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Mutations in SMAD3 cause a syndromic form of aortic aneurysms and dissections with early-onset osteoarthritis


Thoracic aortic aneurysms and dissections are a main feature of connective tissue disorders, such as Marfan syndrome and Loeys-Dietz syndrome. We delineated a new syndrome presenting with aneurysms, dissections and tortuosity throughout the arterial tree in association with mild craniofacial features and skeletal and cutaneous anomalies. In contrast with other aneurysm syndromes, most of these affected individuals presented with early-onset osteoarthritis. We mapped the genetic locus to chromosome 15q22.2–24.2 and show that the disease is caused by mutations in SMAD3. This gene encodes a member of the TGF-β pathway that is essential for TGF-β signal transmission1,2,3. SMAD3 mutations lead to increased aortic expression of several key players in the TGF-β pathway, including SMAD3. Molecular diagnosis will allow early and reliable identification of cases and relatives at risk for major cardiovascular complications. Our findings endorse the TGF-β pathway as the primary pharmacological target for the development of new treatments for aortic aneurysms and osteoarthritis.

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Figure 1: Clinical features of cases from family 1.
Figure 2: SMAD3 and mutations.
Figure 3: Histology of aortic media in aneurysms-osteoarthritis syndrome.
Figure 4: Immunohistochemistry in aneurysms-osteoarthritis syndrome.

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We are indebted to all cases and family members for their enthusiastic participation in the study.

We acknowledge W. van IJcken from the Erasmus Center for Biomics for processing the Affymetrix 250K SNP arrays. We thank E. Steyerberg (Department of Public Health, Erasmus Medical Center, Rotterdam, The Netherlands) for the survival analysis and H. Weinans (Department of Orthopedics, Erasmus Medical Center, Rotterdam, The Netherlands) for helpful discussions. We thank T. de Vries-Lentsch, R. Koppenol (Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands) and F. van der Panne (Department of Pathology, Erasmus Medical Center, Rotterdam, The Netherlands) for the photographic work and W. Dinjens from the Department of Pathology, Erasmus Medical Center, Rotterdam, The Netherlands, for isolation of DNA from paraffin-embedded tissues.

This work was partially funded by an Erasmus Fellowship (Erasmus Medical Center, The Netherlands) to A.M.B.-A. and a grant from the Center for Biomedical Genetics (CBG), The Netherlands to B.A.O.

Author information




A.M.B.-A. designed and directed the study. I.M.B.H.v.d.L., R.A.O., J.W.R.-H., Y.M.H., E.H.G.O., J.M.A.V., P.M.P., D.M.-K., D.P., I.M.E.F.-M., S.M.B.-Z., Y.H.-H., M.C., J.T. and M.W.W. evaluated the cases and relatives. G.P., D.M., J.M.A.V., D.P. and D.M.-K. contributed with DNA sample collections. B.M.d.G. generated and processed genotype and sequence data. L.-A.S. and R.W. performed and interpreted the immunohistochemistry. J.M.K. supervised the histopathological studies. H.V. and G.V. performed, analyzed and described the protein molecular modeling. B.A.O. contributed to the interpretation and supervision of the genetic work. I.M.B.H.v.d.L. and A.M.B.-A. wrote the manuscript. P.J.W., M.W.W. and G.P. contributed to the analysis and interpretation of the genetic data and substantially contributed to the manuscript. All authors have read and contributed to the manuscript.

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Correspondence to Aida M Bertoli-Avella.

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The authors declare no competing financial interests.

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Supplementary Figures 1–5, Supplementary Note and Supplementary Table 1 (PDF 974 kb)

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van de Laar, I., Oldenburg, R., Pals, G. et al. Mutations in SMAD3 cause a syndromic form of aortic aneurysms and dissections with early-onset osteoarthritis. Nat Genet 43, 121–126 (2011).

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