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

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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 (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.

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U2 - 10.1038/ng.2349

DO - 10.1038/ng.2349

M3 - Article

C2 - 22772368

AN - SCOPUS:84864415173

VL - 44

SP - 922

EP - 927

JO - Nature Genetics

JF - Nature Genetics

SN - 1061-4036

IS - 8

ER -

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

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