Elevated transforming growth factor (TGF)-β signaling has been implicated in the 
pathogenesis of syndromic presentations of aortic aneurysm, including Marfan 
syndrome (MFS) and Loeys-Dietz syndrome (LDS). However, the location and 
character of many of the causal mutations in LDS intuitively imply diminished 
TGF-β signaling. Taken together, these data have engendered controversy 
regarding the specific role of TGF-β in disease pathogenesis. 
Shprintzen-Goldberg syndrome (SGS) has considerable phenotypic overlap with MFS 
and LDS, including aortic aneurysm. We identified causative variation in ten 
individuals with SGS in the proto-oncogene SKI, a known repressor of TGF-β 
activity. Cultured dermal fibroblasts from affected individuals showed enhanced 
activation of TGF-β signaling cascades and higher expression of TGF-β-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-β signaling is the mechanism 
underlying SGS and that high signaling contributes to multiple syndromic 
presentations of aortic aneurysm.