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)-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.

• Authors: Mark E Lindsay, 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
• Journal: Nature genetics (Nat Genet) Vol. 44 Issue 8 Pg. 922-7 (Jul 08 2012) ISSN: 1546-1718 [Electronic] United States
• PMID: 22772368 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

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