Details

Autor(en) / Beteiligte

• Bertoli-Avella, Aida M
• Gillis, Elisabeth
• Morisaki, Hiroko
• Verhagen, Judith MA
• de Graaf, Bianca M
• van de Beek, Gerarda
• Gallo, Elena
• Kruithof, Boudewijn PT
• Venselaar, Hanka
• Myers, Loretha A
• Laga, Steven
• Doyle, Alexander J
• Oswald, Gretchen
• van Cappellen, Gert WA
• Yamanaka, Itaru
• van der Helm, Robert M
• Beverloo, Berna
• de Klein, Annelies
• Pardo, Luba
• Lammens, Martin
• Evers, Christina
• Devriendt, Koenraad
• Dumoulein, Michiel
• Timmermans, Janneke
• Bruggenwirth, Hennie T
• Verheijen, Frans
• Rodrigus, Inez
• Baynam, Gareth
• Kempers, Marlies
• Saenen, Johan
• Van Craenenbroeck, Emeline M
• Minatoya, Kenji
• Matsukawa, Ritsu
• Tsukube, Takuro
• Kubo, Noriaki
• Hofstra, Robert
• Goumans, Marie Jose
• Bekkers, Jos A
• Roos-Hesselink, Jolien W
• van de Laar, Ingrid MBH
• Dietz, Harry C
• Van Laer, Lut
• Morisaki, Takayuki
• Wessels, Marja W
• Loeys, Bart L

Titel

Mutations in a TGF-[beta] Ligand, TGFB3, Cause Syndromic Aortic Aneurysms and Dissections

Ist Teil von

• Journal of the American College of Cardiology, 2015-04, Vol.65 (13), p.1324

Ort / Verlag

New York: Elsevier Limited

Erscheinungsjahr

2015

Link zum Volltext

Quelle

Access via ScienceDirect (Elsevier)

Beschreibungen/Notizen

• 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 byTGFB3mutations. We demonstrate thatTGFB3mutations 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,andTGFB2), 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 withTGFB3mutations and highlight the importance of early recognition of the disease because of high cardiovascular risk.