Mutations in a TGF-β ligand, TGFB3, cause syndromic aortic aneurysms and dissections

Aida M. Bertoli-Avella, Elisabeth Gillis, Hiroko Morisaki, Judith M A Verhagen, Bianca M. De Graaf, Gerarda Van De Beek, Elena MacFarlane, Boudewijn P T Kruithof, Hanka Venselaar, Loretha A. Myers, Steven Laga, Alexander J. Doyle, Gretchen Oswald, Gert W A Van Cappellen, Itaru Yamanaka, Robert M. Van Der Helm, Berna Beverloo, Annelies De Klein, Luba Pardo, Martin Lammens & 25 others Christina Evers, Koenraad Devriendt, Michiel Dumoulein, Janneke Timmermans, Hennie T. Bruggenwirth, Frans Verheijen, Inez Rodrigus, Gareth Baynam, Marlies Kempers, Johan Saenen, Emeline M. Van Craenenbroeck, Kenji Minatoya, Ritsu Matsukawa, Takuro Tsukube, Noriaki Kubo, Robert Hofstra, Marie Jose Goumans, Jos A. Bekkers, Jolien W. Roos-Hesselink, Ingrid M B H Van De Laar, Harry C Dietz, Lut Van Laer, Takayuki Morisaki, Marja W. Wessels, Bart L. Loeys

Research output: Contribution to journalArticle

Abstract

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)-β 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 overgrowth, cervical spine instability and clubfoot deformity. In line with previous observations in aortic wall tissues of patients with mutations in effectors of TGF-β signaling (TGFBR1/2, SMAD3, and TGFB2), we confirm a paradoxical up-regulation of both canonical and noncanonical TGF-β signaling in association with up-regulation of the expression of TGF-β 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.

Original languageEnglish (US)
Pages (from-to)1324-1336
Number of pages13
JournalJournal of the American College of Cardiology
Volume65
Issue number13
DOIs
StatePublished - 2015

Fingerprint

Transforming Growth Factor beta3
Aortic Aneurysm
Transforming Growth Factors
Thoracic Aortic Aneurysm
Dissection
Ligands
Mutation
Aorta
Loeys-Dietz Syndrome
Up-Regulation
Uvula
Exome
Clubfoot
Marfan Syndrome
Abdominal Aortic Aneurysm
Cleft Palate
Mitral Valve
Genes
Physical Examination
Aneurysm

Keywords

  • Gene
  • Loeys-Dietz syndrome
  • TGF-β pathway
  • Thoracic aortic aneurysm

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Bertoli-Avella, A. M., Gillis, E., Morisaki, H., Verhagen, J. M. A., De Graaf, B. M., Van De Beek, G., ... Loeys, B. L. (2015). Mutations in a TGF-β ligand, TGFB3, cause syndromic aortic aneurysms and dissections. Journal of the American College of Cardiology, 65(13), 1324-1336. https://doi.org/10.1016/j.jacc.2015.12.056

Mutations in a TGF-β ligand, TGFB3, cause syndromic aortic aneurysms and dissections. / Bertoli-Avella, Aida M.; Gillis, Elisabeth; Morisaki, Hiroko; Verhagen, Judith M A; De Graaf, Bianca M.; Van De Beek, Gerarda; MacFarlane, Elena; Kruithof, Boudewijn P T; Venselaar, Hanka; Myers, Loretha A.; Laga, Steven; Doyle, Alexander J.; Oswald, Gretchen; Van Cappellen, Gert W A; Yamanaka, Itaru; Van Der Helm, Robert M.; Beverloo, Berna; De Klein, Annelies; Pardo, Luba; Lammens, Martin; Evers, Christina; Devriendt, Koenraad; Dumoulein, Michiel; Timmermans, Janneke; Bruggenwirth, Hennie T.; Verheijen, Frans; Rodrigus, Inez; Baynam, Gareth; Kempers, Marlies; Saenen, Johan; Van Craenenbroeck, Emeline M.; Minatoya, Kenji; Matsukawa, Ritsu; Tsukube, Takuro; Kubo, Noriaki; Hofstra, Robert; Goumans, Marie Jose; Bekkers, Jos A.; Roos-Hesselink, Jolien W.; Van De Laar, Ingrid M B H; Dietz, Harry C; Van Laer, Lut; Morisaki, Takayuki; Wessels, Marja W.; Loeys, Bart L.

In: Journal of the American College of Cardiology, Vol. 65, No. 13, 2015, p. 1324-1336.

