Characterization of ANGPT2 mutations associated with primary lymphedema

Veli Matti Leppänen, Pascal Brouillard, Emilia A. Korhonen, Tuomas Sipilä, Sawanjha Kumar, Nicole Revencu, Veerle Labarque, Elodie Fastrè, Matthieu Schlögel, Marie Ravoet, Amihood Singer, Claudia Luzzatto, Donatella Angelone, Giovanni Crichiutti, Angela D'Elia, Jaakko Kuurne, Harri Elamaa, Goukoh Young, Pipsa Saharinen, Miikka VikkulaKari Alitalo

Research output: Contribution to journalArticlepeer-review


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 α 5 β 1 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 α 5 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.

Original languageEnglish
Article numbereaax8013
JournalScience Translational Medicine
Issue number560
Publication statusPublished - Sep 2020
Externally publishedYes

ASJC Scopus subject areas

  • Medicine(all)


Dive into the research topics of 'Characterization of ANGPT2 mutations associated with primary lymphedema'. Together they form a unique fingerprint.

Cite this