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

Nature Genetics volume 44, pages 916–921 (2012)Cite this article

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Abstract

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)-β2, and the mutations are predicted to cause haploinsufficiency for TGFB2; however, aortic tissue from cases paradoxically shows increased TGF-β2 expression and immunostaining. Thus, haploinsufficiency for TGFB2 predisposes to thoracic aortic disease, suggesting that the initial pathway driving disease is decreased cellular TGF-β2 levels leading to a secondary increase in TGF-β2 production in the diseased aorta.

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Figure 1: Identification of TGFB2 as the causative gene in thoracic aortic disease in families TAA288 and MS239.
Figure 2: Transcript and protein analysis of the TGFB2 mutation in exon 6 encoding p.Tyr341Cysfs*25.
Figure 3: Aortic pathology and assessment of TGF-β signaling in individuals with TGFB2 mutations.
Figure 4: Clinical features associated with TGFB2 mutations.

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Acknowledgements

The authors are extremely grateful to the families involved in this study and to the medical professionals who aided in the collection of clinical data from the families. We would like to thank the NHLBI GO Exome Sequencing Project and its ongoing studies that produced and provided exome variant calls for comparison: the Lung Cohorts Sequencing Project (HL-102923), the NHLBI Women's Health Initiative Sequencing Project (HL-102924), the Heart Cohorts Sequencing Project (HL-103010), the Broad Institute Sequencing Project (HL-102925), the Northwest Genomics Center Sequencing Project (HL-102926 to D.A.N., M.J.R. and J.S.) and the Family Studies Project Team. We thank J.M. Serfaty for providing vascular imaging and L. Louedec and Z. Ren for technical assistance.

The following sources provided funding for these studies: the US National Institutes of Health (NIH) RO1 HL62594 (D.M.M.), NIH P50HL083794-01 (D.M.M.), NIH UL1 RR024148 (Centers for Clinical and Translational Sciences), the Vivian L. Smith Foundation (D.M.M.), the TexGen Foundation (D.M.M.), Richard T. Pasani Funds (D.M.M.), Groupement d'Interet Scientifique (GIS)–Maladies Rares (C.B.), Projet Hospitalier de Recherche Clinique (PHRC) AOM09093 (G.J.), PHRC AOM 10108 (C.B.), Agence Nationale de Recherche (ANR) 2010 BLAN 1129 from the French National Research Agency (G.J.) and the European Union Framework Programme 7–integrated project Fighting Aneurysmal Disease (FAD, see URLs) (J.B.M.).

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Author notes

  1. Catherine Boileau, Dong-Chuan Guo and Dianna M Milewicz: These authors contributed equally to this work.

  2. Catherine Boileau, Guillaume Jondeau and Dianna M Milewicz: These authors jointly directed this work.

Authors and Affiliations

  1. Institut National de la Santé et de la Recherche Médicale (INSERM) U698, Hôpital Bichat, Paris, France

    Catherine Boileau, Nadine Hanna, Delphine Detaint, Mathilde Varret, Hyacintha d'Indy, Marianne Abifadel, Marie-Sylvie Gross, Jean Baptiste Michel & Guillaume Jondeau

  2. Assistance Publique–Hôpitaux de Paris (AP-HP), Hôpital Bichat, Centre National de Référence pour les Syndromes de Marfan et Apparentés, Service de Cardiologie, Paris, France

    Catherine Boileau, Nadine Hanna, Delphine Detaint, Bernard Grandchamp, Laurent Gouya, Christine Muti & Guillaume Jondeau

  3. AP-HP, Hôpital Ambroise Paré, Service de Biochimie d'Hormonologie et de Génétique Moléculaire, Boulogne, France

    Catherine Boileau, Nadine Hanna, Hyacintha d'Indy & Laurent Gouya

  4. Unité de Formation et de Recherche (UFR) des Sciences de la Santé, Université Versailles Saint-Quentin-en-Yvelines, Guyancourt, France

    Catherine Boileau & Laurent Gouya

  5. Department of Internal Medicine, University of Texas Health Science Center at Houston, Houston, Texas, USA

    Dong-Chuan Guo, Ellen S Regalado, Limin Gong, Siddharth K Prakash, Alexander H Li, Callie S Kwartler & Dianna M Milewicz

  6. AP-HP, Service de Cardiologie, Hopital Bichat, Paris, France

    Delphine Detaint, Alec Vahanian & Guillaume Jondeau

  7. Memorial Hermann Heart and Vascular Institute, Houston, Texas, USA

    Siddharth K Prakash & Dianna M Milewicz

  8. Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri, USA

    Alan C Braverman

  9. Unité de Formation et de Recherche (UFR) de Médecine, Université Paris 7, Paris, France

    Bernard Grandchamp, Alec Vahanian & Guillaume Jondeau

  10. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA

    Regie Lyn P Santos-Cortez & Suzanne M Leal

  11. Department of Genome Sciences, University of Washington, Seattle, Washington, USA

    Jay Shendure, Mark J Rieder & Deborah A Nickerson

  12. Texas Heart Institute at St. Luke's Episcopal Hospital, Houston, Texas, USA

    Dianna M Milewicz

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National Heart, Lung, and Blood Institute (NHLBI) Go Exome Sequencing Project

Contributions

C.B., D.M.M. and G.J. planned the project, designed the experiments, oversaw all aspects of the research and wrote the manuscript. C.B., S.M.L., R.L.P.S.-C., M.V., D.-C.G., M.-S.G. and M.A. performed linkage analyses and analyzed exome sequencing data. M.J.R., J.S. and D.A.N. performed the exome sequencing in TAA288. D.-C.G., A.H.L. and N.H. analyzed exome sequencing data and performed Sanger sequencing analysis with H.d'I., L.G., D.-C.G. and C.S.K. performed the TGFB2 transcript and protein assays. J.B.M. performed histological and imunostaining analyses with M.-S.G. S.K.P. carried out the genomic deletion analysis. E.S.R., B.G., C.M., A.C.B. and L. Gouya provided clinical and pedigree data. D.D., D.M.M. and G.J. provided clinical data and performed sample collection. A.V. revised the manuscript.

Corresponding authors

Correspondence to Catherine Boileau or Dianna M Milewicz.

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The authors declare no competing financial interests.

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A list of members and affiliations is provided in the Supplementary Note.

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Supplementary Note, Supplementary Tables 1–3 and Supplementary Figures 1–3 (PDF 387 kb)

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Boileau, C., Guo, DC., Hanna, N. et al. TGFB2 mutations cause familial thoracic aortic aneurysms and dissections associated with mild systemic features of Marfan syndrome. Nat Genet 44, 916–921 (2012). https://doi.org/10.1038/ng.2348

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