title: Loss-of-function mutations in TGFB2 cause a syndromic presentation of thoracic aortic aneurysm.
abstract: Loeys-Dietz syndrome (LDS) associates with a tissue signature for high transforming growth factor (TGF)-β signaling but is often caused by heterozygous mutations in genes encoding positive effectors of TGF-β signaling, including either subunit of the TGF-β receptor or SMAD3, thereby engendering controversy regarding the mechanism of disease. Here, we report heterozygous mutations or deletions in the gene encoding the TGF-β2 ligand for a phenotype within the LDS spectrum and show upregulation of TGF-β signaling in aortic tissue from affected individuals. Furthermore, haploinsufficient Tgfb2(+/-) mice have aortic root aneurysm and biochemical evidence of increased canonical and noncanonical TGF-β signaling. Mice that harbor both a mutant Marfan syndrome (MFS) allele (Fbn1(C1039G/+)) and Tgfb2 haploinsufficiency show increased TGF-β signaling and phenotypic worsening in association with normalization of TGF-β2 expression and high expression of TGF-β1. Taken together, these data support the hypothesis that compensatory autocrine and/or paracrine events contribute to the pathogenesis of TGF-β-mediated vasculopathies.
authors: Helen B Taussig Children's Heart Center, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors: Mark E
authors: ME
authors: Lindsay
authors: Dorien
authors: D
authors: Schepers
authors: Nikhita Ajit
authors: NA
authors: Bolar
authors: Jefferson J
authors: JJ
authors: Doyle
authors: Elena
authors: E
authors: Gallo
authors: Justyna
authors: J
authors: Fert-Bober
authors: Marlies J E
authors: MJ
authors: Kempers
authors: Elliot K
authors: EK
authors: Fishman
authors: Yichun
authors: Y
authors: Chen
authors: Loretha
authors: L
authors: Myers
authors: Djahita
authors: D
authors: Bjeda
authors: Gretchen
authors: G
authors: Oswald
authors: Abdallah F
authors: AF
authors: Elias
authors: Howard P
authors: HP
authors: Levy
authors: Britt-Marie
authors: BM
authors: Anderlid
authors: Margaret H
authors: MH
authors: Yang
authors: Ernie M H F
authors: EM
authors: Bongers
authors: Janneke
authors: J
authors: Timmermans
authors: Alan C
authors: AC
authors: Braverman
authors: Natalie
authors: N
authors: Canham
authors: Geert R
authors: GR
authors: Mortier
authors: Han G
authors: HG
authors: Brunner
authors: Peter H
authors: PH
authors: Byers
authors: Jennifer
authors: J
authors: Van Eyk
authors: Lut
authors: L
authors: Van Laer
authors: Harry C
authors: HC
authors: Dietz
authors: Bart L
authors: BL
authors: Loeys
mesh_terms: D000818:Animals; D017545:Aortic Aneurysm, Thoracic / Q000235:genetics* / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D000071838:Fibrillin-1; D000071837:Fibrillins; D057895:Haploinsufficiency; D006801:Humans; D055947:Loeys-Dietz Syndrome / Q000235:genetics / Q000473:pathology; D008297:Male; D008382:Marfan Syndrome / Q000235:genetics / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D008840:Microfilament Proteins / Q000235:genetics; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D015398:Signal Transduction; D013577:Syndrome; D053781:Transforming Growth Factor beta2 / Q000172:deficiency / Q000235:genetics*; D054392:Adipokines
chemical_list: D000071838:Fibrillin-1; D000071837:Fibrillins; D008840:Microfilament Proteins; D053781:Transforming Growth Factor beta2; C000605722:FBN1 protein, human; D054392:Adipokines; C000605724:Fbn1 protein, mouse; C509041:TGFB2 protein, human; C509042:Tgfb2 protein, mouse