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Title
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Loss-of-function mutations in TGFB2 cause a syndromic presentation of thoracic aortic aneurysm
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Author
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Abstract
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| 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. |
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Language
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English
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Source (journal)
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Nature genetics. - New York, N.Y.
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Publication
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New York, N.Y.
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2012
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ISSN
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1061-4036
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Volume/pages
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44
:8
(2012)
, p. 922-927
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ISI
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000306854700019
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Full text (Publisher's DOI)
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