{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,30]],"date-time":"2026-05-30T02:33:39Z","timestamp":1780108419637,"version":"3.54.0"},"reference-count":43,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"10","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circ: Genomic and Precision Medicine"],"published-print":{"date-parts":[[2018,10]]},"abstract":"<jats:sec>\n            <jats:title>Background:<\/jats:title>\n            <jats:p>Arrhythmogenic cardiomyopathy (ACM) is an inherited cardiac disease characterized by progressive fibro-fatty myocardial replacement, ventricular arrhythmia, heart failure, and sudden death. Causative mutations can be identified in 60% of patients, and most of them are found in genes encoding mechanical junction proteins of the intercalated disk.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods:<\/jats:title>\n            <jats:p>\n              Whole-exome sequencing was performed on the proband of an ACM family. Sanger sequencing was used to screen for mutations the tight junction protein 1 (\n              <jats:italic>TJP1<\/jats:italic>\n              ) gene in unrelated patients. Predictions of local structure content and molecular dynamics simulations were performed to investigate the structural impact of the variants.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results:<\/jats:title>\n            <jats:p>\n              A novel c.2006A&gt;G p.(Y669C) variant in\n              <jats:italic>TJP1<\/jats:italic>\n              gene was identified by whole-exome sequencing in a patient with ACM.\n              <jats:italic>TJP1<\/jats:italic>\n              encodes zonula occludens 1, an intercalated disk protein interacting with proteins of gap junctions and area composita. Additional rare\n              <jats:italic>TJP1<\/jats:italic>\n              variants have been identified in 1 of 40 Italian probands (c.793C&gt;T p.(R265W)) with arrhythmogenic right ventricular cardiomyopathy and in 2 of 43 Dutch\/German patients (c. 986C&gt;T, p.(S329L) and c.1079A&gt;T, p.(D360V)) with dilated cardiomyopathy and recurrent ventricular tachycardia. The p.(D360V) variant was identified in a proband also carrying the p.(I156N) pathogenic variant in\n              <jats:italic>DSP<\/jats:italic>\n              . All 4\n              <jats:italic>TJP1<\/jats:italic>\n              variants are predicted to be deleterious and affect highly conserved amino acids, either at the GUK (guanylate kinase)\u2013like domain (p.(Y669C)) or at the disordered region of the protein between the PDZ2 and PDZ3 domains (p.(R265W), p.(S329L), and p.(D360V)). The local unfolding induced by the former promotes structural rearrangements of the GUK domain, whereas the others are predicted to impair the function of the disordered region. Furthermore, rare variants in\n              <jats:italic>TJP1<\/jats:italic>\n              are statistically enriched in patients with ACM relative to controls.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions:<\/jats:title>\n            <jats:p>\n              We provide here the first evidence linking likely pathogenic\n              <jats:italic>TJP1<\/jats:italic>\n              variants to ACM. Prevalence and pathogenic mechanism of\n              <jats:italic>TJP1<\/jats:italic>\n              -mediated ACM remain to be determined.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circgen.118.002123","type":"journal-article","created":{"date-parts":[[2018,10,12]],"date-time":"2018-10-12T09:04:46Z","timestamp":1539335086000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":38,"title":["Whole-Exome Sequencing Identifies Pathogenic Variants in\n            <i>TJP1<\/i>\n            Gene Associated With Arrhythmogenic Cardiomyopathy"],"prefix":"10.1161","volume":"11","author":[{"given":"Marzia","family":"De Bortoli","sequence":"first","affiliation":[{"name":"Departments of Biology (M.D.B., G.P., M.C., A.L., G.V., A.R.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alex V.","family":"Postma","sequence":"additional","affiliation":[{"name":"Department of Medical Biology and Department of Clinical Genetics, Academic Medical Center, Amsterdam, The Netherlands (A.V.P.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulia","family":"Poloni","sequence":"additional","affiliation":[{"name":"Departments of Biology (M.D.B., G.P., M.C., A.L., G.V., A.R.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martina","family":"Calore","sequence":"additional","affiliation":[{"name":"Departments of Biology (M.D.B., G.P., M.C., A.L., G.V., A.R.)"},{"name":"Department of Cardiology, CARIM School for Cardiovascular Diseases, Maastricht University, Maastricht, the Netherland (M.C.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanni","family":"Minervini","sequence":"additional","affiliation":[{"name":"Biomedical Sciences (G.M., S.C.E.T.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisa","family":"Mazzotti","sequence":"additional","affiliation":[{"name":"Cardiac, Thoracic, and Vascular Sciences (E.M., I.R., A.C., R.B., M.P.M.,G.T., L.D., D.C., C.B., B.B.), University of Padua, Italy."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilaria","family":"Rigato","sequence":"additional","affiliation":[{"name":"Cardiac, Thoracic, and Vascular Sciences (E.M., I.R., A.C., R.B., M.P.M.,G.T., L.D., D.C., C.B., B.B.), University of Padua, Italy."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Micaela","family":"Ebert","sequence":"additional","affiliation":[{"name":"Department of Electrophysiology, Heart Center, University of Leipzig, Germany (M.E., D.H.)."},{"name":"Department of Cardiology, Leiden University Medical Center, The Netherlands (M.E.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandra","family":"Lorenzon","sequence":"additional","affiliation":[{"name":"Departments of Biology (M.D.B., G.P., M.C., A.L., G.V., A.R.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanni","family":"Vazza","sequence":"additional","affiliation":[{"name":"Departments of Biology (M.D.B., G.P., M.C., A.L., G.V., A.R.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alberto","family":"Cipriani","sequence":"additional","affiliation":[{"name":"Cardiac, Thoracic, and Vascular Sciences (E.M., I.R., A.C., R.B., M.P.M.,G.T., L.D., D.C., C.B., B.B.), University of Padua, Italy."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Riccardo","family":"Bariani","sequence":"additional","affiliation":[{"name":"Cardiac, Thoracic, and Vascular Sciences (E.M., I.R., A.C., R.B., M.P.M.,G.T., L.D., D.C., C.B., B.B.), University of Padua, Italy."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martina","family":"Perazzolo Marra","sequence":"additional","affiliation":[{"name":"Cardiac, Thoracic, and Vascular Sciences (E.M., I.R., A.C., R.B., M.P.M.,G.T., L.D., D.C., C.B., B.B.), University of Padua, Italy."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela","family":"Husser","sequence":"additional","affiliation":[{"name":"Department of Electrophysiology, Heart Center, University of Leipzig, Germany (M.E., D.H.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gaetano","family":"Thiene","sequence":"additional","affiliation":[{"name":"Cardiac, Thoracic, and Vascular Sciences (E.M., I.R., A.C., R.B., M.P.M.,G.T., L.D., D.C., C.B., B.B.), University of Padua, Italy."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luciano","family":"Daliento","sequence":"additional","affiliation":[{"name":"Cardiac, Thoracic, and Vascular Sciences (E.M., I.R., A.C., R.B., M.P.M.,G.T., L.D., D.C., C.B., B.B.), University of Padua, Italy."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Domenico","family":"Corrado","sequence":"additional","affiliation":[{"name":"Cardiac, Thoracic, and Vascular 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