Bessling, Seneca L.

Doyle, Alexander J.

Doyle, Jefferson J.

et al.

Gillis, Elisabeth

Loeys, Bart

Mortier, Geert

Schepers, Dorien

Van Laer, Lut

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

Institutional Repository Universiteit Antwerpen

Mutations in the TGF-\u3b2 repressor SKI cause Shprintzen-Goldberg syndrome with aortic aneurysm

Mutations in the TGF-\u3b2 repressor SKI cause Shprintzen-Goldberg syndrome with aortic aneurysm

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Institutional Repository Universiteit Antwerpen