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

Nat Genet. 2012 Nov;44(11):1249-54. doi: 10.1038/ng.2421. Epub 2012 Sep 30.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aortic Aneurysm / genetics*
  • Arachnodactyly / genetics*
  • Arachnodactyly / metabolism
  • Cells, Cultured
  • Craniosynostoses / genetics*
  • Craniosynostoses / metabolism
  • DNA-Binding Proteins* / genetics
  • DNA-Binding Proteins* / metabolism
  • Fibroblasts
  • Humans
  • Loeys-Dietz Syndrome / genetics
  • Marfan Syndrome / genetics*
  • Marfan Syndrome / metabolism
  • Mice
  • Mutation
  • Phenotype
  • Phosphorylation
  • Proto-Oncogene Mas
  • Proto-Oncogene Proteins* / genetics
  • Proto-Oncogene Proteins* / metabolism
  • Signal Transduction
  • Transforming Growth Factor beta* / antagonists & inhibitors
  • Transforming Growth Factor beta* / genetics
  • Zebrafish


  • DNA-Binding Proteins
  • MAS1 protein, human
  • Proto-Oncogene Mas
  • Proto-Oncogene Proteins
  • Transforming Growth Factor beta
  • SKI protein, human

Supplementary concepts

  • Shprintzen Golberg craniosynostosis