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Nat Genet. 2012 Jul 8;44(8):922-7. doi: 10.1038/ng.2349.

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

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  • 1Helen B Taussig Children's Heart Center, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Abstract

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.

PMID:
22772368
[PubMed - indexed for MEDLINE]
PMCID:
PMC3616632
Free PMC Article
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