title: TGFBR1 mutations associated with Loeys-Dietz syndrome are inactivating.
abstract: To assess the effect of Loeys-Dietz syndrome (LDS) mutations affecting TGFΒR1 a selection of seven disease-associated amino acid substitutions were introduced into wild type TGFβR1 and constitutively active TGFβR1(T204D). Receptor function was tested by co-transfection with a luciferase reporter or EGFP-tagged SMAD2 in HEK293 cells. All of the mutations were found to be inactivating for canonical TGF-β signaling. Differences in residual activity were not found to correlate with disease subtype. In co-transfection experiments with equal amounts wild-type receptor, the LDS mutations were found to confer a modest dominant negative effect. These results are discussed in relation to LDS and the related Marfan syndrome.
authors.affiliation: Department of Women's and Children's Health, Dunedin School of Medicine, Otago University, Dunedin, New Zealand.
authors.forename: Sarah
authors.initials: S
authors.lastname: Cardoso
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Robertson
authors.forename: Philip B
authors.initials: PB
authors.lastname: Daniel
mesh_terms: D001014:Aortic Aneurysm / Q000235:genetics; D005799:Genes, Dominant; D057809:HEK293 Cells; D006801:Humans; D055947:Loeys-Dietz Syndrome / Q000235:genetics; D008382:Marfan Syndrome / Q000235:genetics; D009154:Mutation; D010641:Phenotype; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics; D051785:Smad Proteins / Q000378:metabolism; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000235:genetics
chemical_list: D018125:Receptors, Transforming Growth Factor beta; D051785:Smad Proteins; D016212:Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; C000625841:TGFBR1 protein, human