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

Alexander J. Doyle, Jefferson Doyle, Seneca L. Bessling, Samantha Maragh, Mark E. Lindsay, Dorien Schepers, Elisabeth Gillis, Geert Mortier, Tessa Homfray, Kimberly Sauls, Russell A. Norris, Nicholas D. Huso, Dan Leahy, David W. Mohr, Mark J. Caulfield, Alan F Scott, Anne Destrée, Raoul C. Hennekam, Pamela H. Arn, Cynthia J. CurryLut Van Laer, Andrew S McCallion, Bart L. Loeys, Harry C Dietz

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)1249-1254
Number of pages6
JournalNature Genetics
Volume44
Issue number11
DOIs
StatePublished - Nov 2012

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Aortic Aneurysm
Transforming Growth Factors
Loeys-Dietz Syndrome
Mutation
Marfan Syndrome
Morpholinos
Proto-Oncogenes
Zebrafish
Shprintzen Golberg craniosynostosis
Fibroblasts
Skin
Genes

ASJC Scopus subject areas

  • Genetics

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Mutations in the TGF-β repressor SKI cause Shprintzen-Goldberg syndrome with aortic aneurysm. / Doyle, Alexander J.; Doyle, Jefferson; Bessling, Seneca L.; Maragh, Samantha; Lindsay, Mark E.; Schepers, Dorien; Gillis, Elisabeth; Mortier, Geert; Homfray, Tessa; Sauls, Kimberly; Norris, Russell A.; Huso, Nicholas D.; Leahy, Dan; Mohr, David W.; Caulfield, Mark J.; Scott, Alan F; Destrée, Anne; Hennekam, Raoul C.; Arn, Pamela H.; Curry, Cynthia J.; Van Laer, Lut; McCallion, Andrew S; Loeys, Bart L.; Dietz, Harry C.

In: Nature Genetics, Vol. 44, No. 11, 11.2012, p. 1249-1254.

Research output: Contribution to journalArticle

Doyle, AJ, Doyle, J, 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 2012, 'Mutations in the TGF-β repressor SKI cause Shprintzen-Goldberg syndrome with aortic aneurysm', Nature Genetics, vol. 44, no. 11, pp. 1249-1254. https://doi.org/10.1038/ng.2421
Doyle, Alexander J. ; Doyle, Jefferson ; Bessling, Seneca L. ; Maragh, Samantha ; Lindsay, Mark E. ; Schepers, Dorien ; Gillis, Elisabeth ; Mortier, Geert ; Homfray, Tessa ; Sauls, Kimberly ; Norris, Russell A. ; Huso, Nicholas D. ; Leahy, Dan ; Mohr, David W. ; Caulfield, Mark J. ; Scott, Alan F ; Destrée, Anne ; Hennekam, Raoul C. ; Arn, Pamela H. ; Curry, Cynthia J. ; Van Laer, Lut ; McCallion, Andrew S ; Loeys, Bart L. ; Dietz, Harry C. / Mutations in the TGF-β repressor SKI cause Shprintzen-Goldberg syndrome with aortic aneurysm. In: Nature Genetics. 2012 ; Vol. 44, No. 11. pp. 1249-1254.
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