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

ABSTRACT

Loeys-Dietz syndrome (LDS) associates with a tissue signature for high transforming growth factor (TGF)-ß signaling but is often caused by heterozygous mutations in genes encoding positive effectors of TGF-ß signaling, including either subunit of the TGF-ß receptor or SMAD3, thereby engendering controversy regarding the mechanism of disease. Here, we report heterozygous mutations or deletions in the gene encoding the TGF-ß2 ligand for a phenotype within the LDS spectrum and show upregulation of TGF-ß signaling in aortic tissue from affected individuals. Furthermore, haploinsufficient Tgfb2(+/-) mice have aortic root aneurysm and biochemical evidence of increased canonical and noncanonical TGF-ß signaling. Mice that harbor both a mutant Marfan syndrome (MFS) allele (Fbn1(C1039G/+)) and Tgfb2 haploinsufficiency show increased TGF-ß signaling and phenotypic worsening in association with normalization of TGF-ß2 expression and high expression of TGF-ß1. Taken together, these data support the hypothesis that compensatory autocrine and/or paracrine events contribute to the pathogenesis of TGF-ß-mediated vasculopathies.