Loss-of-function mutations in TGFB 2 cause a syndromic presentation of thoracic aortic aneurysm

Correspondence should be addressed to Bart L. Loeys M.D., Ph.D. Center of Medical Genetics, Faculty of Medicine and Health Sciences, University of Antwerp/Antwerp University Hospital, Prins Boudewijnlaan 43, 2650 Antwerp (Edegem), Belgium, +32(0)3/2759774, +32(0)3/2759722, Bart.Loeys@ua.ac.be. 16These authors contributed equally to this work 17These authors jointly directed this work Author Contributions 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. Competing Financial Interests The authors declare no competing financial interests. NIH Public Access Author Manuscript Nat Genet. Author manuscript; available in PMC 2013 April 04. Published in final edited form as: Nat Genet. ; 44(8): 922–927. doi:10.1038/ng.2349. N IH PA Athor M anscript N IH PA Athor M anscript N IH PA Athor M anscript 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-b 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.