{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T20:24:25Z","timestamp":1790713465971,"version":"4.1.0"},"reference-count":24,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2016,5,12]],"date-time":"2016-05-12T00:00:00Z","timestamp":1463011200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100006006","name":"ICIN Netherlands Heart Institute","doi-asserted-by":"publisher","award":["12301"],"award-info":[{"award-number":["12301"]}],"id":[{"id":"10.13039\/501100006006","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002996","name":"Hartstichting","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100002996","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001826","name":"ZonMw","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001826","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001722","name":"Koninklijke Nederlandse Akademie van Wetenschappen","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001722","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Histopathology"],"published-print":{"date-parts":[[2016,10]]},"abstract":"<jats:sec><jats:title>Aims<\/jats:title><jats:p>The non\u2010desmosomal phospholamban <jats:styled-content style=\"fixed-case\">PLN<\/jats:styled-content> p.Arg14del mutation was identified in patients diagnosed with dilated cardiomyopathy (<jats:styled-content style=\"fixed-case\">DCM<\/jats:styled-content>) and\/or arrhythmogenic cardiomyopathy (<jats:styled-content style=\"fixed-case\">ACM<\/jats:styled-content>). We aimed to investigate whether this mutation leads to aggregation, aggresome formation and autophagy of mutant <jats:styled-content style=\"fixed-case\">PLN<\/jats:styled-content> protein.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods and results<\/jats:title><jats:p>We studied 20 complete heart specimens of <jats:styled-content style=\"fixed-case\">PLN<\/jats:styled-content> p.Arg14del mutation carriers [mean age 48 \u00b1 15 years; 55% males], either from autopsies or from explants. Gross and microscopic examination showed biventricular cardiomyopathy with histopathological features of both <jats:styled-content style=\"fixed-case\">ACM<\/jats:styled-content> and <jats:styled-content style=\"fixed-case\">DCM<\/jats:styled-content>, i.e. a combination of fibrofatty replacement and interstitial fibrosis. Immunohistochemistry for <jats:styled-content style=\"fixed-case\">PLN<\/jats:styled-content> showed large perinuclear <jats:styled-content style=\"fixed-case\">PLN<\/jats:styled-content> protein aggregates in cardiomyocytes in both ventricles in all examined hearts. The median numbers of <jats:styled-content style=\"fixed-case\">PLN<\/jats:styled-content>\u2010containing aggregates were 12 per 5 mm<jats:sup>2<\/jats:sup> range 3\u201348 mm2 in right ventricular myocardium and 13 per 5 mm<jats:sup>2<\/jats:sup> (range 5\u201389 mm<jats:sup>2<\/jats:sup>) in left ventricular myocardium. Double immunohistochemical staining showed colocalization of autophagy markers p62 (sequestosome\u20101) and microtubule\u2010associated protein light chain 3 with <jats:styled-content style=\"fixed-case\">PLN<\/jats:styled-content> in all aggregates, suggestive of degradation by selective autophagy. On electron microscopy, the ultrastructural appearance of these <jats:styled-content style=\"fixed-case\">PLN<\/jats:styled-content>\u2010containing aggregates was typical of aggresomes; they were not surrounded by a membrane, and were located adjacent to the microtubular organizing centre. <jats:styled-content style=\"fixed-case\">PLN<\/jats:styled-content>\u2010containing aggregates were not found in 10 <jats:styled-content style=\"fixed-case\">PLN<\/jats:styled-content>\u2010negative cases of idiopathic and genetic <jats:styled-content style=\"fixed-case\">DCM<\/jats:styled-content> or in seven cases of desmosomal <jats:styled-content style=\"fixed-case\">ACM<\/jats:styled-content>.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p><jats:styled-content style=\"fixed-case\">PLN<\/jats:styled-content> p.Arg14del cardiomyopathy is a biventricular cardiomyopathy characterized by large perinuclear <jats:styled-content style=\"fixed-case\">PLN<\/jats:styled-content> protein aggregates with a typical ultrastructural appearance of aggresomes. <jats:styled-content style=\"fixed-case\">PLN<\/jats:styled-content> detected by immunohistochemistry appears to be a sensitive and specific marker for this disease.<\/jats:p><\/jats:sec>","DOI":"10.1111\/his.12963","type":"journal-article","created":{"date-parts":[[2016,3,13]],"date-time":"2016-03-13T00:35:38Z","timestamp":1457829338000},"page":"542-550","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":64,"title":["Phospholamban p.Arg14del cardiomyopathy is characterized by phospholamban aggregates, aggresomes, and autophagic degradation"],"prefix":"10.1111","volume":"69","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4852-9379","authenticated-orcid":false,"given":"Wouter P","family":"te Rijdt","sequence":"first","affiliation":[{"name":"Department of Cardiology University of Groningen University Medical Centre Groningen Groningen the Netherlands"},{"name":"Department of Pathology University of Groningen University Medical Centre Groningen Groningen the Netherlands"},{"name":"Interuniversity Cardiology Institute of The Netherlands (ICIN) Utrecht the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J Peter","family":"van Tintelen","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics University of Amsterdam Academic Medical Centre Amsterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aryan","family":"Vink","sequence":"additional","affiliation":[{"name":"Department of Pathology University Medical Centre Utrecht Utrecht the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Allard C","family":"van der Wal","sequence":"additional","affiliation":[{"name":"Department of Pathology University of Amsterdam Academic Medical Centre Amsterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rudolf A","family":"de Boer","sequence":"additional","affiliation":[{"name":"Department of Cardiology University of Groningen University Medical Centre Groningen Groningen the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maarten P","family":"van den Berg","sequence":"additional","affiliation":[{"name":"Department of Cardiology University of Groningen University Medical Centre Groningen Groningen the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Albert J H","family":"Suurmeijer","sequence":"additional","affiliation":[{"name":"Department of Pathology University of Groningen University Medical Centre Groningen Groningen the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2016,5,12]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra0902923"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1093\/eurjhf\/hfs119"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1139\/bcb-2014-0080"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1081578"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI17892"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0510519103"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12471-013-0401-3"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2011.11.012"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1106180"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1508815112"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tcm.2012.05.015"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1053\/euhj.1998.1145"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehq025"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0094820"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2006.07.016"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.hrthm.2009.01.016"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCGENETICS.113.000374"},{"key":"e_1_2_8_19_1","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1242\/jcs.88.1.25","article-title":"The microtubule\u2010organizing complex and the Golgi apparatus are co\u2010localized around the entire nuclear envelope of interphase cardiac myocytes","volume":"88","author":"Kronebusch PJ","year":"1987","journal-title":"J. Cell Sci."},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0962-8924(00)01852-3"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.hrthm.2009.07.041"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00601.2011"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms7955"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.4161\/auto.7.3.14487"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000067471.95890.5C"}],"container-title":["Histopathology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1111%2Fhis.12963","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/his.12963","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,3]],"date-time":"2023-10-03T17:53:33Z","timestamp":1696355613000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/his.12963"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,5,12]]},"references-count":24,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2016,10]]}},"alternative-id":["10.1111\/his.12963"],"URL":"https:\/\/doi.org\/10.1111\/his.12963","archive":["Portico"],"relation":{},"ISSN":["0309-0167","1365-2559"],"issn-type":[{"value":"0309-0167","type":"print"},{"value":"1365-2559","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,5,12]]},"assertion":[{"value":"2015-09-11","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2016-03-07","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2016-05-12","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}