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

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 GrossMark J. Rieder, Alec Vahanian, Deborah A. Nickerson, Jean Baptiste Michel, Guillaume Jondeau, Dianna M. Milewicz

Research output: Contribution to journalArticlepeer-review

232 Scopus citations

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.

Original languageEnglish
Pages (from-to)916-921
Number of pages6
JournalNature Genetics
Volume44
Issue number8
DOIs
StatePublished - Jul 8 2012

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