Loss-of-function Mutations in TGFB2 Cause a Syndromic Presentation of Thoracic Aortic Aneurysm

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aortic Aneurysm, Thoracic / genetics*
  • Aortic Aneurysm, Thoracic / pathology
  • Disease Models, Animal
  • Female
  • Fibrillin-1
  • Fibrillins
  • Haploinsufficiency
  • Humans
  • Loeys-Dietz Syndrome / genetics
  • Loeys-Dietz Syndrome / pathology
  • Male
  • Marfan Syndrome / genetics
  • Marfan Syndrome / pathology
  • Mice
  • Mice, Knockout
  • Mice, Mutant Strains
  • Microfilament Proteins / genetics
  • Mutation*
  • Pedigree
  • Phenotype
  • Signal Transduction
  • Syndrome
  • Transforming Growth Factor beta2 / deficiency
  • Transforming Growth Factor beta2 / genetics*

Substances

  • FBN1 protein, human
  • Fbn1 protein, mouse
  • Fibrillin-1
  • Fibrillins
  • Microfilament Proteins
  • TGFB2 protein, human
  • Tgfb2 protein, mouse
  • Transforming Growth Factor beta2