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

ME Lindsay, D Schepers, NA Bolar, JJ Doyle, E Gallo… - Nature …, 2012 - nature.com
ME Lindsay, D Schepers, NA Bolar, JJ Doyle, E Gallo, J Fert-Bober, MJE Kempers…
Nature genetics, 2012nature.com
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 …
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 (Fbn1C1039G/+) 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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