title: 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). 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.
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Doyle
authors.forename: Jefferson J
authors.initials: JJ
authors.lastname: Doyle
authors.forename: Seneca L
authors.initials: SL
authors.lastname: Bessling
authors.forename: Samantha
authors.initials: S
authors.lastname: Maragh
authors.forename: Mark E
authors.initials: ME
authors.lastname: Lindsay
authors.forename: Dorien
authors.initials: D
authors.lastname: Schepers
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Gillis
authors.forename: Geert
authors.initials: G
authors.lastname: Mortier
authors.forename: Tessa
authors.initials: T
authors.lastname: Homfray
authors.forename: Kimberly
authors.initials: K
authors.lastname: Sauls
authors.forename: Russell A
authors.initials: RA
authors.lastname: Norris
authors.forename: Nicholas D
authors.initials: ND
authors.lastname: Huso
authors.forename: Dan
authors.initials: D
authors.lastname: Leahy
authors.forename: David W
authors.initials: DW
authors.lastname: Mohr
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Caulfield
authors.forename: Alan F
authors.initials: AF
authors.lastname: Scott
authors.forename: Anne
authors.initials: A
authors.lastname: Destrée
authors.forename: Raoul C
authors.initials: RC
authors.lastname: Hennekam
authors.forename: Pamela H
authors.initials: PH
authors.lastname: Arn
authors.forename: Cynthia J
authors.initials: CJ
authors.lastname: Curry
authors.forename: Lut
authors.initials: L
authors.lastname: Van Laer
authors.forename: Andrew S
authors.initials: AS
authors.lastname: McCallion
authors.forename: Bart L
authors.initials: BL
authors.lastname: Loeys
authors.forename: Harry C
authors.initials: HC
authors.lastname: Dietz
mesh_terms: D000818:Animals; D001014:Aortic Aneurysm / Q000235:genetics*; D054119:Arachnodactyly / Q000235:genetics* / Q000378:metabolism; D002478:Cells, Cultured; D003398:Craniosynostoses / Q000235:genetics* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005347:Fibroblasts; D006801:Humans; D055947:Loeys-Dietz Syndrome / Q000235:genetics; D008382:Marfan Syndrome / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D009154:Mutation; D010641:Phenotype; D010766:Phosphorylation; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000235:genetics; D015027:Zebrafish
chemical_list: D004268:DNA-Binding Proteins; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D016212:Transforming Growth Factor beta; C060614:SKI protein, human