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

Abstract

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.

• Authors: 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 Curry, Lut Van Laer, Andrew S McCallion, Bart L Loeys, Harry C Dietz
• Journal: Nature genetics (Nat Genet) Vol. 44 Issue 11 Pg. 1249-54 (Nov 2012) ISSN: 1546-1718 [Electronic] United States
• PMID: 23023332 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

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