Mutations in the TGF-beta repressor SKI cause Shprintzen-Goldberg syndrome with aortic aneurysm
- Authors
- Doyle, A.J., Doyle, J.J., Bessling, S.L., Maragh, S., Lindsay, M.E., Schepers, D., Gillis, E., Mortier, G., Homfray, T., Sauls, K., Norris, R.A., Huso, N.D., Leahy, D., Mohr, D.W., Caulfield, M.J., Scott, A.F., Destrée, A., Hennekam, R.C., Arn, P.H., Curry, C.J., Van Laer, L., McCallion, A.S., Loeys, B.L., and Dietz, H.C.
- ID
- ZDB-PUB-121010-38
- Date
- 2012
- Source
- Nature Genetics 44(11): 1249-1254 (Journal)
- Registered Authors
- McCallion, Andy
- Keywords
- none
- 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 Proteins*/genetics
- Proto-Oncogene Proteins*/metabolism
- Signal Transduction
- Transforming Growth Factor beta*/antagonists & inhibitors
- Transforming Growth Factor beta*/genetics
- Zebrafish
- PubMed
- 23023332 Full text @ Nat. Genet.
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 signaling5. 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.