Nature genetics · 2011
Mutations in SMAD3 cause a syndromic form of aortic aneurysms and dissections with early-onset osteoarthritis.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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van de Laar Ingrid M B H, Oldenburg Rogier A, Pals Gerard, Roos-Hesselink Jolien W, de Graaf Bianca M, Verhagen Judith M A, Hoedemaekers Yvonne M, Willemsen Rob, Severijnen Lies-Anne, Venselaar Hanka, Vriend Gert, Pattynama Peter M, Collée Margriet, Majoor-Krakauer Danielle, Poldermans Don, Frohn-Mulder Ingrid M E, Micha Dimitra, Timmermans Janneke, Hilhorst-Hofstee Yvonne, Bierma-Zeinstra Sita M, Willems Patrick J, Kros Johan M, Oei Edwin H G, Oostra Ben A, Wessels Marja W, Bertoli-Avella Aida M
Аннотация
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.