Mutations in a TGF-β Ligand, TGFB3, Cause Syndromic Aortic Aneurysms and Dissections

被引：257

作者：

Bertoli-Avella, Aida M. ^{[1
,2
,3
,4
]}

Gillis, Elisabeth ^{[2
,3
]}

Morisaki, Hiroko ^{[5
,6
]}

Verhagen, Judith M. A. ^{[1
]}

de Graaf, Bianca M. ^{[1
]}

van de Beek, Gerarda ^{[2
,3
]}

Gallo, Elena ^{[7
]}

Kruithof, Boudewijn P. T. ^{[8
]}

Venselaar, Hanka ^{[9
,10
]}

Myers, Loretha A. ^{[7
]}

Laga, Steven ^{[11
]}

Doyle, Alexander J. ^{[7
,12
,13
]}

Oswald, Gretchen ^{[7
,12
]}

van Cappellen, Gert W. A. ^{[14
,15
]}

Yamanaka, Itaru ^{[5
]}

van der Helm, Robert M. ^{[1
]}

Beverloo, Berna ^{[1
]}

de Klein, Annelies ^{[1
]}

Pardo, Luba ^{[16
]}

Lammens, Martin ^{[17
]}

Evers, Christina ^{[18
]}

Devriendt, Koenraad ^{[19
]}

Dumoulein, Michiel ^{[20
]}

Timmermans, Janneke ^{[21
]}

Bruggenwirth, Hennie T. ^{[1
]}

Verheijen, Frans ^{[1
]}

Rodrigus, Inez ^{[11
]}

Baynam, Gareth ^{[22
,23
]}

Kempers, Marlies ^{[24
]}

Saenen, Johan ^{[25
]}

Van Craenenbroeck, Emeline M. ^{[25
]}

Minatoya, Kenji ^{[26
]}

Matsukawa, Ritsu ^{[27
]}

Tsukube, Takuro ^{[27
]}

Kubo, Noriaki ^{[28
]}

Hofstra, Robert ^{[1
]}

Goumans, Marie Jose ^{[8
]}

Bekkers, Jos A. ^{[29
]}

Roos-Hesselink, Jolien W. ^{[4
]}

van de laar, Ingrid M. B. H. ^{[1
]}

Dietz, Harry C. ^{[7
,12
,30
]}

Van Laer, Lut ^{[2
,3
]}

Morisaki, Takayuki ^{[5
,6
,31
]}

Wessels, Marja W. ^{[1
]}

Loeys, Bart L. ^{[2
,3
,24
]}

机构：

[1] Erasmus Univ, Med Ctr, Dept Clin Genet, NL-3015 CN Rotterdam, Netherlands

[2] Univ Antwerp, Fac Med & Hlth Sci, Ctr Med Genet, B-2650 Antwerp, Belgium

[3] Univ Antwerp Hosp, B-2650 Antwerp, Belgium

[4] Erasmus Univ, Med Ctr, Dept Cardiol, NL-3015 CN Rotterdam, Netherlands

[5] Natl Cerebral & Cardiovasc Ctr, Dept Biosci & Genet, Suita, Osaka, Japan

[6] Natl Cerebral & Cardiovasc Ctr, Dept Med Genet, Suita, Osaka, Japan

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

[8] Leiden Univ, Med Ctr, Dept Mol Cell Biol, Leiden, Netherlands

[9] Radboud Univ Nijmegen, Nijmegen Ctr Mol Life Sci NCMLS, Med Ctr, NL-6525 ED Nijmegen, Netherlands

[10] Ctr Mol & Biomol Informat CMBI, Nijmegen, Netherlands

[11] Univ Antwerp Hosp, Dept Cardiac Surg, B-2650 Antwerp, Belgium

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

[13] Queen Mary Univ London, William Harvey Res Inst, London, England

[14] Erasmus Univ, Med Ctr, Erasmus Opt Imaging Ctr, NL-3015 CN Rotterdam, Netherlands

