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

ABSTRACT: Elevated transforming growth factor (TGF)-? 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-? signaling. Taken together, these data have engendered controversy regarding the specific role of TGF-? 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-? activity. Cultured dermal fibroblasts from affected individuals showed enhanced activation of TGF-? signaling cascades and higher expression of TGF-?-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-? signaling is the mechanism underlying SGS and that high signaling contributes to multiple syndromic presentations of aortic aneurysm.

SUBMITTER: Doyle AJ 

PROVIDER: S-EPMC3545695 | biostudies-literature | 2012 Nov

REPOSITORIES: biostudies-literature