%0 Journal Article %J Nat Genet %D 2012 %T Loss-of-function mutations in TGFB2 cause a syndromic presentation of thoracic aortic aneurysm. %A Lindsay, Mark E %A Schepers, Dorien %A Bolar, Nikhita Ajit %A Doyle, Jefferson J %A Gallo, Elena %A Fert-Bober, Justyna %A Kempers, Marlies J E %A Fishman, Elliot K %A Chen, Yichun %A Myers, Loretha %A Bjeda, Djahita %A Oswald, Gretchen %A Elias, Abdallah F %A Levy, Howard P %A Anderlid, Britt-Marie %A Yang, Margaret H %A Bongers, Ernie M H F %A Timmermans, Janneke %A Braverman, Alan C %A Canham, Natalie %A Mortier, Geert R %A Brunner, Han G %A Byers, Peter H %A Van Eyk, Jennifer %A Van Laer, Lut %A Dietz, Harry C %A Loeys, Bart L %K Animals %K Aortic Aneurysm, Thoracic %K Disease Models, Animal %K Female %K Fibrillin-1 %K Fibrillins %K Haploinsufficiency %K Humans %K Loeys-Dietz Syndrome %K Male %K Marfan Syndrome %K Mice %K Mice, Knockout %K Mice, Mutant Strains %K Microfilament Proteins %K Mutation %K Pedigree %K Phenotype %K Signal Transduction %K Syndrome %K Transforming Growth Factor beta2 %X

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.

%B Nat Genet %V 44 %P 922-7 %8 2012 Jul 08 %G eng %N 8 %1 https://www.ncbi.nlm.nih.gov/pubmed/22772368?dopt=Abstract %R 10.1038/ng.2349