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

被引：345

作者：

Lindsay, Mark E. ^{[2
,3
,4
]}

Schepers, Dorien ^{[1
,5
]}

Bolar, Nikhita Ajit ^{[1
,5
]}

Doyle, Jefferson J. ^{[4
]}

Gallo, Elena ^{[4
]}

Fert-Bober, Justyna ^{[6
]}

Kempers, Marlies J. E. ^{[7
,8
]}

Fishman, Elliot K. ^{[9
]}

Chen, Yichun ^{[4
]}

Myers, Loretha ^{[4
]}

Bjeda, Djahita ^{[4
]}

Oswald, Gretchen ^{[4
]}

Elias, Abdallah F. ^{[4
]}

Levy, Howard P. ^{[4
]}

Anderlid, Britt-Marie ^{[10
]}

Yang, Margaret H. ^{[11
,12
]}

Bongers, Ernie M. H. F. ^{[7
,8
]}

Timmermans, Janneke ^{[13
]}

Braverman, Alan C. ^{[14
]}

Canham, Natalie ^{[15
]}

Mortier, Geert R. ^{[1
,5
]}

Brunner, Han G. ^{[7
,8
]}

Byers, Peter H. ^{[11
,12
]}

Van Eyk, Jennifer ^{[6
]}

Van Laer, Lut ^{[1
,5
]}

Dietz, Harry C. ^{[2
,3
,4
]}

Loeys, Bart L. ^{[1
,5
,7
,8
,16
]}

机构：

[1] Univ Antwerp, Fac Med & Hlth Sci, Ctr Med Genet, B-2020 Antwerp, Belgium

[2] Johns Hopkins Univ, Sch Med, Dept Pediat, Helen B Taussig Childrens Heart Ctr, Baltimore, MD 21205 USA

[3] Johns Hopkins Univ, Sch Med, Howard Hughes Med Inst, Baltimore, MD 21205 USA

[4] Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD USA

[5] Univ Antwerp Hosp, Antwerp, Belgium

[6] Johns Hopkins Univ, Dept Med, Div Cardiol, Bayview Prote Ctr, Baltimore, MD USA

[7] Radboud Univ Nijmegen, Dept Human Genet, Med Ctr, NL-6525 ED Nijmegen, Netherlands

[8] Radboud Univ Nijmegen, Inst Genet & Metab Disorders, Med Ctr, NL-6525 ED Nijmegen, Netherlands

[9] Johns Hopkins Sch Med, Russell H Morgan Dept Radiol & Radiol Sci, Baltimore, MD USA

[10] Karolinska Inst, Dept Clin Genet, Karolinska Univ Hosp, Stockholm, Sweden

[11] Univ Washington, Sch Med, Dept Pathol, Seattle, WA 98195 USA

[12] Univ Washington, Sch Med, Dept Genet, Seattle, WA USA

[13] Radboud Univ Nijmegen, Dept Cardiol, Med Ctr, NL-6525 ED Nijmegen, Netherlands

[14] Washington Univ, Sch Med, Dept Med, St Louis, MO 63110 USA

[15] Northwick Pk Hosp & Clin Res Ctr, Dept Clin Genet, NW Thames Reg Genet Serv, Harrow HA1 3UJ, Middx, England

[16] Univ Ghent, Dept Pediat & Genet, B-9000 Ghent, Belgium

来源：

NATURE GENETICS | 2012年 / 44卷 / 08期

基金：

美国国家卫生研究院;

关键词：

GROWTH-FACTOR-BETA; MARFAN-SYNDROME; MOUSE MODEL; PATHOGENESIS; RECEPTOR; MICE; CONTRIBUTES; ACTIVATION; FIBRILLIN;

D O I：

10.1038/ng.2349

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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-beta 2 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-beta 2 expression and high expression of TGF-beta 1. Taken together, these data support the hypothesis that compensatory autocrine and/or paracrine events contribute to the pathogenesis of TGF-beta-mediated vasculopathies.

引用

页码：922 / +

页数：7

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