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

Mark E. Lindsay, Dorien Schepers, Nikhita Ajit Bolar, Jefferson Doyle, Elena MacFarlane, Justyna Fert-Bober, Marlies J E Kempers, Elliot K Fishman, Yichun Chen, Loretha Myers, Djahita Bjeda, Gretchen Oswald, Abdallah F. Elias, Howard Levy, Britt Marie Anderlid, Margaret H. Yang, Ernie M H F Bongers, Janneke Timmermans, Alan C. Braverman, Natalie Canham & 7 others 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 journalArticle

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 languageEnglish (US)
Pages (from-to)922-927
Number of pages6
JournalNature Genetics
Volume44
Issue number8
DOIs
StatePublished - Aug 2012

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Thoracic Aortic Aneurysm
Transforming Growth Factors
Mutation
Loeys-Dietz Syndrome
Haploinsufficiency
Marfan Syndrome
Growth Factor Receptors
Aortic Aneurysm
Sequence Deletion
Gene Deletion
Up-Regulation
Alleles
Ligands
Phenotype

ASJC Scopus subject areas

  • Genetics

Cite this

Loss-of-function mutations in TGFB2 cause a syndromic presentation of thoracic aortic aneurysm. / Lindsay, Mark E.; Schepers, Dorien; Bolar, Nikhita Ajit; Doyle, Jefferson; MacFarlane, Elena; Fert-Bober, Justyna; Kempers, Marlies J E; Fishman, Elliot K; Chen, Yichun; Myers, Loretha; Bjeda, Djahita; Oswald, Gretchen; Elias, Abdallah F.; Levy, Howard; Anderlid, Britt Marie; Yang, Margaret H.; Bongers, Ernie M H F; Timmermans, Janneke; Braverman, Alan C.; Canham, Natalie; Mortier, Geert R.; Brunner, Han G.; Byers, Peter H.; Van Eyk, Jennifer; Van Laer, Lut; Dietz, Harry C; Loeys, Bart L.

In: Nature Genetics, Vol. 44, No. 8, 08.2012, p. 922-927.

Research output: Contribution to journalArticle

Lindsay, ME, Schepers, D, Bolar, NA, Doyle, J, MacFarlane, E, Fert-Bober, J, Kempers, MJE, Fishman, EK, Chen, Y, Myers, L, Bjeda, D, Oswald, G, Elias, AF, Levy, H, 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
Lindsay, Mark E. ; Schepers, Dorien ; Bolar, Nikhita Ajit ; Doyle, Jefferson ; MacFarlane, Elena ; Fert-Bober, Justyna ; Kempers, Marlies J E ; Fishman, Elliot K ; Chen, Yichun ; Myers, Loretha ; Bjeda, Djahita ; Oswald, Gretchen ; Elias, Abdallah F. ; Levy, Howard ; Anderlid, Britt Marie ; Yang, Margaret H. ; Bongers, Ernie M H F ; Timmermans, Janneke ; Braverman, Alan C. ; Canham, Natalie ; Mortier, Geert R. ; Brunner, Han G. ; Byers, Peter H. ; Van Eyk, Jennifer ; Van Laer, Lut ; Dietz, Harry C ; Loeys, Bart L. / Loss-of-function mutations in TGFB2 cause a syndromic presentation of thoracic aortic aneurysm. In: Nature Genetics. 2012 ; Vol. 44, No. 8. pp. 922-927.
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AU - Doyle, Jefferson

AU - MacFarlane, 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

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.

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