期刊
NATURE GENETICS
卷 44, 期 11, 页码 1249-1254出版社
NATURE PORTFOLIO
DOI: 10.1038/ng.2421
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资金
- US National Institutes of Health [RO1-AR41135, PO1-AR049698]
- National Marfan Foundation
- Smilow Center for Marfan Syndrome Research
- Howard Hughes Medical Institute
- Baylor-Hopkins Center for Mendelian Genetics [1U54HG006542]
- NHLBI [HL107738-01, 1R01HL111267]
- National Institute for Health Research (NIHR) through Barts NIHR Cardiovascular Biomedical Research Unit
- Fund for Scientific Research, Flanders (Belgium) [G.0458.09, G.0221.12]
- European Grant Fighting Aneurysmal Disease (EC-FP7)
- Ghent University [BOF10/GOA/005]
- Agency for Innovation by Science and Technology
- MRC [G0600237, G9521010] Funding Source: UKRI
- Medical Research Council [G0600237, G9521010] Funding Source: researchfish
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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