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

IMBH van de Laar, RA Oldenburg, G Pals… - Nature …, 2011 - nature.com
IMBH van de Laar, RA Oldenburg, G Pals, JW Roos-Hesselink, BM de Graaf, JMA Verhagen…
Nature genetics, 2011nature.com
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 …
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 transmission,,. 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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