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Variants in the RS domain have been reported in many DCM patients, but the pathogenicity of variants within the RNA-recognition motif remains unknown. Two human patients with the I536T-<jats:italic>RBM20<\/jats:italic> variant without an apparent DCM phenotype were identified in sudden death cohorts. A splicing reporter assay was performed, and an I538T knock-in mouse model (<jats:italic>Rbm20<\/jats:italic><jats:sup><jats:italic>I538T<\/jats:italic><\/jats:sup>) was generated to determine the significance of this variant. The reporter assay demonstrated that the human I536T variant affected the <jats:italic>TTN<\/jats:italic> splicing pattern compared to wild-type. In the mouse experiments, <jats:italic>Rbm20<\/jats:italic><jats:sup><jats:italic>I538T<\/jats:italic><\/jats:sup> mice showed different splicing patterns in <jats:italic>Ttn<\/jats:italic>, <jats:italic>Ldb3<\/jats:italic>, <jats:italic>Camk2d<\/jats:italic>, and <jats:italic>Ryr2<\/jats:italic>. The expressions of <jats:italic>Casq1<\/jats:italic>, <jats:italic>Mybpc2<\/jats:italic>, and <jats:italic>Myot<\/jats:italic> were upregulated in <jats:italic>Rbm20<\/jats:italic><jats:sup><jats:italic>I538T<\/jats:italic><\/jats:sup> mice, but <jats:italic>Rbm20<\/jats:italic><jats:sup><jats:italic>I538T<\/jats:italic><\/jats:sup> mice showed neither DCM nor cardiac dysfunction on histopathological examination and ultrasound echocardiography. The I536T-<jats:italic>RBM20<\/jats:italic> (I538T-<jats:italic>Rbm20<\/jats:italic>) variant changes gene splicing and affects gene expression, but the splicing and expression changes in <jats:italic>Ttn<\/jats:italic> and Ca handling genes such as <jats:italic>Casq1<\/jats:italic>, <jats:italic>Camk2d<\/jats:italic>, and <jats:italic>Ryr2<\/jats:italic> do not cause DCM morphology in the mouse model.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Key messages<\/jats:title>\n                <jats:p>\u2022 Two human patients with the I536T-<jats:italic>RBM20<\/jats:italic> variant without a DCM phenotype were identified.<\/jats:p>\n                <jats:p>\u2022 A splicing reporter assay demonstrated that the variant affected the <jats:italic>TTN<\/jats:italic> splicing.<\/jats:p>\n                <jats:p>\u2022\u00a0<jats:italic>Rbm20<\/jats:italic><jats:sup><jats:italic>I538T<\/jats:italic><\/jats:sup> mice showed neither DCM nor cardiac dysfunction.<\/jats:p>\n                <jats:p>\u2022\u00a0<jats:italic>Rbm20<\/jats:italic><jats:sup><jats:italic>I538T<\/jats:italic><\/jats:sup> mice showed different splicing patterns and the gene expressions.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1007\/s00109-022-02262-8","type":"journal-article","created":{"date-parts":[[2022,10,5]],"date-time":"2022-10-05T18:26:18Z","timestamp":1664994378000},"page":"1741-1754","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["I536T variant of RBM20 affects splicing of cardiac structural proteins that are causative for developing dilated cardiomyopathy"],"prefix":"10.1007","volume":"100","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5690-885X","authenticated-orcid":false,"given":"Takuma","family":"Yamamoto","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rie","family":"Sano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aya","family":"Miura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mai","family":"Imasaka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshiro","family":"Naito","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minori","family":"Nishiguchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kensuke","family":"Ihara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naruhito","family":"Otani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshihiko","family":"Kominato","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masaki","family":"Ohmuraya","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hidehito","family":"Kuroyanagi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hajime","family":"Nishio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,10,5]]},"reference":[{"key":"2262_CR1","doi-asserted-by":"publisher","first-page":"655","DOI":"10.1016\/j.hrthm.2014.01.017","volume":"11","author":"RD Bagnall","year":"2014","unstructured":"Bagnall RD, Das KJ, Duflou J, Semsarian C (2014) Exome analysis\u2013based molecular autopsy in cases of sudden unexplained death in the young. 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All animal experiments were performed with the approval of the Hyogo Medical University Institutional Animal Care and Use Committee (18\u2013078) and the ARRIVE guideline.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval"}},{"value":"The authors declare no competing interests.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}]}}