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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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.
The authors declare no competing financial interests.
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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) doi:10.1038/ng.744
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