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

Nature Genetics volume 44, pages 922–927 (2012)Cite this article

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Abstract

Loeys-Dietz syndrome (LDS) associates with a tissue signature for high transforming growth factor (TGF)-β signaling but is often caused by heterozygous mutations in genes encoding positive effectors of TGF-β signaling, including either subunit of the TGF-β receptor or SMAD3, thereby engendering controversy regarding the mechanism of disease. Here, we report heterozygous mutations or deletions in the gene encoding the TGF-β2 ligand for a phenotype within the LDS spectrum and show upregulation of TGF-β signaling in aortic tissue from affected individuals. Furthermore, haploinsufficient Tgfb2+/− mice have aortic root aneurysm and biochemical evidence of increased canonical and noncanonical TGF-β signaling. Mice that harbor both a mutant Marfan syndrome (MFS) allele (Fbn1C1039G/+) and Tgfb2 haploinsufficiency show increased TGF-β signaling and phenotypic worsening in association with normalization of TGF-β2 expression and high expression of TGF-β1. Taken together, these data support the hypothesis that compensatory autocrine and/or paracrine events contribute to the pathogenesis of TGF-β–mediated vasculopathies.

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Figure 1: Phenotypic characteristics of humans with TGFB2 mutation.
Figure 2: Mutational analysis of TGFB2 in humans with aneurysm.
Figure 3: Cardiovascular pathology in human subjects with TGFB2 mutations.
Figure 4: Haploinsufficiency for Tgfb2 causes aortic root aneurysm in mice.
Figure 5: Synergistic pathology in Tgfb2+/−; Fbn1C1039G/+ double-heterozygous mice.

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Acknowledgements

This study was supported in part by funding from the Fund for Scientific Research, Flanders (FWO; Belgium) (G.0458.09 and G.0221.12); a European Grant Fighting Aneurysmal Disease (EC-FP7); the Special Research Fund of Ghent University (BOF10/GOA/005); the US National Institutes of Health (RO1- AR41135 and PO1-AR049698 to H.C.D., 5RC1HL100021-02 to J.V.E. and H.C.D. and an Institutional Clinical and Translational Science Award 1U54RR023561-01A1 to J.V.E.); the National Marfan Foundation; the Smilow Center for Marfan Syndrome Research; the Howard Hughes Medical Institute; the Freudmann Fund for Research in Ehlers Danlos Syndrome and Related Disorders; and the Baylor-Hopkins Center for Mendelian Genetics (1U54HG006542). B.L.L. is senior clinical investigator of the Fund for Scientific Research, Flanders (Belgium); N.A.B. is supported by the Aneurysmal Pathology Foundation; D.S. is supported by a PhD grant from the Agency for Innovation by Science and Technology (IWT); E.G. is supported by a fellowship from the Helen Hay Whitney Foundation; J.J.D. is supported by the McKusick Fellowship of the National Marfan Foundation; and M.E.L. is supported by an NHLBI K08 Award (HL107738-01) and by a Fellow-to-Faculty Award from the National Marfan Foundation.

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Author notes

  1. Mark E Lindsay and Dorien Schepers: These authors contributed equally to this work.

  2. Harry C Dietz and Bart L Loeys: These authors jointly directed this work.

Authors and Affiliations

  1. Department of Pediatrics, Helen B Taussig Children's Heart Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

    Mark E Lindsay & Harry C Dietz

  2. Howard Hughes Medical Institute, Baltimore, Maryland, USA

    Mark E Lindsay & Harry C Dietz

  3. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

    Mark E Lindsay, Jefferson J Doyle, Elena Gallo, Yichun Chen, Loretha Myers, Djahita Bjeda, Gretchen Oswald, Abdallah F Elias, Howard P Levy & Harry C Dietz

  4. Center of Medical Genetics, Faculty of Medicine and Health Sciences, University of Antwerp and Antwerp University Hospital, Antwerp, Belgium

    Dorien Schepers, Nikhita Ajit Bolar, Geert R Mortier, Lut Van Laer & Bart L Loeys

  5. Department of Medicine, Division of Cardiology, Bayview Proteomics Center, Johns Hopkins University, Baltimore, Maryland, USA

    Justyna Fert-Bober & Jennifer Van Eyk

  6. Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands

    Marlies J E Kempers, Ernie M H F Bongers, Han G Brunner & Bart L Loeys

  7. Institute for Genetic and Metabolic Disorders, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands

    Marlies J E Kempers, Ernie M H F Bongers, Han G Brunner & Bart L Loeys

  8. Russell H Morgan Department of Radiology and Radiological Science, Johns Hopkins School of Medicine, Baltimore, Maryland, USA

    Elliot K Fishman

  9. Department of Clinical Genetics, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden

    Britt-Marie Anderlid

  10. Department of Pathology, University of Washington School of Medicine, Seattle, Washington, USA

    Margaret H Yang & Peter H Byers

  11. Department of Genetics, University of Washington School of Medicine, Seattle, Washington, USA

    Margaret H Yang & Peter H Byers

  12. Department of Cardiology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands

    Janneke Timmermans

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

    Alan C Braverman

  14. Department of Clinical Genetics, North West Thames Regional Genetics Service, Northwick Park Hospital, Harrow, UK

    Natalie Canham

  15. Department of Pediatrics and Genetics, Ghent University, Ghent, Belgium

    Bart L Loeys

Authors
  1. Mark E Lindsay
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  2. Dorien Schepers
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  26. Harry C Dietz
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  27. Bart L Loeys
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Contributions

M.E.L., H.C.D., D.S., L.V.L. and B.L.L. conceived of the study and designed all experiments. M.E.L., D.S., L.V.L., H.C.D. and B.L.L. wrote the manuscript. D.S., M.H.Y. and N.A.B. performed microarray experiments and mutation analysis. J.J.D. performed protein blotting experiments. E.G. performed RT-PCR analysis of mouse aortas. J.F.-B. and J.V.E. performed serum TGF-β ligand analysis. E.K.F. performed, interpreted and produced multidetector-computed tomography images. Y.C. performed animal husbandry, genotyping and aorta dissections. L.M. performed IHC on human and mouse samples. D.B. performed all mouse echocardiograms. M.J.E.K., G.O., B.-M.A., E.M.H.F.B., J.T., A.C.B., N.C., G.R.M., H.G.B. and P.H.B. contributed patient material and clinical and pedigree data and revised the manuscript. A.F.E. and H.P.L. contributed to the whole-exome sequencing initiative.

Corresponding author

Correspondence to Bart L Loeys.

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The authors declare no competing financial interests.

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Lindsay, M., Schepers, D., Bolar, N. et al. Loss-of-function mutations in TGFB2 cause a syndromic presentation of thoracic aortic aneurysm. Nat Genet 44, 922–927 (2012). https://doi.org/10.1038/ng.2349

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