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


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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Figure 1: Phenotypic characteristics of humans with TGFB2 mutation.
Figure 2: Mutational analysis of TGFB2 in humans with aneurysm.
Figure 3: Cardiovascular pathology in human subjects with TGFB2 mutations.
Figure 4: Haploinsufficiency for Tgfb2 causes aortic root aneurysm in mice.
Figure 5: Synergistic pathology in Tgfb2+/−; Fbn1C1039G/+ double-heterozygous mice.

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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.

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Authors and Affiliations



M.E.L., H.C.D., D.S., L.V.L. and B.L.L. conceived of the study and designed all experiments. M.E.L., D.S., L.V.L., H.C.D. and B.L.L. wrote the manuscript. D.S., M.H.Y. and N.A.B. performed microarray experiments and mutation analysis. J.J.D. performed protein blotting experiments. E.G. performed RT-PCR analysis of mouse aortas. J.F.-B. and J.V.E. performed serum TGF-β ligand analysis. E.K.F. performed, interpreted and produced multidetector-computed tomography images. Y.C. performed animal husbandry, genotyping and aorta dissections. L.M. performed IHC on human and mouse samples. D.B. performed all mouse echocardiograms. M.J.E.K., G.O., B.-M.A., E.M.H.F.B., J.T., A.C.B., N.C., G.R.M., H.G.B. and P.H.B. contributed patient material and clinical and pedigree data and revised the manuscript. A.F.E. and H.P.L. contributed to the whole-exome sequencing initiative.

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Correspondence to Bart L Loeys.

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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).

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