TGFB2 mutations cause familial thoracic aortic aneurysms and dissections associated with mild systemic features of Marfan syndrome |
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Authors: | Catherine Boileau,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, Blood Institute Go Exome Sequencing Project,Guillaume Jondeau,Dianna M Milewicz |
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Affiliation: | Institut National de la Santé et de la Recherche Médicale (INSERM) U698, H?pital Bichat, Paris, France. catherine.boileau@inserm.fr |
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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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