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

Ingrid De Graaf - van de Laar, Rogier Oldenburg, G Pals, Jolien Roos - Hesselink, Bianca de Graaf, Judith Verhagen, YM Hoedemaekers, Rob Willemsen, Lies-anne Severijnen, H Venselaar, G Vriend, Peter Pattynama, M Collee, Danielle Majoor - Krakauer, D Poldermans, Ingrid Mulder, D Micha, J Timmermans, Y Hilhorst-Hofstee, Sita Bierma - ZeinstraPJ Willems, J.M. Kros, Edwin Oei, Ben Oostra, Marja Wessels, AM Bertoli Avella

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533 Citations (Scopus)


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-beta pathway that is essential for TGF-beta signal transmission(1-3). SMAD3 mutations lead to increased aortic expression of several key players in the TGF-beta 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-beta pathway as the primary pharmacological target for the development of new treatments for aortic aneurysms and osteoarthritis.
Original languageUndefined/Unknown
Pages (from-to)121-U65
JournalNature Genetics
Issue number2
Publication statusPublished - 2011

Research programs

  • EMC COEUR-09
  • EMC MGC-02-96-01
  • EMC MM-01-51-01
  • EMC MM-03-24-01
  • EMC NIHES-02-67-01
  • EMC NIHES-03-30-01

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