{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T04:46:29Z","timestamp":1783658789680,"version":"3.55.0"},"reference-count":40,"publisher":"Oxford University Press (OUP)","issue":"17","license":[{"start":{"date-parts":[[2024,4,18]],"date-time":"2024-04-18T00:00:00Z","timestamp":1713398400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"DMK"},{"name":"HVB"},{"name":"ASIJ"},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82203318"],"award-info":[{"award-number":["82203318"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005230","name":"Natural Science Foundation of Chongqing","doi-asserted-by":"publisher","award":["CSTB2022NSCQ-MSX0880"],"award-info":[{"award-number":["CSTB2022NSCQ-MSX0880"]}],"id":[{"id":"10.13039\/501100005230","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,12,31]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Aims<\/jats:title>\n                  <jats:p>Aortic aneurysms (AA) frequently involve dysregulation of transforming growth factor \u03b2 (TGF-\u03b2)-signalling in the aorta. Here, FURIN was tested as aneurysm predisposition gene given its role as proprotein convertase in pro-TGF-\u03b2 maturation.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods and results<\/jats:title>\n                  <jats:p>Rare FURIN variants were detected by whole-exome sequencing of 781 unrelated aortic aneurysm patients and affected relatives. Thirteen rare heterozygous FURIN variants occurred in 3.7% (29) unrelated index AA patients, of which 72% had multiple aneurysms or a dissection. FURIN maturation and activity of these variants were decreased in vitro. Patient-derived fibroblasts showed decreased pro-TGF-\u03b2 processing, phosphorylation of downstream effector SMAD2 and kinases ERK1\/2, and steady-state mRNA levels of the TGF-\u03b2-responsive ACTA2 gene. In aortic tissue, collagen and fibrillin fibres were affected. One variant (R745Q), observed in 10 unrelated cases, affected TGF-\u03b2 signalling variably, indicating effect modification by individual genetic backgrounds.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>FURIN is a novel, frequent genetic predisposition for abdominal-, thoracic-, and multiple aortic or middle sized artery aneurysms in older patients, by affecting intracellular TGF-\u03b2 signalling, depending on individual genetic backgrounds.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/cvr\/cvae078","type":"journal-article","created":{"date-parts":[[2024,4,18]],"date-time":"2024-04-18T01:05:18Z","timestamp":1713402318000},"page":"2278-2292","source":"Crossref","is-referenced-by-count":9,"title":["The proprotein convertase <i>FURIN<\/i> is a novel aneurysm predisposition gene impairing TGF-\u03b2 signalling"],"prefix":"10.1093","volume":"120","author":[{"given":"Zongsheng","family":"He","sequence":"first","affiliation":[{"name":"Laboratory of Biochemical Neuroendocrinology, Department of Human Genetics, KU Leuven , Gasthuisberg O\/N 06, Herestraat 49, Box 607, Leuven B-3000 ,","place":["Belgium"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arne S","family":"IJpma","sequence":"additional","affiliation":[{"name":"Department of Pathology, Erasmus MC University Medical Center , Dr. Molewater 40, PO BOX 2040, Rotterdam 3000 CA ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dianne","family":"Vreeken","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Erasmus MC University Medical Center , Dr. Molewaterplein 40, PO BOX 2040, Rotterdam 3015 GD ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daphne","family":"Heijsman","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics , Erasmus MC University Medical Center, Dr Molewaterplein 40 PO BOX 2040, 3000CA Rotterdam ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen","family":"Rosier","sequence":"additional","affiliation":[{"name":"Laboratory of Biochemical Neuroendocrinology, Department of Human Genetics, KU Leuven , Gasthuisberg O\/N 06, Herestraat 49, Box 607, Leuven B-3000 ,","place":["Belgium"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hence J M","family":"Verhagen","sequence":"additional","affiliation":[{"name":"Department of Surgery, Erasmus MC University Medical Center , Dr. Molewaterplein 40, PO BOX 2040, 3000 CA Rotterdam ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jorg L","family":"de Bruin","sequence":"additional","affiliation":[{"name":"Department of Surgery, Erasmus MC University Medical Center , Dr. Molewaterplein 40, PO BOX 2040, 3000 CA Rotterdam ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hennie T","family":"Br\u00fcggenwirth","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics , Erasmus MC University Medical Center, Dr Molewaterplein 40 PO BOX 2040, 3000CA Rotterdam ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jolien W","family":"Roos-Hesselink","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Erasmus MC University Medical Center , Dr. Molewaterplein 40, PO BOX 2040, Rotterdam 3015 GD ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos A","family":"Bekkers","sequence":"additional","affiliation":[{"name":"Department of Cardiothoracic Surgery, Erasmus MC University Medical Center , Dr. Molewaterplein 40, PO BOX 2040, 3000 CA Rotterdam ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danny F E","family":"Huylebroeck","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, Erasmus MC University Medical Center , Dr. Molewaterplein 40, PO BOX 2040, 3000 CA Rotterdam ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heleen M M","family":"van Beusekom","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Erasmus MC University Medical Center , Dr. Molewaterplein 40, PO BOX 2040, Rotterdam 3015 GD ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2518-9295","authenticated-orcid":false,"given":"John W M","family":"Creemers","sequence":"additional","affiliation":[{"name":"Laboratory of Biochemical Neuroendocrinology, Department of Human 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