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

Mark E. Lindsay; Dorien Schepers; Nikhita Ajit Bolar; Jefferson J. Doyle; Elena Gallo; Justyna Fert-Bober; Marlies J.E. Kempers; Elliot K. Fishman; Yichun Chen; Loretha Myers; Djahita Bjeda; Gretchen Oswald; Abdallah F. Elias; Howard P. Levy; Britt Marie Anderlid; Margaret H. Yang; Ernie M.H.F. Bongers; Janneke Timmermans; Alan C. Braverman; Natalie Canham; Geert R. Mortier; Han G. Brunner; Peter H. Byers; Jennifer Van Eyk; Lut Van Laer; Harry C. Dietz; Bart L. Loeys

doi:10.1038/ng.2349

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

Mark E. Lindsay
, Dorien Schepers
, Nikhita Ajit Bolar
, Jefferson J. Doyle
, Elena Gallo
, Justyna Fert-Bober
, Marlies J.E. Kempers
, Elliot K. Fishman
, Yichun Chen
, Loretha Myers
, Djahita Bjeda
, Gretchen Oswald
, Abdallah F. Elias
, Howard P. Levy
, Britt Marie Anderlid
, Margaret H. Yang
, Ernie M.H.F. Bongers
, Janneke Timmermans
, Alan C. Braverman
, Natalie Canham

Geert R. Mortier, Han G. Brunner, Peter H. Byers, Jennifer Van Eyk, Lut Van Laer, Harry C. Dietz, Bart L. Loeys

Research output: Contribution to journal › Article › peer-review

419 Scopus citations

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 (Fbn1 C1039G/+) 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.

Original language	English
Pages (from-to)	922-927
Number of pages	6
Journal	Nature Genetics
Volume	44
Issue number	8
DOIs	https://doi.org/10.1038/ng.2349
State	Published - Aug 2012

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Lindsay, M. E., Schepers, D., Bolar, N. A., Doyle, J. J., Gallo, E., Fert-Bober, J., Kempers, M. J. E., Fishman, E. K., Chen, Y., Myers, L., Bjeda, D., Oswald, G., Elias, A. F., Levy, H. P., Anderlid, B. M., Yang, M. H., Bongers, E. M. H. F., Timmermans, J., Braverman, A. C., ... Loeys, B. L. (2012). Loss-of-function mutations in TGFB2 cause a syndromic presentation of thoracic aortic aneurysm. Nature Genetics, 44(8), 922-927. https://doi.org/10.1038/ng.2349

@article{a9d1b3800bf641babc96ea333a4a7c21,

title = "Loss-of-function mutations in TGFB2 cause a syndromic presentation of thoracic aortic aneurysm",

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 (Fbn1 C1039G/+) 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.",

author = "Lindsay, \{Mark E.\} and Dorien Schepers and Bolar, \{Nikhita Ajit\} and Doyle, \{Jefferson J.\} and Elena Gallo and Justyna Fert-Bober and Kempers, \{Marlies J.E.\} and Fishman, \{Elliot K.\} and Yichun Chen and Loretha Myers and Djahita Bjeda and Gretchen Oswald and Elias, \{Abdallah F.\} and Levy, \{Howard P.\} and Anderlid, \{Britt Marie\} and Yang, \{Margaret H.\} and Bongers, \{Ernie M.H.F.\} and Janneke Timmermans and Braverman, \{Alan C.\} and Natalie Canham and Mortier, \{Geert R.\} and Brunner, \{Han G.\} and Byers, \{Peter H.\} and \{Van Eyk\}, Jennifer and \{Van Laer\}, Lut and Dietz, \{Harry C.\} and Loeys, \{Bart L.\}",

note = "Funding Information: 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. Funding Information: 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",

year = "2012",

month = aug,

doi = "10.1038/ng.2349",

language = "English",

volume = "44",

pages = "922--927",

journal = "Nature Genetics",

issn = "1061-4036",

number = "8",

}

Lindsay, ME, Schepers, D, Bolar, NA, Doyle, JJ, Gallo, E, Fert-Bober, J, Kempers, MJE, Fishman, EK, Chen, Y, Myers, L, Bjeda, D, Oswald, G, Elias, AF, Levy, HP, Anderlid, BM, Yang, MH, Bongers, EMHF, Timmermans, J, Braverman, AC, Canham, N, Mortier, GR, Brunner, HG, Byers, PH, Van Eyk, J, Van Laer, L, Dietz, HC & Loeys, BL 2012, 'Loss-of-function mutations in TGFB2 cause a syndromic presentation of thoracic aortic aneurysm', Nature Genetics, vol. 44, no. 8, pp. 922-927. https://doi.org/10.1038/ng.2349

TY - JOUR

T1 - Loss-of-function mutations in TGFB2 cause a syndromic presentation of thoracic aortic aneurysm

AU - Lindsay, Mark E.

AU - Schepers, Dorien

AU - Bolar, Nikhita Ajit

AU - Doyle, Jefferson J.

AU - Gallo, Elena

AU - Fert-Bober, Justyna

AU - Kempers, Marlies J.E.

AU - Fishman, Elliot K.

AU - Chen, Yichun

AU - Myers, Loretha

AU - Bjeda, Djahita

AU - Oswald, Gretchen

AU - Elias, Abdallah F.

AU - Levy, Howard P.

AU - Anderlid, Britt Marie

AU - Yang, Margaret H.

AU - Bongers, Ernie M.H.F.

AU - Timmermans, Janneke

AU - Braverman, Alan C.

AU - Canham, Natalie

AU - Mortier, Geert R.

AU - Brunner, Han G.

AU - Byers, Peter H.

AU - Van Eyk, Jennifer

AU - Van Laer, Lut

AU - Dietz, Harry C.

AU - Loeys, Bart L.

N1 - Funding Information: 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. Funding Information: 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

PY - 2012/8

Y1 - 2012/8

N2 - 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 (Fbn1 C1039G/+) 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.

AB - 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 (Fbn1 C1039G/+) 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.

UR - https://www.scopus.com/pages/publications/84864415173

U2 - 10.1038/ng.2349

DO - 10.1038/ng.2349

M3 - Article

C2 - 22772368

AN - SCOPUS:84864415173

SN - 1061-4036

VL - 44

SP - 922

EP - 927

JO - Nature Genetics

JF - Nature Genetics

IS - 8

ER -

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

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