Journal article
Mutations in a TGF-β Ligand, TGFB3, Cause Syndromic Aortic Aneurysms and Dissections
Journal of the American College of Cardiology, Vol.65(13), pp.1324-1336
2015
Abstract
Background
Aneurysms affecting the aorta are a common condition associated with high mortality as a result of aortic dissection or rupture. Investigations of the pathogenic mechanisms involved in syndromic types of thoracic aortic aneurysms, such as Marfan and Loeys-Dietz syndromes, have revealed an important contribution of disturbed transforming growth factor (TGF)-β signaling.
Objectives
This study sought to discover a novel gene causing syndromic aortic aneurysms in order to unravel the underlying pathogenesis.
Methods
We combined genome-wide linkage analysis, exome sequencing, and candidate gene Sanger sequencing in a total of 470 index cases with thoracic aortic aneurysms. Extensive cardiological examination, including physical examination, electrocardiography, and transthoracic echocardiography was performed. In adults, imaging of the entire aorta using computed tomography or magnetic resonance imaging was done.
Results
Here, we report on 43 patients from 11 families with syndromic presentations of aortic aneurysms caused by TGFB3 mutations. We demonstrate that TGFB3 mutations are associated with significant cardiovascular involvement, including thoracic/abdominal aortic aneurysm and dissection, and mitral valve disease. Other systemic features overlap clinically with Loeys-Dietz, Shprintzen-Goldberg, and Marfan syndromes, including cleft palate, bifid uvula, skeletal overgrowth, cervical spine instability and clubfoot deformity. In line with previous observations in aortic wall tissues of patients with mutations in effectors of TGF-β signaling (TGFBR1/2, SMAD3, and TGFB2), we confirm a paradoxical up-regulation of both canonical and noncanonical TGF-β signaling in association with up-regulation of the expression of TGF-β ligands.
Conclusions
Our findings emphasize the broad clinical variability associated with TGFB3 mutations and highlight the importance of early recognition of the disease because of high cardiovascular risk.
Details
- Title
- Mutations in a TGF-β Ligand, TGFB3, Cause Syndromic Aortic Aneurysms and Dissections
- Authors/Creators
- A.M. Bertoli-Avella (Author/Creator) - Department of Clinical GeneticsE. Gillis (Author/Creator) - Antwerp University HospitalH. Morisaki (Author/Creator) - National Cerebral and Cardiovascular CenterJ.M.A. Verhagen (Author/Creator) - Erasmus MCB.M. de Graaf (Author/Creator) - Erasmus MCG. van de Beek (Author/Creator) - Antwerp University HospitalE. Gallo (Author/Creator) - Johns Hopkins MedicineB.P.T. Kruithof (Author/Creator) - Leiden University Medical CenterH. Venselaar (Author/Creator) - Radboud University NijmegenL.A. Myers (Author/Creator) - Johns Hopkins MedicineS. Laga (Author/Creator) - Antwerp University HospitalA.J. Doyle (Author/Creator) - Johns Hopkins MedicineG. Oswald (Author/Creator) - Howard Hughes Medical InstituteG.W.A. van Cappellen (Author/Creator) - Erasmus MCI. Yamanaka (Author/Creator) - National Cerebral and Cardiovascular CenterR.M. van der Helm (Author/Creator) - Erasmus MCB. Beverloo (Author/Creator) - Erasmus MCA. de Klein (Author/Creator) - Erasmus MCL. Pardo (Author/Creator) - Erasmus MCM. Lammens (Author/Creator) - University of AntwerpC. Evers (Author/Creator) - Institute of Human Genetics, Heidelberg University; Heidelberg; GermanyK. Devriendt (Author/Creator) - Center for Human GeneticsM. Dumoulein (Author/Creator) - AZ GroeningeJ. Timmermans (Author/Creator) - Radboud University Medical CenterH.T. Bruggenwirth (Author/Creator) - Erasmus MCF. Verheijen (Author/Creator) - Erasmus MCI. Rodrigus (Author/Creator) - Antwerp University HospitalG. Baynam (Author/Creator) - The University of Western AustraliaM. Kempers (Author/Creator) - Radboud University NijmegenJ. Saenen (Author/Creator) - Antwerp University HospitalE.M. Van Craenenbroeck (Author/Creator) - Antwerp University HospitalK. Minatoya (Author/Creator) - National Cerebral and Cardiovascular CenterR. Matsukawa (Author/Creator) - Japanese Red Cross Kobe HospitalT. Tsukube (Author/Creator) - Japanese Red Cross Kobe HospitalN. Kubo (Author/Creator) - Red Cross HospitalR. Hofstra (Author/Creator)M.J. Goumans (Author/Creator) - Leiden University Medical CenterJ.A. Bekkers (Author/Creator) - Erasmus MCJ.W. Roos-Hesselink (Author/Creator) - Erasmus MCI.M.B.H. van de Laar (Author/Creator) - Erasmus MCH.C. Dietz (Author/Creator) - Johns Hopkins MedicineL. Van Laer (Author/Creator) - Antwerp University HospitalT. Morisaki (Author/Creator) - The University of OsakaM.W. Wessels (Author/Creator) - Erasmus MCB.L. Loeys (Author/Creator) - Medical Genetics Center
- Publication Details
- Journal of the American College of Cardiology, Vol.65(13), pp.1324-1336
- Publisher
- Elsevier
- Identifiers
- 991005544180307891
- Murdoch Affiliation
- Murdoch University
- Language
- English
- Resource Type
- Journal article
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- Collaboration types
- Domestic collaboration
- International collaboration
- Citation topics
- 1 Clinical & Life Sciences
- 1.168 Vascular, Cardiac & Thoracic Surgery
- 1.168.235 Aortic Aneurysms
- Web Of Science research areas
- Cardiac & Cardiovascular Systems
- ESI research areas
- Clinical Medicine