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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)1,2,3,4. 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 aneurysm6,7,8. We identified causative variation in ten individuals with SGS in the proto-oncogene SKI, a known repressor of TGF-β activity9,10. 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.

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Figure 1: SKI mutations in individuals with SGS.
Figure 2: TGF-β signaling in dermal fibroblasts.
Figure 3: Assessment of SKI expression in model systems.

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Acknowledgements

The authors would like to thank E. Gerber and H. Bjornsson for their contributions to the cell culture experiments. This work was funded by grants to H.C.D. from the US National Institutes of Health (RO1-AR41135 and PO1-AR049698), the Bloomberg Fund of the National Marfan Foundation, the Smilow Center for Marfan Syndrome Research, the Howard Hughes Medical Institute and the Baylor-Hopkins Center for Mendelian Genetics (1U54HG006542). A.J.D. was supported as a Research Associate by the Howard Hughes Medical Institute. J.J.D. was supported by a Victor A. McKusick Fellowship from the National Marfan Foundation. M.E.L. was supported by an NHLBI K08 Award (HL107738-01) and by a Fellow-to-Faculty Award from the National Marfan Foundation. A.S.M. was supported in part by the NHLBI (1R01HL111267). M.J.C. was supported by the National Institute for Health Research (NIHR) through Barts NIHR Cardiovascular Biomedical Research Unit. This study was also supported in part by funding from the Fund for Scientific Research, Flanders (Belgium) (G.0458.09 and G.0221.12), a European Grant Fighting Aneurysmal Disease (EC-FP7) and the Special Research Fund of Ghent University (BOF10/GOA/005). B.L.L. is a Senior Clinical Investigator of the Fund for Scientific Research, Flanders (FWO, Belgium). D.S. was supported by a Ph.D. grant from the Agency for Innovation by Science and Technology.

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H.C.D., B.L.L., G.M., T.H., A.D., R.C.H., P.H.A. and C.J.C. recruited participants for the study. H.C.D., A.J.D., J.J.D. and M.E.L. were instrumental in the experimental design and interpretation of the data. A.J.D. performed bioinformatics analysis, with the assistance of D.W.M. and A.F.S., and carried out DNA sequencing and analysis, receiving guidance and supervision from M.J.C. and H.C.D. J.J.D. performed all cell culture experiments and protein blot and quantitative PCR analyses, with the assistance of N.D.H. S.L.B. and S.M. performed all zebrafish experiments under the supervision of A.S.M. B.L.L. and L.V.L. supervised D.S. and E.G., who performed DNA sequencing and analysis. K.S. and R.A.N. performed the mouse developmental survey. D.L. performed structural prediction analyses. A.J.D. and J.J.D. drafted and are co-lead authors for the manuscript. H.C.D., B.L.L. and L.V.L. critically revised and gave final approval for the manuscript to be published.

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Correspondence to Harry C Dietz.

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Doyle, A., Doyle, J., Bessling, S. et al. Mutations in the TGF-β repressor SKI cause Shprintzen-Goldberg syndrome with aortic aneurysm. Nat Genet 44, 1249–1254 (2012). https://doi.org/10.1038/ng.2421

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