1. Mutations in the TGF-β repressor SKI cause Shprintzen-Goldberg syndrome with aortic aneurysm.
- Author
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Doyle AJ, Doyle JJ, Bessling SL, Maragh S, Lindsay ME, Schepers D, Gillis E, Mortier G, Homfray T, Sauls K, Norris RA, Huso ND, Leahy D, Mohr DW, Caulfield MJ, Scott AF, Destrée A, Hennekam RC, Arn PH, Curry CJ, Van Laer L, McCallion AS, Loeys BL, and Dietz HC
- Subjects
- Animals, Arachnodactyly metabolism, Cells, Cultured, Craniosynostoses metabolism, Fibroblasts, Humans, Loeys-Dietz Syndrome genetics, Marfan Syndrome metabolism, Mice, Mutation, Phenotype, Phosphorylation, Proto-Oncogene Mas, Signal Transduction, Zebrafish, Aortic Aneurysm genetics, Arachnodactyly genetics, Craniosynostoses genetics, DNA-Binding Proteins genetics, DNA-Binding Proteins metabolism, Marfan Syndrome genetics, Proto-Oncogene Proteins genetics, Proto-Oncogene Proteins metabolism, Transforming Growth Factor beta antagonists & inhibitors, Transforming Growth Factor beta genetics
- 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.
- Published
- 2012
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