title: Mutations in SMAD3 cause a syndromic form of aortic aneurysms and dissections with early-onset osteoarthritis.
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.
authors.affiliation: Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Ingrid M B H
authors.initials: IM
authors.lastname: van de Laar
authors.forename: Rogier A
authors.initials: RA
authors.lastname: Oldenburg
authors.forename: Gerard
authors.initials: G
authors.lastname: Pals
authors.forename: Jolien W
authors.initials: JW
authors.lastname: Roos-Hesselink
authors.forename: Bianca M
authors.initials: BM
authors.lastname: de Graaf
authors.forename: Judith M A
authors.initials: JM
authors.lastname: Verhagen
authors.forename: Yvonne M
authors.initials: YM
authors.lastname: Hoedemaekers
authors.forename: Rob
authors.initials: R
authors.lastname: Willemsen
authors.forename: Lies-Anne
authors.initials: LA
authors.lastname: Severijnen
authors.forename: Hanka
authors.initials: H
authors.lastname: Venselaar
authors.forename: Gert
authors.initials: G
authors.lastname: Vriend
authors.forename: Peter M
authors.initials: PM
authors.lastname: Pattynama
authors.forename: Margriet
authors.initials: M
authors.lastname: Collée
authors.forename: Danielle
authors.initials: D
authors.lastname: Majoor-Krakauer
authors.forename: Don
authors.initials: D
authors.lastname: Poldermans
authors.forename: Ingrid M E
authors.initials: IM
authors.lastname: Frohn-Mulder
authors.forename: Dimitra
authors.initials: D
authors.lastname: Micha
authors.forename: Janneke
authors.initials: J
authors.lastname: Timmermans
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Hilhorst-Hofstee
authors.forename: Sita M
authors.initials: SM
authors.lastname: Bierma-Zeinstra
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Willems
authors.forename: Johan M
authors.initials: JM
authors.lastname: Kros
authors.forename: Edwin H G
authors.initials: EH
authors.lastname: Oei
authors.forename: Ben A
authors.initials: BA
authors.lastname: Oostra
authors.forename: Marja W
authors.initials: MW
authors.lastname: Wessels
authors.forename: Aida M
authors.initials: AM
authors.lastname: Bertoli-Avella
mesh_terms: D017668:Age of Onset; D001013:Aorta, Thoracic / Q000378:metabolism; D001014:Aortic Aneurysm / Q000150:complications / Q000000981:diagnostic imaging / Q000235:genetics*; D002884:Chromosomes, Human, Pair 15; D005192:Family Health; D005260:Female; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D008297:Male; D009154:Mutation; D010003:Osteoarthritis / Q000150:complications / Q000235:genetics* / Q000378:metabolism; D011859:Radiography; D015398:Signal Transduction; D051900:Smad3 Protein / Q000235:genetics*; D013577:Syndrome; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: C497790:SMAD3 protein, human; D051900:Smad3 Protein; D016212:Transforming Growth Factor beta