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Mutations in desmosomal genes are a major cause of ACM, but the role of desmocollin-2 (DSC2) remains understudied.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods and results<\/jats:title>\n                  <jats:p>We conducted a multi-cohort study with 52 ACM patients, 29 with dilated cardiomyopathy (DCM), 17 with hypertrophic cardiomyopathy (HCM), and 45 controls. Immunofluorescence, immunohistochemical staining, and western blot were used to assess DSC2 expression. DSC2 expression was significantly reduced in ACM myocardium compared to controls and other cardiomyopathies (P &amp;lt; 0.0001), consistent across ACM subtypes and validated in an independent cohort. DSC2 down-regulation correlated with clinical characteristics such as age at onset of arrhythmia and heart transplantation. DSC2 reduction in the right ventricle effectively discriminated ACM patients from controls (ROC AUC = 0.8017, P &amp;lt; 0.0001) and distinguished ACM from other cardiac diseases. Immunohistochemical staining in the Swiss cohort confirmed that 11 out of 12 (91.7%) ACM cases exhibited significantly reduced DSC2 signal intensity compared to normal donors. RNA-Seq analysis revealed significant down-regulation of DSC2 genes in ACM tissues.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>DSC2 remodelling is a hallmark of ACM, harbouring significant diagnostic implications. DSC2 reduction is a robust biomarker for ACM, showing high sensitivity and specificity across different subtypes. Future research should elucidate the mechanisms underlying DSC2 down-regulation.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/europace\/euaf199","type":"journal-article","created":{"date-parts":[[2025,8,29]],"date-time":"2025-08-29T12:53:07Z","timestamp":1756471987000},"source":"Crossref","is-referenced-by-count":6,"title":["Comprehensive analysis of desmosomal protein remodelling identifies desmocollin-2 as potential biomarker for arrhythmogenic cardiomyopathy"],"prefix":"10.1093","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4595-3281","authenticated-orcid":false,"given":"Jie","family":"Ren","sequence":"first","affiliation":[{"name":"State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College , No. 167 North Lishi Road, Xicheng District, Beijing 100037, 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Zurich, R\u00e4mistrasse 100, Zurich CH-8091 ,","place":["Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiquan","family":"Ye","sequence":"additional","affiliation":[{"name":"Center of Forensic Science, Jinan University, No. 110 Dongguanzhuang Road, Tianhe District, Guangzhou 510610 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1896-0803","authenticated-orcid":false,"given":"Ardan M","family":"Saguner","sequence":"additional","affiliation":[{"name":"University Heart Center, University Hospital Zurich and University of Zurich, R\u00e4mistrasse 100, Zurich CH-8091 ,","place":["Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingming","family":"Su","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College , No. 167 North Lishi Road, Xicheng District, Beijing 100037, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-5286-5571","authenticated-orcid":false,"given":"Hongbin","family":"Dong","sequence":"additional","affiliation":[{"name":"Department of Radiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 167 North Lishi Road, Xicheng District, Beijing 100037 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3135-2669","authenticated-orcid":false,"given":"Zhongli","family":"Chen","sequence":"additional","affiliation":[{"name":"Cardiac Arrhythmias Center, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 167 North Lishi Road, Xicheng District, Beijing 100037 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0994-8434","authenticated-orcid":false,"given":"Dan","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Heart Failure and Cardiomyopathy, Department of Cardiology & Cardiovascular Research Institute, Renmin Hospital of Wuhan University, 238 Jiefang Road, Wuhan 430060 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-7192-1149","authenticated-orcid":false,"given":"Shengshou","family":"Hu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College , No. 167 North Lishi Road, Xicheng District, Beijing 100037, 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