TY - JOUR
T1 - The proprotein convertase FURIN is a novel aneurysm predisposition gene impairing TGF-β signalling
AU - He, Zongsheng
AU - IJpma, Arne S.
AU - Vreeken, Dianne
AU - Heijsman, Daphne
AU - Rosier, Karen
AU - Verhagen, Hence J.M.
AU - de Bruin, Jorg L.
AU - Brüggenwirth, Hennie T.
AU - Roos-Hesselink, Jolien W.
AU - Bekkers, Jos A.
AU - Huylebroeck, Danny F.E.
AU - van Beusekom, Heleen M.M.
AU - Creemers, John W.M.
AU - Majoor-Krakauer, Danielle
N1 - Publisher Copyright:
© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.
PY - 2024/12
Y1 - 2024/12
N2 - AIMS: Aortic aneurysms (AA) frequently involve dysregulation of transforming growth factor β (TGF-β)-signalling in the aorta. Here, FURIN was tested as aneurysm predisposition gene given its role as proprotein convertase in pro-TGF-β maturation. METHODS AND RESULTS: 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-β processing, phosphorylation of downstream effector SMAD2 and kinases ERK1/2, and steady-state mRNA levels of the TGF-β-responsive ACTA2 gene. In aortic tissue, collagen and fibrillin fibres were affected. One variant (R745Q), observed in 10 unrelated cases, affected TGF-β signalling variably, indicating effect modification by individual genetic backgrounds. CONCLUSION: 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-β signalling, depending on individual genetic backgrounds.
AB - AIMS: Aortic aneurysms (AA) frequently involve dysregulation of transforming growth factor β (TGF-β)-signalling in the aorta. Here, FURIN was tested as aneurysm predisposition gene given its role as proprotein convertase in pro-TGF-β maturation. METHODS AND RESULTS: 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-β processing, phosphorylation of downstream effector SMAD2 and kinases ERK1/2, and steady-state mRNA levels of the TGF-β-responsive ACTA2 gene. In aortic tissue, collagen and fibrillin fibres were affected. One variant (R745Q), observed in 10 unrelated cases, affected TGF-β signalling variably, indicating effect modification by individual genetic backgrounds. CONCLUSION: 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-β signalling, depending on individual genetic backgrounds.
UR - http://www.scopus.com/inward/record.url?scp=85210664793&partnerID=8YFLogxK
U2 - 10.1093/cvr/cvae078
DO - 10.1093/cvr/cvae078
M3 - Article
C2 - 38636100
AN - SCOPUS:85210664793
SN - 0008-6363
VL - 120
SP - 2278
EP - 2292
JO - Cardiovascular Research
JF - Cardiovascular Research
IS - 17
ER -