TGFB2 mutations cause familial thoracic aortic aneurysms and dissections associated with mild systemic features of Marfan syndrome

被引：287

作者：

Boileau, Catherine ^{[2
,3
,4
,5
]}

Guo, Dong-Chuan ^{[1
]}

Hanna, Nadine ^{[2
,3
,4
]}

Regalado, Ellen S. ^{[1
]}

Detaint, Delphine ^{[2
,3
]}

Gong, Limin ^{[1
]}

Varret, Mathilde ^{[2
]}

Prakash, Siddharth K. ^{[1
,6
]}

Li, Alexander H. ^{[1
]}

d'Indy, Hyacintha ^{[2
,4
]}

Braverman, Alan C. ^{[7
]}

Grandchamp, Bernard ^{[3
,8
]}

Kwartler, Callie S. ^{[1
]}

Gouya, Laurent ^{[3
,5
]}

Santos-Cortez, Regie Lyn P. ^{[9
]}

Abifadel, Marianne ^{[2
]}

Leal, Suzanne M. ^{[9
]}

Muti, Christine ^{[3
]}

Shendure, Jay ^{[10
]}

Gross, Marie-Sylvie ^{[2
]}

Rieder, Mark J. ^{[10
]}

Vahanian, Alec ^{[8
]}

Nickerson, Deborah A. ^{[10
]}

Michel, Jean Baptiste ^{[2
]}

Jondeau, Guillaume ^{[2
,3
,8
]}

Milewicz, Dianna M. ^{[1
,6
,11
]}

机构：

[1] Univ Texas Hlth Sci Ctr Houston, Dept Internal Med, Houston, TX USA

[2] Hop Bichat Claude Bernard, INSERM, U698, F-75877 Paris, France

[3] Hop Bichat Claude Bernard, AP HP, Ctr Natl Reference Syndromes Marfan & Apparentes, Serv Cardiologie, F-75877 Paris, France

[4] Hop Ambroise Pare, AP HP, Serv Biochim Hormonologie & Genet Mol, Boulogne, France

[5] Univ Versailles St Quentin En Yvelines, Unite Format & Rech UFR Sci Sante, Guyancourt, France

[6] Mem Hermann Heart & Vasc Inst, Houston, TX USA

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

[8] Univ Paris 07, Unite Format & Rech UFR Med, Paris, France

[9] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA

[10] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA

[11] St Lukes Episcopal Hosp, Texas Heart Inst, Houston, TX USA

来源：

NATURE GENETICS | 2012年 / 44卷 / 08期

基金：

美国国家卫生研究院;

关键词：

SMOOTH-MUSCLE; FBN1; MUTATIONS; OSTEOARTHRITIS; PHENOTYPES; SPECTRUM; PATHWAY; CELLS; MICE;

D O I：

10.1038/ng.2348

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

A predisposition for thoracic aortic aneurysms leading to acute aortic dissections can be inherited in families in an autosomal dominant manner. Genome-wide linkage analysis of two large unrelated families with thoracic aortic disease followed by whole-exome sequencing of affected relatives identified causative mutations in TGFB2. These mutations-a frameshift mutation in exon 6 and a nonsense mutation in exon 4-segregated with disease with a combined logarithm of odds (LOD) score of 7.7. Sanger sequencing of 276 probands from families with inherited thoracic aortic disease identified 2 additional TGFB2 mutations. TGFB2 encodes transforming growth factor (TGF)-beta 2, and the mutations are predicted to cause haploinsufficiency for TGFB2; however, aortic tissue from cases paradoxically shows increased TGF-beta 2 expression and immunostaining. Thus, haploinsufficiency for TGFB2 predisposes to thoracic aortic disease, suggesting that the initial pathway driving disease is decreased cellular TGF-beta 2 levels leading to a secondary increase in TGF-beta 2 production in the diseased aorta.

引用

页码：916 / +

页数：8

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