Title
Mutations in the TGF-β repressor SKI cause Shprintzen-Goldberg syndrome with aortic aneurysm
Author
Faculty/Department
Faculty of Medicine and Health Sciences
Publication type
article
Publication
New York, N.Y. ,
Subject
Human medicine
Source (journal)
Nature genetics. - New York, N.Y.
Volume/pages
44(2012) :11 , p. 1249-1254
ISSN
1061-4036
ISI
000310495800018
Carrier
E
Target language
English (eng)
Full text (Publishers DOI)
Affiliation
University of Antwerp
Abstract
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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