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

TitleMutations in the TGF-β repressor SKI cause Shprintzen-Goldberg syndrome with aortic aneurysm.
Publication TypeJournal Article
Year of Publication2012
AuthorsDoyle, 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, Dietz, HC
JournalNat Genet
Date Published2012 Nov
KeywordsAnimals, Aortic Aneurysm, Arachnodactyly, Cells, Cultured, Craniosynostoses, DNA-Binding Proteins, Fibroblasts, Humans, Loeys-Dietz Syndrome, Marfan Syndrome, Mice, Mutation, Phenotype, Phosphorylation, Proto-Oncogene Proteins, Signal Transduction, Transforming Growth Factor beta, Zebrafish

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.

Alternate JournalNat. Genet.
PubMed ID23023332
PubMed Central IDPMC3545695
Grant ListG9521010 / / Medical Research Council / United Kingdom
T32 GM007814 / GM / NIGMS NIH HHS / United States
U54 HG006542 / HG / NHGRI NIH HHS / United States
R01 GM099321 / GM / NIGMS NIH HHS / United States
1R01HL111267 / HL / NHLBI NIH HHS / United States
1U54HG006542 / HG / NHGRI NIH HHS / United States
R01 AR041135 / AR / NIAMS NIH HHS / United States
P01 AR049698 / AR / NIAMS NIH HHS / United States
/ / Howard Hughes Medical Institute / United States
R01-AR41135 / AR / NIAMS NIH HHS / United States
K08 HL107738-01 / HL / NHLBI NIH HHS / United States
K08 HL107738 / HL / NHLBI NIH HHS / United States
P01-AR049698 / AR / NIAMS NIH HHS / United States
G0600237 / / Medical Research Council / United Kingdom
R01 HL111267 / HL / NHLBI NIH HHS / United States

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