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Mutations in a TGF-β ligand, TGFB3, cause syndromic aortic aneurysms and dissections.

Bertoli-Avella AM, Gillis E, Morisaki H, Verhagen JM, de Graaf BM, van de Beek G, Gallo E, Kruithof BP, Venselaar H, Myers LA, Laga S, Doyle AJ, Oswald G, van Cappellen GW, Yamanaka I, van der Helm RM, Beverloo B, de Klein A, Pardo L, Lammens M, Evers C, Devriendt K, Dumoulein M, Timmermans J, Bruggenwirth HT, Verheijen F, Rodrigus I, Baynam G, Kempers M, Saenen J, Van Craenenbroeck EM, Minatoya K, Matsukawa R, Tsukube T, Kubo N, Hofstra R, Goumans MJ, Bekkers JA, Roos-Hesselink JW, van de Laar IM, Dietz HC, Van Laer L, Morisaki T, Wessels MW, Loeys BL - J. Am. Coll. Cardiol. (2015)

Bottom Line: Aneurysms affecting the aorta are a common condition associated with high mortality as a result of aortic dissection or rupture.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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, the Netherlands; Center of Medical Genetics, Faculty of Medicine and Health Sciences, University of Antwerp and Antwerp University Hospital, Antwerp, Belgium; Department of Cardiology, Erasmus University Medical Center, Rotterdam, the Netherlands. Electronic address: a.bertoliavella@erasmusmc.nl.

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The Pathway From Patient to Gene and BackThe figure summarizes how initial identification of patients and families, followed by linkage and mutation analysis led to the discovery of TGFB3 mutations. Further exploration of the TGF-β pathway allowed a better phenotypical delineation and characterization that will have implications in personalized clinical management.
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fig1: The Pathway From Patient to Gene and BackThe figure summarizes how initial identification of patients and families, followed by linkage and mutation analysis led to the discovery of TGFB3 mutations. Further exploration of the TGF-β pathway allowed a better phenotypical delineation and characterization that will have implications in personalized clinical management.

Mentions: We demonstrate that mutations in the TGFB3 ligand are responsible for a syndromic form of aortic aneurysmal disease. Consistent with our previous findings in TGFBR1/2, SMAD3, and TGFB2 mutation carriers, our study also provides evidence for a paradoxical increase in TGF-β signaling in the aorta. The clinical histories of the patients in our cohort warrant lifelong and widespread cardiovascular surveillance in patients with TGFB3 mutations (Central Illustration). Further research explaining the wide clinical variability is strongly indicated.


Mutations in a TGF-β ligand, TGFB3, cause syndromic aortic aneurysms and dissections.

Bertoli-Avella AM, Gillis E, Morisaki H, Verhagen JM, de Graaf BM, van de Beek G, Gallo E, Kruithof BP, Venselaar H, Myers LA, Laga S, Doyle AJ, Oswald G, van Cappellen GW, Yamanaka I, van der Helm RM, Beverloo B, de Klein A, Pardo L, Lammens M, Evers C, Devriendt K, Dumoulein M, Timmermans J, Bruggenwirth HT, Verheijen F, Rodrigus I, Baynam G, Kempers M, Saenen J, Van Craenenbroeck EM, Minatoya K, Matsukawa R, Tsukube T, Kubo N, Hofstra R, Goumans MJ, Bekkers JA, Roos-Hesselink JW, van de Laar IM, Dietz HC, Van Laer L, Morisaki T, Wessels MW, Loeys BL - J. Am. Coll. Cardiol. (2015)

The Pathway From Patient to Gene and BackThe figure summarizes how initial identification of patients and families, followed by linkage and mutation analysis led to the discovery of TGFB3 mutations. Further exploration of the TGF-β pathway allowed a better phenotypical delineation and characterization that will have implications in personalized clinical management.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4380321&req=5

fig1: The Pathway From Patient to Gene and BackThe figure summarizes how initial identification of patients and families, followed by linkage and mutation analysis led to the discovery of TGFB3 mutations. Further exploration of the TGF-β pathway allowed a better phenotypical delineation and characterization that will have implications in personalized clinical management.
Mentions: We demonstrate that mutations in the TGFB3 ligand are responsible for a syndromic form of aortic aneurysmal disease. Consistent with our previous findings in TGFBR1/2, SMAD3, and TGFB2 mutation carriers, our study also provides evidence for a paradoxical increase in TGF-β signaling in the aorta. The clinical histories of the patients in our cohort warrant lifelong and widespread cardiovascular surveillance in patients with TGFB3 mutations (Central Illustration). Further research explaining the wide clinical variability is strongly indicated.

Bottom Line: Aneurysms affecting the aorta are a common condition associated with high mortality as a result of aortic dissection or rupture.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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, the Netherlands; Center of Medical Genetics, Faculty of Medicine and Health Sciences, University of Antwerp and Antwerp University Hospital, Antwerp, Belgium; Department of Cardiology, Erasmus University Medical Center, Rotterdam, the Netherlands. Electronic address: a.bertoliavella@erasmusmc.nl.

Show MeSH
Related in: MedlinePlus