2. Academic Validation
  3. Loss-of-function mutations in TGFB2 cause a syndromic presentation of thoracic aortic aneurysm

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.
Mark E Lindsay 1,  Dorien Schepers,  Nikhita Ajit Bolar,  Jefferson J Doyle,  Elena Gallo,  Justyna Fert-Bober,  Marlies J E Kempers,  Elliot K Fishman,  Yichun Chen,  Loretha Myers,  Djahita Bjeda,  Gretchen Oswald,  Abdallah F Elias,  Howard P Levy,  Britt-Marie Anderlid,  Margaret H Yang,  Ernie M H F Bongers,  Janneke Timmermans,  Alan C Braverman,  Natalie Canham,  Geert R Mortier,  Han G Brunner,  Peter H Byers,  Jennifer Van Eyk,  Lut Van Laer,  Harry C Dietz,  Bart L Loeys
Affiliations

Affiliation

  • 1 Helen B Taussig Children's Heart Center, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
PMID: 22772368 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.

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