[15] Erasmus Univ, Med Ctr, Dept Pathol, NL-3015 CN Rotterdam, Netherlands

[16] Erasmus Univ, Med Ctr, Dept Dermatol, NL-3015 CN Rotterdam, Netherlands

[17] Univ Antwerp, Dept Pathol, Univ Antwerp Hosp, B-2650 Antwerp, Belgium

[18] Heidelberg Univ, Inst Human Genet, Heidelberg, Germany

[19] Ctr Human Genet, Leuven, Belgium

[20] AZ Groeninge Kortrijk, Dept Cardiol, Kortrijk, Belgium

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

[22] Genet Serv Western Australia, Subiaco, WA, Australia

[23] Univ Western Australia, Sch Paediat & Child Hlth, Crawley, WA, Australia

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

[25] Univ Antwerp Hosp, Dept Cardiol, B-2650 Antwerp, Belgium

[26] Natl Cerebral & Cardiovasc Ctr, Dept Cardiovasc Surg, Suita, Osaka, Japan

[27] Japanese Red Cross Kobe Hosp, Dept Cardiovasc Surg, Kobe, Hyogo, Japan

[28] Urakawa Red Cross Hosp, Dept Pediat, Urakawa, Hokkaido, Japan

[29] Erasmus Univ, Med Ctr, Dept Cardiothorac Surg, NL-3015 CN Rotterdam, Netherlands

[30] Johns Hopkins Univ, Sch Med, Dept Pediat, Div Pediat Cardiol, Baltimore, MD 21205 USA

[31] Osaka Univ, Grad Sch Pharmaceut Sci, Dept Mol Pathophysiol, Suita, Osaka, Japan

来源：

JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY | 2015年 / 65卷 / 13期

基金：

美国国家卫生研究院;

关键词：

Loeys-Dietz syndrome; gene; TGF-beta pathway; thoracic aortic aneurysm; GROWTH-FACTOR-BETA; DE-NOVO MUTATION; REFERENCE VALUES; PEPTIDE DOMAIN; MARFAN; PATHOGENESIS; OVERGROWTH; PREDICTION; PHENOTYPE; FEATURES;

D O I：

10.1016/j.jacc.2015.01.040

中图分类号：

R5 [内科学];

学科分类号：

100201 [内科学];

摘要：

BACKGROUND Aneurysms affecting the aorta are a common condition associated with high mortality as a result of aortic dissection or rupture. Investigations of the pathogenic mechanisms involved in syndromic types of thoracic aortic aneurysms, such as Marfan and Loeys-Dietz syndromes, have revealed an important contribution of disturbed transforming growth factor (TGF)-beta signaling. OBJECTIVES This study sought to discover a novel gene causing syndromic aortic aneurysms in order to unravel the underlying pathogenesis. METHODS We combined genome-wide linkage analysis, exome sequencing, and candidate gene Sanger sequencing in a total of 470 index cases with thoracic aortic aneurysms. Extensive cardiological examination, including physical examination, electrocardiography, and transthoracic echocardiography was performed. In adults, imaging of the entire aorta using computed tomography or magnetic resonance imaging was done. RESULTS Here, we report on 43 patients from 11 families with syndromic presentations of aortic aneurysms caused by TGFB3 mutations. We demonstrate that TGFB3 mutations are associated with significant cardiovascular involvement, including thoracic/abdominal aortic aneurysm and dissection, and mitral valve disease. Other systemic features overlap clinically with Loeys-Dietz, Shprintzen-Goldberg, and Marfan syndromes, including cleft palate, bifid uvula, skeletal over-growth, cervical spine instability and clubfoot deformity. In line with previous observations in aortic wall tissues of patients with mutations in effectors of TGF-beta signaling (TGFBR1/2, SMAD3, and TGFB2), we confirm a paradoxical up-regulation of both canonical and noncanonical TGF-beta signaling in association with up-regulation of the expression of TGF-beta ligands. CONCLUSIONS Our findings emphasize the broad clinical variability associated with TGFB3 mutations and highlight the importance of early recognition of the disease because of high cardiovascular risk. (C) 2015 by the American College of Cardiology Foundation.

引用

页码：1324 / 1336

页数：13

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