TGFB2 loss of function mutations cause familial thoracic aortic aneurysms and acute aortic dissections associated with mild systemic features of the Marfan syndrome

作者：C. Boileau, D. Guo, N. Hanna, Ellen S. Regalado, D. Détaint, L. Gong, M. Varret, Siddharth K. Prakash, Alexander Hanbo Li, H. d’Indy, A. Braverman, B. Grandchamp, Callie S. Kwartler, L. Gouya, R. Santos-Cortez, M. Abifadel, S. Leal, C. Muti, J. Shendure, M. Gross, M. Rieder, A. Vahanian, D. Nickerson, J. Michel, G. Jondeau, D. Milewicz · 发表于：Nature Genetics · 年份：2012 · DOI：10.1038/ng.2348 · 被引用次数：267 · 研究领域：Medicine、Biology

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)-β2, and the mutations are predicted to cause haploinsufficiency for TGFB2; however, aortic tissue from cases paradoxically shows increased TGF-β2 expression and immunostaining. Thus, haploinsufficiency for TGFB2 predisposes to thoracic aortic disease, suggesting that the initial pathway driving disease is decreased cellular TGF-β2 levels leading to a secondary increase in TGF-β2 production in the diseased aorta.