%0 Journal Article %J Nat Genet %D 2012 %T Mutations in the TGF-β repressor SKI cause Shprintzen-Goldberg syndrome with aortic aneurysm. %A Doyle, Alexander J %A Doyle, Jefferson J %A Bessling, Seneca L %A Maragh, Samantha %A Lindsay, Mark E %A Schepers, Dorien %A Gillis, Elisabeth %A Mortier, Geert %A Homfray, Tessa %A Sauls, Kimberly %A Norris, Russell A %A Huso, Nicholas D %A Leahy, Dan %A Mohr, David W %A Caulfield, Mark J %A Scott, Alan F %A Destrée, Anne %A Hennekam, Raoul C %A Arn, Pamela H %A Curry, Cynthia J %A Van Laer, Lut %A McCallion, Andrew S %A Loeys, Bart L %A Dietz, Harry C %K Animals %K Aortic Aneurysm %K Arachnodactyly %K Cells, Cultured %K Craniosynostoses %K DNA-Binding Proteins %K Fibroblasts %K Humans %K Loeys-Dietz Syndrome %K Marfan Syndrome %K Mice %K Mutation %K Phenotype %K Phosphorylation %K Proto-Oncogene Mas %K Proto-Oncogene Proteins %K Signal Transduction %K Transforming Growth Factor beta %K Zebrafish %X

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.

%B Nat Genet %V 44 %P 1249-54 %8 2012 Nov %G eng %N 11 %1 https://www.ncbi.nlm.nih.gov/pubmed/23023332?dopt=Abstract %R 10.1038/ng.2421