University of Oulu

Leppänen, V.-M., Brouillard, P., Korhonen, E. A., Sipilä, T., Jha, S. K., Revencu, N., Labarque, V., Fastré, E., Schlögel, M., Ravoet, M., Singer, A., Luzzatto, C., Angelone, D., Crichiutti, G., D’Elia, A., Kuurne, J., Elamaa, H., Koh, G. Y., Saharinen, P., … Alitalo, K. (2020). Characterization of ANGPT2 mutations associated with primary lymphedema. Science Translational Medicine, 12(560), eaax8013.

Characterization of ANGPT2 mutations associated with primary lymphedema

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Author: Leppänen, Veli-Matti1,2; Brouillard, Pascal3; Korhonen, Emilia A.1;
Organizations: 1Wihuri Research Institute, Biomedicum Helsinki, Haartmaninkatu 8, 00290 Helsinki, Finland
2Translational Cancer Medicine Program, Faculty of Medicine and Helsinki Institute of Life Science, 00014 University of Helsinki, Finland
3Human Molecular Genetics, de Duve Institute, University of Louvain, 1200 Brussels, Belgium
4Center for Human Genetics, Cliniques universitaires Saint-Luc, University of Louvain, 1200 Brussels, Belgium
5Centre for Molecular and Vascular Biology, University of Leuven, 3000 Leuven, Belgium
6Barzilai Medical Center, 78306 Ashekelon, Israel
7Padova University Hospital, 35128 Padova, Italy
8A. Gemelli Hospital, 00168 Roma, Italy
9Azienda Ospedaliero-Universitaria Santa Maria della Misericordia, 33100 Udine, Italy
10Oulu Centre for Cell-Matrix Research, Faculty of Biochemistry and Molecular Medicine, Biocenter Oulu, University of Oulu, 90220 Oulu, Finland
11Center for Vascular Research, Institute of Basic Science (IBS), 34141 Daejeon, Republic of Korea
12Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), 34141 Daejeon, Republic of Korea
13Walloon Excellence in Lifesciences and Biotechnology (WELBIO), University of Louvain, 1200 Brussels, Belgium
Format: article
Version: accepted version
Access: open
Online Access: PDF Full Text (PDF, 1.9 MB)
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Language: English
Published: American Association for the Advancement of Science, 2020
Publish Date: 2022-03-02


Primary lymphedema is caused by developmental and functional defects of the lymphatic vascular system that result in accumulation of protein-rich fluid in tissues, resulting in edema. The 28 currently known genes causing primary lymphedema can explain <30% of cases. Angiopoietin 1 (ANGPT1) and ANGPT2 function via the TIE1-TIE2 (tyrosine kinase with immunoglobulin-like and epidermal growth factor–like domains 1 and 2) receptor complex and α5β1 integrin to form an endothelial cell signaling pathway that is critical for blood and lymphatic vessel formation and remodeling during embryonic development, as well as for homeostasis of the mature vasculature. By screening a cohort of 543 individuals affected by primary lymphedema, we identified one heterozygous de novo ANGPT2 whole-gene deletion and four heterozygous ANGPT2 missense mutations. Functional analyses revealed three missense mutations that resulted in decreased ANGPT2 secretion and inhibited the secretion of wild-type (WT)–ANGPT2, suggesting that they have a dominant-negative effect on ANGPT2 signaling. WT-ANGPT2 and soluble mutants T299M and N304K activated TIE1 and TIE2 in an autocrine assay in human lymphatic endothelial cells. Molecular modeling and biophysical studies showed that amino-terminally truncated ANGPT subunits formed asymmetrical homodimers that bound TIE2 in a 2:1 ratio. The T299M mutant, located in the dimerization interphase, showed reduced integrin α5 binding, and its expression in mouse skin promoted hyperplasia and dilation of cutaneous lymphatic vessels. These results demonstrate that primary lymphedema can be associated with ANGPT2 mutations and provide insights into TIE1 and TIE2 activation mechanisms.

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Series: Science translational medicine
ISSN: 1946-6234
ISSN-E: 1946-6242
ISSN-L: 1946-6234
Volume: 12
Issue: 560
Article number: eaax8013
DOI: 10.1126/scitranslmed.aax8013
Type of Publication: A1 Journal article – refereed
Field of Science: 1182 Biochemistry, cell and molecular biology
Funding: The work was funded by the F.R.S.-FNRS (Fonds de la Recherche Scientifique, Belgium) grants T.0026.14 and T.0247.19; the Fund Generet managed by the King Baudouin Foundation (2018-J1810250-211305) (Belgium) and the Walloon Excellence in Lifesciences & BIOtechnology (FNRS-WELBIO; WELBIO-CR-2019C; all four to M.V.); the F.R.S.-FNRS (Fonds de la Recherche Scientifique, Belgium) for the equipment grant U.N035.17 (to M.V.) for the “Big data analysis cluster for NGS at UCL” and the Foundation against Cancer, Belgium (to M.V.); the Wihuri Research Institute, maintained by the Jenny and Antti Wihuri Foundation; the Jane and Aatos Erkko Foundation (K.A.); European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme under grant agreement (743155 and 874708 to K.A. and 773076 to P.S.); the Academy of Finland Centre of Excellence Program 2014-2019 (307366 to K.A.); Academy of Finland, iCAN—The Digital Precision Cancer Medicine Platform (grant 320185 to K.A.); Academy of Finland Terva Program (grant 314498 to K.A.); Academy of Finland (grant 312516 to K.A. and 310075 to P.S.); Novo Nordisk Foundation (K.A.); and the Sigrid Jusélius Foundation (K.A. and P.S.).
Copyright information: © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.