Characterization of ANGPT2 mutations associated with primary lymphedema

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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 , Vikkula , M & Alitalo , K 2020 , ' Characterization of ANGPT2 mutations associated with primary lymphedema ' , Science translational medicine , vol. 12 , no. 560 , 8013 . https://doi.org/10.1126/scitranslmed.aax8013

Title: Characterization of ANGPT2 mutations associated with primary lymphedema
Author: Leppänen, Veli-Matti; Brouillard, Pascal; Korhonen, Emilia A.; Sipilä, Tuomas; Jha, Sawan Kumar; Revencu, Nicole; Labarque, Veerle; Fastré, Elodie; Schlögel, Matthieu; Ravoet, Marie; Singer, Amihood; Luzzatto, Claudia; Angelone, Donatella; Crichiutti, Giovanni; D’Elia, Angela; Kuurne, Jaakko; Elamaa, Harri; Koh, Gou Young; Saharinen, Pipsa; Vikkula, Miikka; Alitalo, Kari
Contributor: University of Helsinki, CAN-PRO - Translational Cancer Medicine Program
University of Helsinki, Wihuri Research Institute
University of Helsinki, Wihuri Research Institute
University of Helsinki, CAN-PRO - Translational Cancer Medicine Program
University of Helsinki, Department of Biochemistry and Developmental Biology
University of Helsinki, HUSLAB
Date: 2020-09-09
Language: eng
Number of pages: 10
Belongs to series: Science translational medicine
ISSN: 1946-6234
URI: http://hdl.handle.net/10138/334163
Abstract: Lymphedema can occur when tissue fluid cannot enter or leaks from the lymphatic system into surrounding tissues. Some genetic causes of primary lymphedema are known, but these currently explain a minority of cases. Previous studies have shown that dominant-negative mutations in angiopoietin 2 (ANGPT2), which is involved in lymphatic vessel formation and maturation, promote lymphangiogenesis in mice. Leppänen et al. now show that inactivating mutations in angiopoietin 2 associate with primary lymphedema in humans.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.
Subject: 3122 Cancers
3111 Biomedicine
1184 Genetics, developmental biology, physiology
1182 Biochemistry, cell and molecular biology
LYMPHATIC VESSEL DEVELOPMENT
TIE-2 LIGAND ANGIOPOIETIN-2
ENDOTHELIAL CELL-CELL
X-RAY
RECEPTOR
VALVE
SCATTERING
ANGIOGENESIS
DIMERIZATION
ANTAGONIST
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