Research output: Contribution to journalArticle

Bertoli-Avella, AM, Gillis, E, Morisaki, H, Verhagen, JMA, De Graaf, BM, Van De Beek, G, MacFarlane, E, Kruithof, BPT, Venselaar, H, Myers, LA, Laga, S, Doyle, AJ, Oswald, G, Van Cappellen, GWA, Yamanaka, I, Van Der Helm, RM, Beverloo, B, De Klein, A, Pardo, L, Lammens, M, Evers, C, Devriendt, K, Dumoulein, M, Timmermans, J, Bruggenwirth, HT, Verheijen, F, Rodrigus, I, Baynam, G, Kempers, M, Saenen, J, Van Craenenbroeck, EM, Minatoya, K, Matsukawa, R, Tsukube, T, Kubo, N, Hofstra, R, Goumans, MJ, Bekkers, JA, Roos-Hesselink, JW, Van De Laar, IMBH, Dietz, HC, Van Laer, L, Morisaki, T, Wessels, MW & Loeys, BL 2015, 'Mutations in a TGF-β ligand, TGFB3, cause syndromic aortic aneurysms and dissections', Journal of the American College of Cardiology, vol. 65, no. 13, pp. 1324-1336. https://doi.org/10.1016/j.jacc.2015.12.056
Bertoli-Avella AM, Gillis E, Morisaki H, Verhagen JMA, De Graaf BM, Van De Beek G et al. Mutations in a TGF-β ligand, TGFB3, cause syndromic aortic aneurysms and dissections. Journal of the American College of Cardiology. 2015;65(13):1324-1336. https://doi.org/10.1016/j.jacc.2015.12.056
Bertoli-Avella, Aida M. ; Gillis, Elisabeth ; Morisaki, Hiroko ; Verhagen, Judith M A ; De Graaf, Bianca M. ; Van De Beek, Gerarda ; MacFarlane, Elena ; Kruithof, Boudewijn P T ; Venselaar, Hanka ; Myers, Loretha A. ; Laga, Steven ; Doyle, Alexander J. ; Oswald, Gretchen ; Van Cappellen, Gert W A ; Yamanaka, Itaru ; Van Der Helm, Robert M. ; Beverloo, Berna ; De Klein, Annelies ; Pardo, Luba ; Lammens, Martin ; Evers, Christina ; Devriendt, Koenraad ; Dumoulein, Michiel ; Timmermans, Janneke ; Bruggenwirth, Hennie T. ; Verheijen, Frans ; Rodrigus, Inez ; Baynam, Gareth ; Kempers, Marlies ; Saenen, Johan ; Van Craenenbroeck, Emeline M. ; Minatoya, Kenji ; Matsukawa, Ritsu ; Tsukube, Takuro ; Kubo, Noriaki ; Hofstra, Robert ; Goumans, Marie Jose ; Bekkers, Jos A. ; Roos-Hesselink, Jolien W. ; Van De Laar, Ingrid M B H ; Dietz, Harry C ; Van Laer, Lut ; Morisaki, Takayuki ; Wessels, Marja W. ; Loeys, Bart L. / Mutations in a TGF-β ligand, TGFB3, cause syndromic aortic aneurysms and dissections. In: Journal of the American College of Cardiology. 2015 ; Vol. 65, No. 13. pp. 1324-1336.
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abstract = "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)-β 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 overgrowth, cervical spine instability and clubfoot deformity. In line with previous observations in aortic wall tissues of patients with mutations in effectors of TGF-β signaling (TGFBR1/2, SMAD3, and TGFB2), we confirm a paradoxical up-regulation of both canonical and noncanonical TGF-β signaling in association with up-regulation of the expression of TGF-β 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.",
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TY - JOUR

T1 - Mutations in a TGF-β ligand, TGFB3, cause syndromic aortic aneurysms and dissections

AU - Bertoli-Avella, Aida M.

AU - Gillis, Elisabeth

AU - Morisaki, Hiroko

AU - Verhagen, Judith M A

AU - De Graaf, Bianca M.

AU - Van De Beek, Gerarda

AU - MacFarlane, Elena

AU - Kruithof, Boudewijn P T

AU - Venselaar, Hanka

AU - Myers, Loretha A.

AU - Laga, Steven

AU - Doyle, Alexander J.

AU - Oswald, Gretchen

AU - Van Cappellen, Gert W A

AU - Yamanaka, Itaru

AU - Van Der Helm, Robert M.

AU - Beverloo, Berna

AU - De Klein, Annelies

AU - Pardo, Luba

AU - Lammens, Martin

AU - Evers, Christina

AU - Devriendt, Koenraad

AU - Dumoulein, Michiel

AU - Timmermans, Janneke

AU - Bruggenwirth, Hennie T.

AU - Verheijen, Frans

AU - Rodrigus, Inez

AU - Baynam, Gareth

AU - Kempers, Marlies

AU - Saenen, Johan

AU - Van Craenenbroeck, Emeline M.

AU - Minatoya, Kenji

AU - Matsukawa, Ritsu

AU - Tsukube, Takuro

AU - Kubo, Noriaki

AU - Hofstra, Robert

AU - Goumans, Marie Jose

AU - Bekkers, Jos A.

AU - Roos-Hesselink, Jolien W.

AU - Van De Laar, Ingrid M B H

AU - Dietz, Harry C

AU - Van Laer, Lut

AU - Morisaki, Takayuki

AU - Wessels, Marja W.

AU - Loeys, Bart L.

PY - 2015

Y1 - 2015

N2 - 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)-β 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 overgrowth, cervical spine instability and clubfoot deformity. In line with previous observations in aortic wall tissues of patients with mutations in effectors of TGF-β signaling (TGFBR1/2, SMAD3, and TGFB2), we confirm a paradoxical up-regulation of both canonical and noncanonical TGF-β signaling in association with up-regulation of the expression of TGF-β 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.

AB - 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)-β 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 overgrowth, cervical spine instability and clubfoot deformity. In line with previous observations in aortic wall tissues of patients with mutations in effectors of TGF-β signaling (TGFBR1/2, SMAD3, and TGFB2), we confirm a paradoxical up-regulation of both canonical and noncanonical TGF-β signaling in association with up-regulation of the expression of TGF-β 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.

KW - Gene

KW - Loeys-Dietz syndrome

KW - TGF-β pathway

KW - Thoracic aortic aneurysm

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DO - 10.1016/j.jacc.2015.12.056

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JF - Journal of the American College of Cardiology

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