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- Title
TGFB2 mutations cause familial thoracic aortic aneurysms and dissections associated with mild systemic features of Marfan syndrome.
- Authors
Boileau, Catherine; Guo, Dong-Chuan; Hanna, Nadine; Regalado, Ellen S; Detaint, Delphine; Gong, Limin; Varret, Mathilde; Prakash, Siddharth K; Li, Alexander H; d'Indy, Hyacintha; Braverman, Alan C; Grandchamp, Bernard; Kwartler, Callie S; Gouya, Laurent; Santos-Cortez, Regie Lyn P; Abifadel, Marianne; Leal, Suzanne M; Muti, Christine; Shendure, Jay; Gross, Marie-Sylvie
- Abstract
A predisposition for thoracic aortic aneurysms leading to acute aortic dissections can be inherited in families in an autosomal dominant manner. Genome-wide linkage analysis of two large unrelated families with thoracic aortic disease followed by whole-exome sequencing of affected relatives identified causative mutations in TGFB2. These mutations-a frameshift mutation in exon 6 and a nonsense mutation in exon 4-segregated with disease with a combined logarithm of odds (LOD) score of 7.7. Sanger sequencing of 276 probands from families with inherited thoracic aortic disease identified 2 additional TGFB2 mutations. TGFB2 encodes transforming growth factor (TGF)-?2, and the mutations are predicted to cause haploinsufficiency for TGFB2; however, aortic tissue from cases paradoxically shows increased TGF-?2 expression and immunostaining. Thus, haploinsufficiency for TGFB2 predisposes to thoracic aortic disease, suggesting that the initial pathway driving disease is decreased cellular TGF-?2 levels leading to a secondary increase in TGF-?2 production in the diseased aorta.
- Subjects
TRANSFORMING growth factors-beta; NONSENSE mutation; THORACIC aneurysms; MARFAN syndrome; AORTIC dissection; GENE expression; GENETIC code
- Publication
Nature Genetics, 2012, Vol 44, Issue 8, p916
- ISSN
1061-4036
- Publication type
Article
- DOI
10.1038/ng.2348