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

Alexander J. Doyle, Jefferson J. Doyle, Seneca L. Bessling, Samantha Maragh, Mark E. Lindsay, Dorien Schepers, Elisabeth Gillis, Geert Mortier, Tessa Homfray, Kimberly Sauls, Russell A. Norris, Nicholas D. Huso, Dan Leahy, David W. Mohr, Mark J. Caulfield, Alan F. Scott, Anne Destrée, Raoul C. Hennekam, Pamela H. Arn, Cynthia J. CurryLut Van Laer, Andrew S. McCallion, Bart L. Loeys, Harry C. Dietz

Research output: Contribution to journalArticlepeer-review

166 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)1249-1254
Number of pages6
JournalNature genetics
Issue number11
StatePublished - Nov 2012

ASJC Scopus subject areas

  • Genetics


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