\u00e9 Universit\u00e4tsmedizin  Berlin Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henk","family":"Granzier","sequence":"additional","affiliation":[{"name":"Department of Cellular and 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