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.
Subscribe to Journal
Get full journal access for 1 year
only $4.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
NCBI Reference Sequence
Zhang, Y., Feng, X., We, R. & Derynck, R. Receptor-associated Mad homologues synergize as effectors of the TGF-beta response. Nature 383, 168–172 (1996).
Massague, J., Seoane, J. & Wotton, D. Smad transcription factors. Genes Dev. 19, 2783–2810 (2005).
Datto, M.B. et al. Targeted disruption of Smad3 reveals an essential role in transforming growth factor beta-mediated signal transduction. Mol. Cell. Biol. 19, 2495–2504 (1999).
Lilienfeld, D.E., Gunderson, P.D., Sprafka, J.M. & Vargas, C. Epidemiology of aortic aneurysms: I. Mortality trends in the United States, 1951 to 1981. Arteriosclerosis 7, 637–643 (1987).
Loeys, B.L. et al. A syndrome of altered cardiovascular, craniofacial, neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2. Nat. Genet. 37, 275–281 (2005).
Coucke, P.J. et al. Mutations in the facilitative glucose transporter GLUT10 alter angiogenesis and cause arterial tortuosity syndrome. Nat. Genet. 38, 452–457 (2006).
Maleszewski, J.J., Miller, D.V., Lu, J., Dietz, H.C. & Halushka, M.K. Histopathologic findings in ascending aortas from individuals with Loeys-Dietz syndrome (LDS). Am. J. Surg. Pathol. 33, 194–201 (2009).
Neptune, E.R. et al. Dysregulation of TGF-beta activation contributes to pathogenesis in Marfan syndrome. Nat. Genet. 33, 407–411 (2003).
Wang, X. et al. Increased collagen deposition and elevated expression of connective tissue growth factor in human thoracic aortic dissection. Circulation 114, I200–I205 (2006).
Verrecchia, F., Chu, M.L. & Mauviel, A. Identification of novel TGF-beta /Smad gene targets in dermal fibroblasts using a combined cDNA microarray/promoter transactivation approach. J. Biol. Chem. 276, 17058–17062 (2001).
Loeys, B.L. et al. Aneurysm syndromes caused by mutations in the TGF-beta receptor. N. Engl. J. Med. 355, 788–798 (2006).
Silverman, D.I. et al. Life expectancy in the Marfan syndrome. Am. J. Cardiol. 75, 157–160 (1995).
Chacko, B.M. et al. Structural basis of heteromeric smad protein assembly in TGF-beta signaling. Mol. Cell 15, 813–823 (2004).
Prokova, V., Mavridou, S., Papakosta, P., Petratos, K. & Kardassis, D. Novel mutations in Smad proteins that inhibit signaling by the transforming growth factor beta in mammalian cells. Biochemistry 46, 13775–13786 (2007).
Gomez, D. et al. Syndromic and non-syndromic aneurysms of the human ascending aorta share activation of the Smad2 pathway. J. Pathol. 218, 131–142 (2009).
Yang, X. et al. TGF-beta/Smad3 signals repress chondrocyte hypertrophic differentiation and are required for maintaining articular cartilage. J. Cell Biol. 153, 35–46 (2001).
Li, C.G. et al. A continuous observation of the degenerative process in the intervertebral disc of Smad3 gene knock-out mice. Spine 34, 1363–1369 (2009).
Lacro, R.V. et al. Rationale and design of a randomized clinical trial of beta-blocker therapy (atenolol) versus angiotensin II receptor blocker therapy (losartan) in individuals with Marfan syndrome. Am. Heart J. 154, 624–631 (2007).
Faivre, L. et al. Effect of mutation type and location on clinical outcome in 1,013 probands with Marfan syndrome or related phenotypes and FBN1 mutations: an international study. Am. J. Hum. Genet. 81, 454–466 (2007).
Roman, M.J., Devereux, R.B., Kramer-Fox, R. & O′Loughlin, J. Two-dimensional echocardiographic aortic root dimensions in normal children and adults. Am. J. Cardiol. 64, 507–512 (1989).
Lin, F.Y. et al. Assessment of the thoracic aorta by multidetector computed tomography: age- and sex-specific reference values in adults without evident cardiovascular disease. J. Cardiovasc. Comput. Tomogr. 2, 298–308 (2008).
Kellgren, J.H. & Lawrence, J.S. Radiological assessment of osteo-arthrosis. Ann. Rheum. Dis. 16, 494–502 (1957).
Lane, N.E., Nevitt, M.C., Genant, H.K. & Hochberg, M.C. Reliability of new indices of radiographic osteoarthritis of the hand and hip and lumbar disc degeneration. J. Rheumatol. 20, 1911–1918 (1993).
van de Laar, I. et al. First locus for primary pulmonary vein stenosis maps to chromosome 2q. Eur. Heart J. 30, 2485–2492 (2009).
Hoffmann, K. & Lindner, T.H. easyLINKAGE-Plus–automated linkage analyses using large-scale SNP data. Bioinformatics 21, 3565–3567 (2005).
Krieger, E., Koraimann, G. & Vriend, G. Increasing the precision of comparative models with YASARA NOVA–a self-parameterizing force field. Proteins 47, 393–402 (2002).
Vriend, G. WHAT IF: a molecular modeling and drug design program. J. Mol. Graph. 8, 52–56 (1990).
Bakker, C.E. et al. Immunocytochemical and biochemical characterization of FMRP, FXR1P, and FXR2P in the mouse. Exp. Cell Res. 258, 162–170 (2000).
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.
About this article
Cite this article
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). https://doi.org/10.1038/ng.744
Endovascular repair of a dissecting pararenal abdominal aortic aneurysm in a patient with type III Loeys-Dietz syndrome
Journal of Vascular Surgery Cases and Innovative Techniques (2021)
Arrhythmic Mitral Valve Prolapse: Introducing an Era of Multimodality Imaging-Based Diagnosis and Risk Stratification
Inhibition of lysyl oxidase stimulates TGF-β signaling and metalloproteinases-2 and -9 expression and contributes to the disruption of ascending aorta in rats: protection by propylthiouracil
Heart and Vessels (2021)
The Journal of Thoracic and Cardiovascular Surgery (2021)
Surgical Outcome and Histological Differences between Individuals with <i>TGFBR1</i> and <i>TGFBR2</i> Mutations in Loeys-Dietz Syndrome
Annals of Thoracic and Cardiovascular Surgery (2021)