Loss-of-function mutations in TGFB2 cause a syndromic presentation of thoracic aortic aneurysm.

TitleLoss-of-function mutations in TGFB2 cause a syndromic presentation of thoracic aortic aneurysm.
Publication TypeJournal Article
Year of Publication2012
AuthorsLindsay, ME, Schepers, D, Bolar, NAjit, Doyle, JJ, Gallo, E, Fert-Bober, J, Kempers, MJE, Fishman, EK, Chen, Y, Myers, L, Bjeda, D, Oswald, G, Elias, AF, Levy, HP, Anderlid, B-M, Yang, MH, Bongers, EMHF, Timmermans, J, Braverman, AC, Canham, N, Mortier, GR, Brunner, HG, Byers, PH, Van Eyk, J, Van Laer, L, Dietz, HC, Loeys, BL
JournalNat Genet
Volume44
Issue8
Pagination922-7
Date Published2012 Aug
ISSN1546-1718
KeywordsAnimals, Aortic Aneurysm, Thoracic, Disease Models, Animal, Female, Haploinsufficiency, Humans, Loeys-Dietz Syndrome, Male, Marfan Syndrome, Mice, Mice, Knockout, Mice, Mutant Strains, Microfilament Proteins, Mutation, Pedigree, Phenotype, Signal Transduction, Syndrome, Transforming Growth Factor beta2
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.

DOI10.1038/ng.2349
Alternate JournalNat. Genet.
PubMed ID22772368
PubMed Central IDPMC3616632
Grant List1U54HG006542 / HG / NHGRI NIH HHS / United States
1U54RR023561-01A1 / RR / NCRR NIH HHS / United States
5RC1HL100021-02 / HL / NHLBI NIH HHS / United States
HL107738-01 / HL / NHLBI NIH HHS / United States
K08 HL107738 / HL / NHLBI NIH HHS / United States
P01-AR049698 / AR / NIAMS NIH HHS / United States
R01 AR041135 / AR / NIAMS NIH HHS / United States
R01- AR41135 / AR / NIAMS NIH HHS / United States
U54 HG006542 / HG / NHGRI NIH HHS / United States
/ / Howard Hughes Medical Institute / United States