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Title
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Mutations in the TGF-β repressor SKI cause Shprintzen-Goldberg syndrome with aortic aneurysm
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Author
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Abstract
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| Elevated transforming growth factor (TGF)-beta signaling has been implicated in the pathogenesis of syndromic presentations of aortic aneurysm, including Marfan syndrome (MFS) and Loeys-Dietz syndrome (LDS)(1-4). However, the location and character of many of the causal mutations in LDS intuitively imply diminished TGF-beta signaling(5). Taken together, these data have engendered controversy regarding the specific role of TGF-beta in disease pathogenesis. Shprintzen-Goldberg syndrome (SGS) has considerable phenotypic overlap with MFS and LDS, including aortic aneurysm(6-8). We identified causative variation in ten individuals with SGS in the proto-oncogene SKI, a known repressor of TGF-beta activity(9,10). Cultured dermal fibroblasts from affected individuals showed enhanced activation of TGF-beta signaling cascades and higher expression of TGF-beta-responsive genes relative to control cells. Morpholino-induced silencing of SKI paralogs in zebrafish recapitulated abnormalities seen in humans with SGS. These data support the conclusions that increased TGF-beta signaling is the mechanism underlying SGS and that high signaling contributes to multiple syndromic presentations of aortic aneurysm. |
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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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DOI
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10.1038/NG.2421
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Volume/pages
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44
:11
(2012)
, p. 1249-1254
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ISI
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000310495800018
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Full text (Publisher's DOI)
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