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Patient dermal fibroblasts were reprogrammed to hiPSC, isogenic controls were established by CRISPR\/Cas9, and cardiomyocytes were differentiated. Mutant cardiomyocytes revealed significantly prolonged Ca\n                    <jats:sup>2+<\/jats:sup>\n                    transient decay time, Ca\n                    <jats:sup>2+<\/jats:sup>\n                    \u2010load dependent irregular beating pattern, and lower force. Proteomic analysis revealed less endoplasmic reticulum (ER) and ribosomal and mitochondrial proteins. Electron microscopy showed dilation of the ER and large lipid droplets in close association with mitochondria. Follow\u2010up experiments confirmed impairment of the ER\/mitochondria compartment. PLN p.Arg14del end\u2010stage heart failure samples revealed perinuclear aggregates positive for ER marker proteins and oxidative stress in comparison with ischemic heart failure and non\u2010failing donor heart samples. Transduction of PLN p.Arg14del EHTs with the Ca\n                    <jats:sup>2+<\/jats:sup>\n                    \u2010binding proteins GCaMP6f or parvalbumin improved the disease phenotype. This study identified impairment of the ER\/mitochondria compartment without SR dysfunction as a novel disease mechanism underlying PLN p.Arg14del cardiomyopathy. The pathology was improved by Ca\n                    <jats:sup>2+<\/jats:sup>\n                    \u2010scavenging, suggesting impaired local Ca\n                    <jats:sup>2+<\/jats:sup>\n                    cycling as an important disease culprit.\n                  <\/jats:p>","DOI":"10.15252\/emmm.202013074","type":"journal-article","created":{"date-parts":[[2021,5,17]],"date-time":"2021-05-17T02:15:08Z","timestamp":1621217708000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":66,"title":["Impairment of the ER\/mitochondria compartment in human cardiomyocytes with PLN p.Arg14del mutation"],"prefix":"10.1038","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1612-1715","authenticated-orcid":false,"given":"Friederike","family":"Cuello","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anika E","family":"Knaust","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Umber","family":"Saleem","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Malte","family":"Loos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janice","family":"Raabe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2306-3915","authenticated-orcid":false,"given":"Diogo","family":"Mosqueira","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra","family":"Laufer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michaela","family":"Schweizer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Petra","family":"van der Kraak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frederik","family":"Flenner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"B\u00e4rbel M","family":"Ulmer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ingke","family":"Braren","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoke","family":"Yin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Konstantinos","family":"Theofilatos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jorge","family":"Ruiz\u2010Orera","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giannino","family":"Patone","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Birgit","family":"Klampe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Schulze","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angelika","family":"Piasecki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yigal","family":"Pinto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aryan","family":"Vink","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Norbert","family":"H\u00fcbner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sian","family":"Harding","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manuel","family":"Mayr","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chris","family":"Denning","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Eschenhagen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2628-0453","authenticated-orcid":false,"given":"Arne","family":"Hansen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,5,16]]},"reference":[{"key":"BFEMMM202013074_CR1","doi-asserted-by":"crossref","first-page":"9229","DOI":"10.1038\/s41598-019-45047-9","volume":"9","author":"MA Branco","year":"2019","unstructured":"Branco MA, Cotovio JP, Rodrigues CAV, Vaz SH, Fernandes TG, Moreira LM, Cabral JMS, Diogo MM (2019) Transcriptomic analysis of 3D cardiac differentiation of human induced pluripotent stem cells reveals faster cardiomyocyte maturation compared to 2D culture. 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