{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,25]],"date-time":"2026-07-25T22:18:54Z","timestamp":1785017934918,"version":"3.55.0"},"reference-count":54,"publisher":"Wiley","issue":"14","license":[{"start":{"date-parts":[[2017,6,1]],"date-time":"2017-06-01T00:00:00Z","timestamp":1496275200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["HL128683"],"award-info":[{"award-number":["HL128683"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002996","name":"Hartstichting","doi-asserted-by":"publisher","award":["Dekker scholarship\u2010Junior Staff Member 2014T001"],"award-info":[{"award-number":["Dekker scholarship\u2010Junior Staff Member 2014T001"]}],"id":[{"id":"10.13039\/501100002996","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002996","name":"Hartstichting","doi-asserted-by":"publisher","award":["CVON2011\u201011 ARENA"],"award-info":[{"award-number":["CVON2011\u201011 ARENA"]}],"id":[{"id":"10.13039\/501100002996","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002996","name":"Hartstichting","doi-asserted-by":"publisher","award":["CVON2014\u201040 DOSIS"],"award-info":[{"award-number":["CVON2014\u201040 DOSIS"]}],"id":[{"id":"10.13039\/501100002996","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2017,7,15]]},"abstract":"<jats:sec><jats:title>Key points<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>Mutations in genes encoding cardiac troponin I (<jats:italic>TNNI3<\/jats:italic>) and cardiac troponin T (<jats:italic>TNNT2<\/jats:italic>) caused altered troponin protein stoichiometry in patients with dilated cardiomyopathy.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p><jats:italic>TNNI3<jats:sub>p.98trunc<\/jats:sub><\/jats:italic> resulted in haploinsufficiency, increased Ca<jats:sup>2+<\/jats:sup>\u2010sensitivity and reduced length\u2010dependent activation.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p><jats:italic>TNNT2<jats:sub>p.K217del<\/jats:sub><\/jats:italic> caused increased passive tension.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>A mutation in the gene encoding Lamin A\/C (<jats:italic>LMNA<\/jats:italic><jats:italic><jats:sub>p.R331Q<\/jats:sub><\/jats:italic>) led to reduced maximal force development through secondary disease remodelling in patients suffering from dilated cardiomyopathy.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Our study shows that different gene mutations induce dilated cardiomyopathy via diverse cellular pathways.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec><jats:sec><jats:title>Abstract<\/jats:title><jats:p>Dilated cardiomyopathy (DCM) can be caused by mutations in sarcomeric and non\u2010sarcomeric genes. In this study we defined the pathogenic effects of three DCM\u2010causing mutations: the sarcomeric mutations in genes encoding cardiac troponin I (<jats:italic>TNNI3<jats:sub>p.98truncation<\/jats:sub><\/jats:italic>) and cardiac troponin T (<jats:italic>TNNT2<jats:sub>p.K217deletion<\/jats:sub><\/jats:italic>; also known as the p.K210del) and the non\u2010sarcomeric gene mutation encoding lamin A\/C (<jats:italic>LMNA<jats:sub>p.R331Q<\/jats:sub><\/jats:italic>). We assessed sarcomeric protein expression and phosphorylation and contractile behaviour in single membrane\u2010permeabilized cardiomyocytes in human left ventricular heart tissue. Exchange with recombinant troponin complex was used to establish the direct pathogenic effects of the mutations in <jats:italic>TNNI3<\/jats:italic> and <jats:italic>TNNT2<\/jats:italic>. The <jats:italic>TNNI3<jats:sub>p.98trunc<\/jats:sub><\/jats:italic> and <jats:italic>TNNT2<jats:sub>p.K217del<\/jats:sub><\/jats:italic> mutation showed reduced expression of troponin I to 39% and 51%, troponin T to 64% and 53%, and troponin C to 73% and 97% of controls, respectively, and altered stoichiometry between the three cardiac troponin subunits. The <jats:italic>TNNI3<jats:sub>p.98trunc<\/jats:sub><\/jats:italic> showed pure haploinsufficiency, increased Ca<jats:sup>2+<\/jats:sup>\u2010sensitivity and impaired length\u2010dependent activation. The <jats:italic>TNNT2<jats:sub>p.K217del<\/jats:sub><\/jats:italic> mutation showed a significant increase in passive tension that was not due to changes in titin isoform composition or phosphorylation. Exchange with wild\u2010type troponin complex corrected troponin protein levels to 83% of controls in the <jats:italic>TNNI3<jats:sub>p.98trunc<\/jats:sub><\/jats:italic> sample. Moreover, upon exchange all functional deficits in the <jats:italic>TNNI3<jats:sub>p.98trunc<\/jats:sub><\/jats:italic> and <jats:italic>TNNT2<jats:sub>p.K217del<\/jats:sub><\/jats:italic> samples were normalized to control values confirming the pathogenic effects of the troponin mutations. The <jats:italic>LMNA<jats:sub>p.R331Q<\/jats:sub><\/jats:italic> mutation resulted in reduced maximal force development due to disease remodelling. Our study shows that different gene mutations induce DCM via diverse cellular pathways.<\/jats:p><\/jats:sec>","DOI":"10.1113\/jp274145","type":"journal-article","created":{"date-parts":[[2017,4,24]],"date-time":"2017-04-24T05:56:59Z","timestamp":1493013419000},"page":"4677-4693","source":"Crossref","is-referenced-by-count":40,"title":["Genotype\u2010specific pathogenic effects in human dilated cardiomyopathy"],"prefix":"10.1113","volume":"595","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6378-9825","authenticated-orcid":false,"given":"Ilse A. 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