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

Nat Genet. 2012 Jul 8;44(8):916-21. doi: 10.1038/ng.2348.

Catherine Boileau ¹, Dong-Chuan Guo, Nadine Hanna, Ellen S Regalado, Delphine Detaint, Limin Gong, Mathilde Varret, Siddharth K Prakash, Alexander H Li, Hyacintha d'Indy, Alan C Braverman, Bernard Grandchamp, Callie S Kwartler, Laurent Gouya, Regie Lyn P Santos-Cortez, Marianne Abifadel, Suzanne M Leal, Christine Muti, Jay Shendure, Marie-Sylvie Gross, Mark J Rieder, Alec Vahanian, Deborah A Nickerson, Jean Baptiste Michel, National Heart, Lung, and Blood Institute (NHLBI) Go Exome Sequencing Project, Guillaume Jondeau, Dianna M Milewicz

PMID: 22772371 DOI: 10.1038/ng.2348

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)-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.

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