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)-? signaling but is often caused by heterozygous mutations in genes encoding positive effectors of TGF-? signaling, including either subunit of the TGF-? receptor or SMAD3, thereby engendering controversy regarding the mechanism of disease. Here, we report heterozygous mutations or deletions in the gene encoding the TGF-?2 ligand for a phenotype within the LDS spectrum and show upregulation of TGF-? signaling in aortic tissue from affected individuals. Furthermore, haploinsufficient Tgfb2(+/-) mice have aortic root aneurysm and biochemical evidence of increased canonical and noncanonical TGF-? signaling. Mice that harbor both a mutant Marfan syndrome (MFS) allele (Fbn1(C1039G/+)) and Tgfb2 haploinsufficiency show increased TGF-? signaling and phenotypic worsening in association with normalization of TGF-?2 expression and high expression of TGF-?1. Taken together, these data support the hypothesis that compensatory autocrine and/or paracrine events contribute to the pathogenesis of TGF-?-mediated vasculopathies.

SUBMITTER: Lindsay ME 

PROVIDER: S-EPMC3616632 | biostudies-literature | 2012 Jul

REPOSITORIES: biostudies-literature