{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T02:56:08Z","timestamp":1792205768594,"version":"4.4.0"},"reference-count":50,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2015,4,29]],"date-time":"2015-04-29T00:00:00Z","timestamp":1430265600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2015,4,29]],"date-time":"2015-04-29T00:00:00Z","timestamp":1430265600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nat Commun"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    A number of genetic mutations is associated with cardiomyopathies. A mutation in the coding region of the phospholamban (\n                    <jats:italic>PLN<\/jats:italic>\n                    ) gene (R14del) is identified in families with hereditary heart failure. Heterozygous patients exhibit left ventricular dilation and ventricular arrhythmias. Here we generate induced pluripotent stem cells (iPSCs) from a patient harbouring the\n                    <jats:italic>PLN<\/jats:italic>\n                    R14del mutation and differentiate them into cardiomyocytes (iPSC-CMs). We find that the\n                    <jats:italic>PLN<\/jats:italic>\n                    R14del mutation induces Ca\n                    <jats:sup>2+<\/jats:sup>\n                    handling abnormalities, electrical instability, abnormal cytoplasmic distribution of PLN protein and increases expression of molecular markers of cardiac hypertrophy in iPSC-CMs. Gene correction using transcription activator-like effector nucleases (TALENs) ameliorates the R14del-associated disease phenotypes in iPSC-CMs. In addition, we show that knocking down the endogenous\n                    <jats:italic>PLN<\/jats:italic>\n                    and simultaneously expressing a codon-optimized\n                    <jats:italic>PLN<\/jats:italic>\n                    gene reverses the disease phenotype\n                    <jats:italic>in vitro<\/jats:italic>\n                    . Our findings offer novel strategies for targeting the pathogenic mutations associated with cardiomyopathies.\n                  <\/jats:p>","DOI":"10.1038\/ncomms7955","type":"journal-article","created":{"date-parts":[[2015,4,29]],"date-time":"2015-04-29T09:25:34Z","timestamp":1430299534000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":188,"title":["Correction of human phospholamban R14del mutation associated with cardiomyopathy using targeted nucleases and combination therapy"],"prefix":"10.1038","volume":"6","author":[{"given":"Ioannis","family":"Karakikes","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Stillitano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mathieu","family":"Nonnenmacher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christos","family":"Tzimas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3704-1941","authenticated-orcid":false,"given":"Despina","family":"Sanoudou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vittavat","family":"Termglinchan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chi-Wing","family":"Kong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie","family":"Rushing","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jens","family":"Hansen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Delaine","family":"Ceholski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fotis","family":"Kolokathis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dimitrios","family":"Kremastinos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandros","family":"Katoulis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lihuan","family":"Ren","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ninette","family":"Cohen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johannes M.I.H.","family":"Gho","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dimitrios","family":"Tsiapras","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aryan","family":"Vink","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph C.","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1692-8669","authenticated-orcid":false,"given":"Folkert W.","family":"Asselbergs","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ronald A.","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Sebastien","family":"Hulot","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evangelia G.","family":"Kranias","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roger J.","family":"Hajjar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2015,4,29]]},"reference":[{"key":"BFncomms7955_CR1","doi-asserted-by":"publisher","first-page":"531","DOI":"10.1038\/nrcardio.2013.105","volume":"10","author":"RE Hershberger","year":"2013","unstructured":"Hershberger, R. E., Hedges, D. J. & Morales, A. Dilated cardiomyopathy: the complexity of a diverse genetic architecture. Nat. Rev. Cardiol. 10, 531\u2013547 (2013).","journal-title":"Nat. Rev. Cardiol."},{"key":"BFncomms7955_CR2","doi-asserted-by":"publisher","first-page":"198","DOI":"10.1097\/HCO.0b013e328337ba52","volume":"25","author":"L Dellefave","year":"2010","unstructured":"Dellefave, L. & McNally, E. M. The genetics of dilated cardiomyopathy. Curr. Opin. Cardiol. 25, 198\u2013204 (2010).","journal-title":"Curr. Opin. Cardiol."},{"key":"BFncomms7955_CR3","doi-asserted-by":"publisher","first-page":"1410","DOI":"10.1126\/science.1081578","volume":"299","author":"JP Schmitt","year":"2003","unstructured":"Schmitt, J. P. et al. Dilated cardiomyopathy and heart failure caused by a mutation in phospholamban. 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Genetic deletion of arginine 14 in phospholamban causes dilated cardiomyopathy with attenuated electrocardiographic R amplitudes. Heart Rhythm 6, 480\u2013486 (2009).","journal-title":"Heart Rhythm"},{"key":"BFncomms7955_CR9","doi-asserted-by":"publisher","first-page":"1199","DOI":"10.1093\/eurjhf\/hfs119","volume":"14","author":"PA van der Zwaag","year":"2012","unstructured":"van der Zwaag, P. A. et al. Phospholamban R14del mutation in patients diagnosed with dilated cardiomyopathy or arrhythmogenic right ventricular cardiomyopathy: evidence supporting the concept of arrhythmogenic cardiomyopathy. Eur. J. Heart Fail. 14, 1199\u20131207 (2012).","journal-title":"Eur. J. Heart Fail."},{"key":"BFncomms7955_CR10","doi-asserted-by":"publisher","first-page":"773","DOI":"10.1016\/j.yjmcc.2011.11.012","volume":"52","author":"K Haghighi","year":"2012","unstructured":"Haghighi, K. et al. 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