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

Mark E Lindsay1, Dorien Schepers, Nikhita Ajit Bolar

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

Nature Genetics
|July 10, 2012
PubMed

Insights

Loeys-Dietz syndrome (LDS) can be caused by mutations in the TGF-β2 ligand, leading to increased TGF-β signaling and aortic disease. Compensatory signaling pathways may drive the pathogenesis of these TGF-β-mediated vasculopathies.

Area of Science:

  • Genetics
  • Molecular Biology
  • Cardiovascular Biology

Background:

  • Loeys-Dietz syndrome (LDS) is associated with heightened transforming growth factor-beta (TGF-β) signaling.
  • The precise mechanism of LDS pathogenesis remains debated, particularly regarding the role of TGF-β signaling effectors versus ligands.

Purpose of the Study:

  • To investigate the role of the TGF-β2 ligand in LDS pathogenesis.
  • To elucidate the signaling pathways involved in TGF-β-mediated vasculopathies.

Main Methods:

  • Analysis of heterozygous mutations in the TGF-β2 gene in individuals with LDS spectrum phenotypes.
  • Assessment of TGF-β signaling in aortic tissue from affected individuals.
  • Generation and analysis of haploinsufficient Tgfb2(+/-) mice.
  • Phenotypic and biochemical analysis of mice with combined Marfan syndrome (MFS) allele and Tgfb2 haploinsufficiency.

Main Results:

  • Heterozygous mutations in the TGF-β2 gene were identified in individuals with LDS spectrum phenotypes.
  • Increased TGF-β signaling was observed in aortic tissue of affected individuals.
  • Haploinsufficient Tgfb2(+/-) mice developed aortic root aneurysm and showed evidence of increased canonical and noncanonical TGF-β signaling.
  • Combined MFS allele and Tgfb2 haploinsufficiency exacerbated the phenotype, with altered TGF-β1 and TGF-β2 expression.

Conclusions:

  • TGF-β2 ligand mutations contribute to LDS spectrum phenotypes.
  • Increased TGF-β signaling is a key feature in TGF-β2-associated vasculopathies.
  • Compensatory autocrine and/or paracrine signaling events are implicated in the pathogenesis of TGF-β-mediated vasculopathies.

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