title: A missense TGFB2 variant p.(Arg320Cys) causes a paradoxical and striking increase in aortic TGFB1/2 expression.
abstract: Loeys-Dietz syndrome (LDS) is an autosomal dominant connective tissue disorder with a range of cardiovascular, skeletal, craniofacial and cutaneous manifestations. LDS type 4 is caused by mutations in TGFβ ligand 2 (TGFB2) and based on the family pedigrees described to date, appears to have a milder clinical phenotype, often presenting with isolated aortic disease. We sought to investigate its molecular basis in a new pedigree. We identified a missense variant p.(Arg320Cys) (NM_003238.3) in a highly evolutionary conserved region of TGFB2 in a new LDS type 4 pedigree with multiple cases of aortic aneurysms and dissections. There was striking upregulation of TGFB1 and TGFB2 expression on immunofluorescent staining, and western blotting of the aortic tissue from the index case confirming the functional importance of the variant. This case highlights the striking paradox of predicted loss-of-function mutations in TGFB2 causing enhanced TGFβ signaling in this emerging familial aortopathy.
authors: Department of Medicine (EMIT and CVD divisions), University of Cambridge, Cambridge, UK.
authors: Raya
authors: R
authors: Al Maskari
authors: Department of Medicine (EMIT and CVD divisions), University of Cambridge, Cambridge, UK.
authors: Yasmin
authors: Department of Medicine (EMIT and CVD divisions), University of Cambridge, Cambridge, UK.
authors: S
authors: S
authors: Cleary
authors: Department of Medicine (EMIT and CVD divisions), University of Cambridge, Cambridge, UK.
authors: Nikki
authors: N
authors: Figg
authors: Department of Medical Genetics, Addenbrookes Hospital, Cambridge, UK.
authors: Sarju
authors: http://orcid.org/0000-0003-0446-3435
authors: S
authors: Mehta
authors: Department of Pathology, Papworth Hospital, Cambridge, UK.
authors: Doris
authors: D
authors: Rassl
authors: Department of Medicine (EMIT and CVD divisions), University of Cambridge, Cambridge, UK.
authors: Ian
authors: I
authors: Wilkinson
authors: Department of Medicine (EMIT and CVD divisions), University of Cambridge, Cambridge, UK. kmo22@medschl.cam.ac.uk.
authors: Kevin M
authors: KM
authors: O'Shaughnessy
mesh_terms: D001014:Aortic Aneurysm / Q000235:genetics* / Q000473:pathology; D005786:Gene Expression Regulation; D006801:Humans; D055947:Loeys-Dietz Syndrome / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D010375:Pedigree; D053773:Transforming Growth Factor beta1 / Q000096:biosynthesis* / Q000235:genetics; D053781:Transforming Growth Factor beta2 / Q000096:biosynthesis / Q000235:genetics*
chemical_list: C508960:TGFB1 protein, human; C509041:TGFB2 protein, human; D053773:Transforming Growth Factor beta1; D053781:Transforming Growth Factor beta2