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.