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

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Title:	Loss-of-function mutations in TGFB2 cause a syndromic presentation of thoracic aortic aneurysm.
Author(s):	Lindsay, M.E.; Schepers, D.; Bolar, N.A.; Doyle, J.J.; Gallo, E.; Fert-Bober, J.; Kempers, M.J.E. ; Fishman, E.K.; Chen, Y.; Myers, L.; Bjeda, D.; Oswald, G.; Elias, A.F.; Levy, H.P.; Anderlid, B.M.; Yang, M.H.; Bongers, M.H.F. ; Timmermans, J. ; Braverman, A.C.; Canham, N.; Mortier, G.R.; Brunner, H.G. ; Byers, P.H.; Eyk, J. Van; Laer, L. van; Dietz, H.C.; Loeys, B.L.
Publication year:	2012
Source:	Nature Genetics, vol. 44, iss. 8, (2012), pp. 922-927
ISSN:	1061-4036
DOI:	https://doi.org/10.1038/ng.2349
Publication type:	Article / Letter to editor
Please use this identifier to cite or link to this item : https://hdl.handle.net/2066/108560
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Subject:	IGMD 3: Genomic disorders and inherited multi-system disorders IGMD 9: Renal disorder NCEBP 14: Cardiovascular diseases NCMLS 6: Genetics and epigenetic pathways of disease IGMD 3: Genomic disorders and inherited multi-system disorders
Organization:	Human Genetics Cardiology
Journal title:	Nature Genetics
Volume:	vol. 44
Issue:	iss. 8
Page start:	p. 922
Page end:	p. 927
Abstract:	Loeys-Dietz syndrome (LDS) associates with a tissue signature for high transforming growth factor (TGF)-beta signaling but is often caused by heterozygous mutations in genes encoding positive effectors of TGF-beta signaling, including either subunit of the TGF-beta receptor or SMAD3, thereby engendering controversy regarding the mechanism of disease. Here, we report heterozygous mutations or deletions in the gene encoding the TGF-beta2 ligand for a phenotype within the LDS spectrum and show upregulation of TGF-beta signaling in aortic tissue from affected individuals. Furthermore, haploinsufficient Tgfb2(+/-) mice have aortic root aneurysm and biochemical evidence of increased canonical and noncanonical TGF-beta signaling. Mice that harbor both a mutant Marfan syndrome (MFS) allele (Fbn1(C1039G/+)) and Tgfb2 haploinsufficiency show increased TGF-beta signaling and phenotypic worsening in association with normalization of TGF-beta2 expression and high expression of TGF-beta1. Taken together, these data support the hypothesis that compensatory autocrine and/or paracrine events contribute to the pathogenesis of TGF-beta-mediated vasculopathies.