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The proprotein convertase FURIN is a novel aneurysm predisposition gene impairing TGF-ß signaling.
He, Zongsheng; IJpma, Arne S; Vreeken, Dianne; Heijsman, Daphne; Rosier, Karen; Verhagen, Hence J M; de Bruin, Jorg; Brüggenwirth, Hennie T; Roos-Hesselink, Jolien W; Bekkers, Jos A; Huylebroeck, Danny; van Beusekom, Heleen; Creemers, John W M; Majoor-Krakauer, Danielle.
Afiliación
  • He Z; Department of Human Genetics, KU Leuven, Leuven, B-3000, Belgium.
  • IJpma AS; Departments of Pathology, Erasmus MC University Medical Center, Rotterdam, 3015 GD, the Netherlands.
  • Vreeken D; Cardiology, Erasmus MC University Medical Center, Rotterdam, 3015 GD, the Netherlands.
  • Heijsman D; Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, 3015 GD, the Netherlands.
  • Rosier K; Department of Human Genetics, KU Leuven, Leuven, B-3000, Belgium.
  • Verhagen HJM; Surgery, Erasmus MC University Medical Center, Rotterdam, 3015 GD, the Netherlands.
  • de Bruin J; Surgery, Erasmus MC University Medical Center, Rotterdam, 3015 GD, the Netherlands.
  • Brüggenwirth HT; Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, 3015 GD, the Netherlands.
  • Roos-Hesselink JW; Cardiology, Erasmus MC University Medical Center, Rotterdam, 3015 GD, the Netherlands.
  • Bekkers JA; Cardiothoracic Surgery, Erasmus MC University Medical Center, Rotterdam, 3015 GD, the Netherlands.
  • Huylebroeck D; Cell Biology, Erasmus MC University Medical Center, Rotterdam, 3015 GD, the Netherlands.
  • van Beusekom H; Cardiology, Erasmus MC University Medical Center, Rotterdam, 3015 GD, the Netherlands.
  • Creemers JWM; Department of Human Genetics, KU Leuven, Leuven, B-3000, Belgium.
  • Majoor-Krakauer D; Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, 3015 GD, the Netherlands.
Cardiovasc Res ; 2024 Apr 18.
Article en En | MEDLINE | ID: mdl-38636100
ABSTRACT

AIM:

Aortic aneurysms (AA) frequently involve dysregulation of transforming growth factor ß (TGF-ß)-signaling in the aorta. Here, FURIN was tested as aneurysm predisposition gene given its role as proprotein convertase in pro-TGF-ß 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-ß processing, phosphorylation of downstream effector SMAD2 and kinases ERK1/2, and steady-state mRNA levels of the TGF-ß-responsive ACTA2 gene. In aortic tissue, collagen and fibrillin fibers were affected. One variant (R745Q), observed in 10 unrelated cases, affected TGF-ß signaling 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-ß signaling, depending on individual genetic backgrounds.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Cardiovasc Res Año: 2024 Tipo del documento: Article País de afiliación: Bélgica Pais de publicación: Reino Unido
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Cardiovasc Res Año: 2024 Tipo del documento: Article País de afiliación: Bélgica Pais de publicación: Reino Unido