ANGPT2 mutations for improved diagnosis of Primary Lymphedema


Lymphedema is a chronic disease resulting from abnormal development or function of the lymphatic system. In affected patients, lymph is poorly drained from tissues, causing swelling, and fibrosis, limiting the mobility of the affected body part, and increasing the likelihood of infections. The 28 currently known genes causing primary lymphedema can explain <30% of cases.

In Europe, over a million people are affected by lymphedema. Therapy is limited to repeated manual lymphatic massage and use of compressive garments that are intended to decrease tissue swelling. In some cases, surgery may be helpful. Another lymphatic vessel growth factor, VEGF-C, is currently undergoing a clinical trial in combination with surgery for the treatment of lymphedema in patients whose lymph nodes in the armpit have been removed due to breast cancer metastasis. So far, no cure exists for lymphedema, and only in a minority of cases it resolves or ameliorates with time.

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 and previous studies have shown that dominant-negative mutations in angiopoietin 2 (ANGPT2) promote lymphangiogenesis in mice. New research shows that inactivating mutations in ANGPT2 are associated with primary lymphedema in humans.

The mutations result in loss of the normal function of the ANGPT2 protein that is known to play a role in lymphatic and blood vessel maturation. This important discovery opens possibilities for the development of improved treatments of lymphedema,”

Researchers collected samples from patients (and family members) suffering from primary lymphedema. By screening 543 individuals affected by primary lymphedema, using whole-exome sequencing, mutations in ANGPT2 were discovered in patients from five families; one heterozygous de novo ANGPT2 whole-gene deletion and four heterozygous ANGPT2 missense mutations. The study is published in Science Translational Medicine is led by Professor Kari Alitalo, MD, at the Finnish Academy of Sciences in the Faculty of Medicine of the University of Helsinki, and a director of the Centre of Excellence in Translational Cancer Biology and the Wihuri Research Institute.

The ANGPT2 encodes the angiopoietin 2 protein, a growth factor that binds to receptors in blood and lymphatic vessels.

Among the identified mutations, one deletes one copy of the entire gene, whereas the four other ones are amino acid substitutions. Functional analyses revealed three missense mutations that resulted in decreased ANGPT2 secretion and inhibited the secretion of wild-type (WT)–ANGPT2, suggesting to the authors that these mutations. The fourth mutant demonstrated altered integrin binding and its expression in mouse skin, according to the authors, “promoted hyperplasia and dilation of cutaneous lymphatic vessels.”

The mutations that resulted in primary lymphedema in patients provided investigators important insights into the function of the ANGPT2 protein and mechanisms that lead to lymphedema.

Identifying the genetic causes is crucial for better management of the disease. It makes a more precise and reliable diagnosis possible, where today many people with the disease are still not diagnosed. Research on lymphedema leads to insight into the underlying cellular mechanisms, which may be targets for the development of new therapies.

ANGPT2 mutations for improved diagnosis of Primary Lymphedema - Medicine Innovates

About the author

Kari Alitalo

University of Helsinki


Dr. Kari Alitalo is a tenured Research Professor of the Finnish Academy of Sciences and Director of the Wihuri Research Institute and the Centre of Excellence on Translational Cancer Biology in the Faculty of Medicine of the University of Helsinki. He was born in Kuopio, Finland in 1952 and obtained MD and PhD from the University of Helsinki in Finland in 1981. He did his posdoctoral studies with Dr. Paul Bornstein in University of Washinton in Seattle, followed by a postdoctoral period with Drs. Michael Bishop and Harold Varmus in University of California in San Francisco. He was appointed as Professor of Medical Biochemistry in Finland in 1986, Research Professor of the Finnish Cancer Institute in 1987, Professor of Cancer Biology in 1988 and Research Professor of the Finnish Academy of Sciences in 1993. He served as the Director of the Molecular/Cancer Biology Research Program starting from 1999, Academy of Finland Center of Excellence in Cancer Biology from 2000, and in his curernt positions since 2013.

Research Interests

Dr. Alitalo is best known for his work on oncogenes and mechanisms of angiogenesis. He discovered lymphangiogenesis its regulation by growth factors, receptors and signaling mechanisms. He has isolated and characterized several tyrosine kinases including the endothelial receptor tyrosine kinase Tie1, which is related to the Tie2 receptor for angiopoietins and implicated in tumor angiogenesis. He cloned the vascular endothelial growth factor (VEGF) receptor-3, purified and cloned its ligand VEGF-C, and showed that the VEGF-C/VEGFR-3 pathway is required for angiogenesis and lymphangiogenesis. He was also central in the cloning and characterization of the VEGF-B. His laboratory is curerntly studying its function as a coronary vascular growth factor and metabolic regulator in the heart. Studies in his laboratory have demonstrated VEGF-C induced tumor angiogenesis and lymphangiogenesis, intralymphatic tumor growth, and VEGF-C association with tumor metastasis and its inhibition by blocking the VEGFR-3 signal transduction pathway. The inhibitors of these pathways from his laboratory have now entered phase I clinical trials. He is also interested in molecular therapies for lymphedema, which are entering clinical trials. Recent work in his laboratory heve also led to studies of the homeobox transcription factor Prox1 in colon carcinoma stem cells and tumor progression.

About the author

Professor Miikka Vikkula

Geneticist, Vascular Anomalies Specialist


Prof Vikkula obtained his M.D. at the University of Helsinki in 1992 and his Ph.D. in molecular genetics, in 1993. He was a Research Associate at Harvard Medical School 1993-1997, during which time he became interested in vascular and lymphatic anomalies. With his wife, Prof Laurence Boon, Plastic Surgeon, Co-ordinator of the Vascular Anomaly Center, Brussels, he discovered the gene for familial venous malformation (1996), and since then many others. They settled in Brussels in 1997, where Dr Vikkula developed his own laboratory. He obtained a “docentship PhD” in 2000, and was nominated Assistant Professor at the Faculty of Medicine (UCL). He is a member of the Directorate of the de Duve Institute since 2004, and a full professor of Human Genetics since 2013. He has received numerous honours and awards; most recently, the Inbev-Baillet Latour Clinical Prize. He served as president of the Belgian Society of Human Genetics (2004-2008), and as a member of the Scientific Program Committee of the European Society of Human Genetics (2008-2012). He is a Member of the Royal Belgian Academy of Medecine since 2012. Prof Vikkula is well known internationally as a major contributor to the understanding of molecular basis of vascular anomalies and lymphedema with >150 peer-reviewed publications and numerous chapters in major bio-medical text books.


Veli-Matti Leppänen, Pascal Brouillard, Emilia A. Korhonen, Tuomas Sipilä, Sawan Kumar Jha, Nicole Revencu, Veerle Labarque, Elodie Fastré, Matthieu Schlögel, Marie Ravoet, Amihood Singer, Claudia Luzzatto, Donatella Angelone, Giovanni Crichiutti, Angela D’Elia, Jaakko Kuurne, Harri Elamaa, Gou Young Koh, Pipsa Saharinen, Miikka Vikkula, Kari Alitalo. Characterization of ANGPT2 mutations associated with primary lymphedema. Science Translational Medicine, 2020: Vol. 12, Issue 560, eaax8013

Go To Science Translational Medicine