Details

Autor(en) / Beteiligte

• Lindsay, Mark E
• Schepers, Dorien
• Bolar, Nikhita Ajit
• Doyle, Jefferson J
• Gallo, Elena
• Fert-Bober, Justyna
• Kempers, Marlies J E
• Fishman, Elliot K
• Chen, Yichun
• Myers, Loretha
• Bjeda, Djahita
• Oswald, Gretchen
• Elias, Abdallah F
• Levy, Howard P
• Anderlid, Britt-Marie
• Yang, Margaret H
• Bongers, Ernie M H F
• Timmermans, Janneke
• Braverman, Alan C
• Canham, Natalie
• Mortier, Geert R
• Brunner, Han G
• Byers, Peter H
• Van Eyk, Jennifer
• Van Laer, Lut
• Dietz, Harry C
• Loeys, Bart L

Titel

Loss-of-function mutations in TGFB2 cause a syndromic presentation of thoracic aortic aneurysm

Ist Teil von

• Nature genetics, 2012-08, Vol.44 (8), p.922-927

Ort / Verlag

New York: Nature Publishing Group US

Erscheinungsjahr

2012

Quelle

MEDLINE

Beschreibungen/Notizen

• Bart Loeys and colleagues identify mutations or deletions of TGFB2 in individuals with thoracic aortic aneurysm and other features of Loeys-Dietz syndrome. TGFB2 encodes the transforming growth factor-β2 ligand. Loeys-Dietz syndrome (LDS) associates with a tissue signature for high transforming growth factor (TGF)-β signaling but is often caused by heterozygous mutations in genes encoding positive effectors of TGF-β signaling, including either subunit of the TGF-β receptor or SMAD3, thereby engendering controversy regarding the mechanism of disease. Here, we report heterozygous mutations or deletions in the gene encoding the TGF-β2 ligand for a phenotype within the LDS spectrum and show upregulation of TGF-β signaling in aortic tissue from affected individuals. Furthermore, haploinsufficient Tgfb2 +/− mice have aortic root aneurysm and biochemical evidence of increased canonical and noncanonical TGF-β signaling. Mice that harbor both a mutant Marfan syndrome (MFS) allele ( Fbn1 C1039G/+ ) and Tgfb2 haploinsufficiency show increased TGF-β signaling and phenotypic worsening in association with normalization of TGF-β2 expression and high expression of TGF-β1. Taken together, these data support the hypothesis that compensatory autocrine and/or paracrine events contribute to the pathogenesis of TGF-β–mediated vasculopathies.