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We identified a rare c.740C&gt;T (p.T247M) mutation in\n                    <jats:italic>ACTN2<\/jats:italic>\n                    , encoding \u03b1\u2010actinin 2 in a HCM patient, who presented with left ventricular hypertrophy, outflow tract obstruction, and atrial fibrillation. We generated patient\u2010derived human\u2010induced pluripotent stem cells (hiPSCs) and show that hiPSC\u2010derived cardiomyocytes and engineered heart tissues recapitulated several hallmarks of HCM, such as hypertrophy, myofibrillar disarray, hypercontractility, impaired relaxation, and higher myofilament Ca\n                    <jats:sup>2+<\/jats:sup>\n                    sensitivity, and also prolonged action potential duration and enhanced L\u2010type Ca\n                    <jats:sup>2+<\/jats:sup>\n                    current. The L\u2010type Ca\n                    <jats:sup>2+<\/jats:sup>\n                    channel blocker diltiazem reduced force amplitude, relaxation, and action potential duration to a greater extent in HCM than in isogenic control. We translated our findings to patient care and showed that diltiazem application ameliorated the prolonged QTc interval in HCM\u2010affected son and sister of the index patient. These data provide evidence for this\n                    <jats:italic>ACTN2<\/jats:italic>\n                    mutation to be disease\u2010causing in cardiomyocytes, guiding clinical therapy in this HCM family. This study may serve as a proof\u2010of\u2010principle for the use of hiPSC for personalized treatment of cardiomyopathies.\n                  <\/jats:p>","DOI":"10.15252\/emmm.201911115","type":"journal-article","created":{"date-parts":[[2019,11,4]],"date-time":"2019-11-04T02:59:42Z","timestamp":1572836382000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":118,"title":["Disease modeling of a mutation in \u03b1\u2010actinin 2 guides clinical therapy in hypertrophic cardiomyopathy"],"prefix":"10.1038","volume":"11","author":[{"given":"Maksymilian","family":"Prondzynski","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc D","family":"Lemoine","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonia TL","family":"Zech","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andr\u00e1s","family":"Horv\u00e1th","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vittoria","family":"Di Mauro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jussi T","family":"Koivum\u00e4ki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nico","family":"Kresin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Josefine","family":"Busch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tobias","family":"Krause","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisabeth","family":"Kr\u00e4mer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saskia","family":"Schlossarek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Spohn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Felix W","family":"Friedrich","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"M\u00fcnch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra D","family":"Laufer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles","family":"Redwood","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander E","family":"Volk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arne","family":"Hansen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulia","family":"Mearini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniele","family":"Catalucci","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Meyer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Torsten","family":"Christ","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monica","family":"Patten","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Eschenhagen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8776-5820","authenticated-orcid":false,"given":"Lucie","family":"Carrier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2019,11,3]]},"reference":[{"key":"BFEMMM201911115_CR1","doi-asserted-by":"crossref","first-page":"697","DOI":"10.1016\/j.jacc.2004.11.043","volume":"45","author":"AS Adabag","year":"2005","unstructured":"Adabag AS, Casey SA, Kuskowski MA, Zenovich AG, Maron BJ (2005) Spectrum and prognostic significance of arrhythmias on ambulatory Holter electrocardiogram in hypertrophic cardiomyopathy. 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