| Title |
|
|
|
Loss-of-function mutations in TGFB2 cause a syndromic presentation of thoracic aortic aneurysm
| |
| Author |
|
|
|
| |
| Abstract |
|
|
|
| Loeys-Dietz syndrome (LDS) associates with a tissue signature for high transforming growth factor (TGF)-beta signaling but is often caused by heterozygous mutations in genes encoding positive effectors of TGF-beta signaling, including either subunit of the TGF-beta receptor or SMAD3, thereby engendering controversy regarding the mechanism of disease. Here, we report heterozygous mutations or deletions in the gene encoding the TGF-beta 2 ligand for a phenotype within the LDS spectrum and show upregulation of TGF-beta signaling in aortic tissue from affected individuals. Furthermore, haploinsufficient Tgfb2(+/-) mice have aortic root aneurysm and biochemical evidence of increased canonical and noncanonical TGF-beta signaling. Mice that harbor both a mutant Marfan syndrome (MFS) allele (Fbn1(C1039G/+)) and Tgfb2 haploinsufficiency show increased TGF-beta signaling and phenotypic worsening in association with normalization of TGF-beta 2 expression and high expression of TGF-beta 1. Taken together, these data support the hypothesis that compensatory autocrine and/or paracrine events contribute to the pathogenesis of TGF-beta-mediated vasculopathies. | | |
| Language |
|
|
|
English
| |
| Source (journal) |
|
|
|
Nature genetics. - New York, N.Y. | |
| Publication |
|
|
|
New York, N.Y. : 2012
| |
| ISSN |
|
|
|
1061-4036
| |
| Volume/pages |
|
|
|
44:8(2012), p. 922-927
| |
| ISI |
|
|
|
000306854700019
| |
| Full text (Publishers DOI) |
|
|
| | |
|