Mutations in the TGF-beta repressor SKI cause Shprintzen-Goldberg syndrome with aortic aneurysm

Abstract

Item does not contain fulltextElevated 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). However, the location and character of many of the causal mutations in LDS intuitively imply diminished TGF-beta signaling. 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. We identified causative variation in ten individuals with SGS in the proto-oncogene SKI, a known repressor of TGF-beta activity. 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