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 (Fbn1C1039G/+) 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.
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This study was supported in part by funding from the Fund for Scientific Research, Flanders (FWO; Belgium) (G.0458.09 and G.0221.12); a European Grant Fighting Aneurysmal Disease (EC-FP7); the Special Research Fund of Ghent University (BOF10/GOA/005); the US National Institutes of Health (RO1- AR41135 and PO1-AR049698 to H.C.D., 5RC1HL100021-02 to J.V.E. and H.C.D. and an Institutional Clinical and Translational Science Award 1U54RR023561-01A1 to J.V.E.); the National Marfan Foundation; the Smilow Center for Marfan Syndrome Research; the Howard Hughes Medical Institute; the Freudmann Fund for Research in Ehlers Danlos Syndrome and Related Disorders; and the Baylor-Hopkins Center for Mendelian Genetics (1U54HG006542). B.L.L. is senior clinical investigator of the Fund for Scientific Research, Flanders (Belgium); N.A.B. is supported by the Aneurysmal Pathology Foundation; D.S. is supported by a PhD grant from the Agency for Innovation by Science and Technology (IWT); E.G. is supported by a fellowship from the Helen Hay Whitney Foundation; J.J.D. is supported by the McKusick Fellowship of the National Marfan Foundation; and M.E.L. is supported by an NHLBI K08 Award (HL107738-01) and by a Fellow-to-Faculty Award from the National Marfan Foundation.
The authors declare no competing financial interests.
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Lindsay, M., Schepers, D., Bolar, N. et al. Loss-of-function mutations in TGFB2 cause a syndromic presentation of thoracic aortic aneurysm. Nat Genet 44, 922–927 (2012). https://doi.org/10.1038/ng.2349
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