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

Nature Genetics volume 43, pages 121–126 (2011)Cite this article

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Abstract

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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NCBI Reference Sequence

References

  1. 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).

    Article  CAS  Google Scholar 

  2. Massague, J., Seoane, J. & Wotton, D. Smad transcription factors. Genes Dev. 19, 2783–2810 (2005).

    Article  CAS  Google Scholar 

  3. 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).

    Article  CAS  Google Scholar 

  4. 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).

    Article  CAS  Google Scholar 

  5. 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).

    Article  CAS  Google Scholar 

  6. 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).

    Article  CAS  Google Scholar 

  7. 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).

    Article  Google Scholar 

  8. Neptune, E.R. et al. Dysregulation of TGF-beta activation contributes to pathogenesis in Marfan syndrome. Nat. Genet. 33, 407–411 (2003).

    Article  CAS  Google Scholar 

  9. 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).

    Article  Google Scholar 

  10. 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).

    Article  CAS  Google Scholar 

  11. Loeys, B.L. et al. Aneurysm syndromes caused by mutations in the TGF-beta receptor. N. Engl. J. Med. 355, 788–798 (2006).

    Article  CAS  Google Scholar 

  12. Silverman, D.I. et al. Life expectancy in the Marfan syndrome. Am. J. Cardiol. 75, 157–160 (1995).

    Article  CAS  Google Scholar 

  13. Chacko, B.M. et al. Structural basis of heteromeric smad protein assembly in TGF-beta signaling. Mol. Cell 15, 813–823 (2004).

    Article  CAS  Google Scholar 

  14. 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).

    Article  CAS  Google Scholar 

  15. 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).

    Article  CAS  Google Scholar 

  16. 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).

    Article  CAS  Google Scholar 

  17. 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).

    Article  Google Scholar 

  18. 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).

    Article  CAS  Google Scholar 

  19. 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).

    Article  CAS  Google Scholar 

  20. 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).

    Article  CAS  Google Scholar 

  21. 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).

    Article  Google Scholar 

  22. Kellgren, J.H. & Lawrence, J.S. Radiological assessment of osteo-arthrosis. Ann. Rheum. Dis. 16, 494–502 (1957).

    Article  CAS  Google Scholar 

  23. 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).

    CAS  PubMed  Google Scholar 

  24. van de Laar, I. et al. First locus for primary pulmonary vein stenosis maps to chromosome 2q. Eur. Heart J. 30, 2485–2492 (2009).

    Article  CAS  Google Scholar 

  25. Hoffmann, K. & Lindner, T.H. easyLINKAGE-Plus–automated linkage analyses using large-scale SNP data. Bioinformatics 21, 3565–3567 (2005).

    Article  CAS  Google Scholar 

  26. 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).

    Article  CAS  Google Scholar 

  27. Vriend, G. WHAT IF: a molecular modeling and drug design program. J. Mol. Graph. 8, 52–56 (1990).

    Article  CAS  Google Scholar 

  28. Bakker, C.E. et al. Immunocytochemical and biochemical characterization of FMRP, FXR1P, and FXR2P in the mouse. Exp. Cell Res. 258, 162–170 (2000).

    Article  CAS  Google Scholar 

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Acknowledgements

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.

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Author notes

  1. Ingrid M B H van de Laar and Rogier A Oldenburg: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands

    Ingrid M B H van de Laar, Rogier A Oldenburg, Bianca M de Graaf, Judith M A Verhagen, Yvonne M Hoedemaekers, Rob Willemsen, Lies-Anne Severijnen, Margriet Collée, Danielle Majoor-Krakauer, Ben A Oostra, Marja W Wessels & Aida M Bertoli-Avella

  2. Department of Clinical Genetics, Vrije Universiteit Medical Center, Amsterdam, The Netherlands

    Gerard Pals & Dimitra Micha

  3. Department of Cardiology, Erasmus Medical Center, Rotterdam, The Netherlands

    Jolien W Roos-Hesselink

  4. Nijmegen Center for Molecular Life Sciences (NCMLS), Radboud University Nijmegen Medical Center, The Netherlands

    Hanka Venselaar & Gert Vriend

  5. Center for Molecular and Biomolecular Informatics (CMBI), Nijmegen, The Netherlands

    Hanka Venselaar & Gert Vriend

  6. Department of Radiology, Erasmus Medical Center, Rotterdam, The Netherlands

    Peter M Pattynama & Edwin H G Oei

  7. Department of Vascular Surgery, Erasmus Medical Center, Rotterdam, The Netherlands

    Don Poldermans

  8. Department of Pediatric Cardiology, Erasmus Medical Center, Rotterdam, The Netherlands

    Ingrid M E Frohn-Mulder

  9. Department of Cardiology, Radboud University Nijmegen Medical Center, The Netherlands

    Janneke Timmermans

  10. Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands

    Yvonne Hilhorst-Hofstee

  11. Department of General Practice, Erasmus Medical Center, Rotterdam, The Netherlands

    Sita M Bierma-Zeinstra

  12. GENDIA (GENetic DIAgnostic Network), Antwerp, Belgium

    Patrick J Willems

  13. Department of Pathology, Erasmus Medical Center, Rotterdam, The Netherlands

    Johan M Kros

Authors
  1. Ingrid M B H van de Laar
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Contributions

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.

Corresponding author

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). https://doi.org/10.1038/ng.744

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