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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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Overview of Families With TGFB3 MutationsThe causal TGFB3 mutation is shown for each family. Probands are indicated with an arrow. Circle: female; square: male; open symbol: unaffected; solid symbol: affected; diagonal line: deceased; brackets: adopted; question mark: clinical affection status unknown. Plus and minus signs indicate presence or absence of a TGFB3 mutation, respectively.
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fig2: Overview of Families With TGFB3 MutationsThe causal TGFB3 mutation is shown for each family. Probands are indicated with an arrow. Circle: female; square: male; open symbol: unaffected; solid symbol: affected; diagonal line: deceased; brackets: adopted; question mark: clinical affection status unknown. Plus and minus signs indicate presence or absence of a TGFB3 mutation, respectively.

Mentions: Genomic DNA was extracted from peripheral blood samples (Gentra Systems, Qiagen, Hilden, Germany). RNA from 2 patients (1-II:12 and III:11) (Figure 1) was extracted from peripheral blood (collected in PAXgene tubes, PreAnalyliX, Qiagen) according to the manufacturer’s protocol (PreAnalyliX, Qiagen).


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)

Overview of Families With TGFB3 MutationsThe causal TGFB3 mutation is shown for each family. Probands are indicated with an arrow. Circle: female; square: male; open symbol: unaffected; solid symbol: affected; diagonal line: deceased; brackets: adopted; question mark: clinical affection status unknown. Plus and minus signs indicate presence or absence of a TGFB3 mutation, respectively.
© Copyright Policy
Related In: Results  -  Collection

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

fig2: Overview of Families With TGFB3 MutationsThe causal TGFB3 mutation is shown for each family. Probands are indicated with an arrow. Circle: female; square: male; open symbol: unaffected; solid symbol: affected; diagonal line: deceased; brackets: adopted; question mark: clinical affection status unknown. Plus and minus signs indicate presence or absence of a TGFB3 mutation, respectively.
Mentions: Genomic DNA was extracted from peripheral blood samples (Gentra Systems, Qiagen, Hilden, Germany). RNA from 2 patients (1-II:12 and III:11) (Figure 1) was extracted from peripheral blood (collected in PAXgene tubes, PreAnalyliX, Qiagen) according to the manufacturer’s protocol (PreAnalyliX, Qiagen).

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