Loss-of-function mutations in TGFB2 cause a syndromic presentation of thoracic aortic aneurysm

Mark E. Lindsay, Dorien Schepers, Nikhita Ajit Bolar, Jefferson J. Doyle, Elena Gallo, Justyna Fert-Bober, Marlies J.E. Kempers, Elliot K. Fishman, Yichun Chen, Loretha Myers, Djahita Bjeda, Gretchen Oswald, Abdallah F. Elias, Howard P. Levy, Britt Marie Anderlid, Margaret H. Yang, Ernie M.H.F. Bongers, Janneke Timmermans, Alan C. Braverman, Natalie CanhamGeert R. Mortier, Han G. Brunner, Peter H. Byers, Jennifer Van Eyk, Lut Van Laer, Harry C. Dietz, Bart L. Loeys

Research output: Contribution to journalArticlepeer-review

307 Scopus citations


Loeys-Dietz syndrome (LDS) associates with a tissue signature for high transforming growth factor (TGF)-β signaling but is often caused by heterozygous mutations in genes encoding positive effectors of TGF-β signaling, including either subunit of the TGF-β receptor or SMAD3, thereby engendering controversy regarding the mechanism of disease. Here, we report heterozygous mutations or deletions in the gene encoding the TGF-β2 ligand for a phenotype within the LDS spectrum and show upregulation of TGF-β signaling in aortic tissue from affected individuals. Furthermore, haploinsufficient Tgfb2 +-mice have aortic root aneurysm and biochemical evidence of increased canonical and noncanonical TGF-β signaling. Mice that harbor both a mutant Marfan syndrome (MFS) allele (Fbn1 C1039G/+) and Tgfb2 haploinsufficiency show increased TGF-β signaling and phenotypic worsening in association with normalization of TGF-β2 expression and high expression of TGF-β1. Taken together, these data support the hypothesis that compensatory autocrine and/or paracrine events contribute to the pathogenesis of TGF-β-mediated vasculopathies.

Original languageEnglish
Pages (from-to)922-927
Number of pages6
JournalNature Genetics
Issue number8
StatePublished - Aug 2012


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