Publication in Science Translational Medicine

Discovery of a novel gene involved in primary lymphedema

Identifying the genetic causes is crucial for a better management of the disease


The Human Molecular Genetics laboratory of the de Duve Institute (UCLouvain), headed by Professor Miikka Vikkula, WELBIO investigator, has identified a novel gene responsible for a lymphatic disease called primary lymphedema. Together with the group of Professor Kari Alitalo in Finland, they identified mutations that alter the function of a protein that is known to play a role in vascularization. They also found how these mutations result in loss of the protein’s normal function. This important discovery, published in Science Translational Medicine, is essential for the proper diagnosis of patients suffering from primary lymphedema, and opens a novel pathway for developing treatments.

Lymphedema is a strongly invalidating chronic disease resulting from abnormal development or function of the lymphatic system. Lymph is not drained from interstitial tissues, but accumulates, most often in the legs or arms, causing swelling, fibrosis, predisposition to secondary infections, and limited mobility of the affected body part. Lymphedema can be either primary, where there is no known underlying cause, or secondary, where it results from removed or damaged lymph vessels, e.g. after surgery, infection or cancer treatment. Primary lymphedema is sometimes inherited.

The team of WELBIO investigator Miikka Vikkula has a large international network of collaborators, including the Center for Vascular Anomalies and the Center for Medical Genetics of the Saint-Luc hospital, Brussels. Together, they have collected samples from almost 900 patients (and family members) suffering from primary lymphedema. By using whole-exome sequencing (i.e. the sequencing of all the coding parts of the genes in our genome), the team was able to discover mutations in a gene called ANGPT2 in five families with occurrence of lymphedema.
ANGPT2 encodes the angiopoietin 2 molecule, a ligand of the TIE2 receptor. Angpt2 had previously been shown to influence lymphatic development in mice, but this is the first time that mutations in this gene are found to cause a disease in human being. Among the identified mutations, one deletes one copy of the entire gene, whereas the four other ones are amino acid substitutions in well conserved positions. To characterize the impact of these changes on the function of ANGPT2, the Finnish collaborators (group of Prof K. Alitalo – a Foreign Member of the Royal Academy of Medicine of Belgium) produced and analyzed in detail the mutant proteins. They were able to show that three of the mutants are not properly secreted, even hampering partially the secretion of the protein produced from the remaining normal allele and thus having so called dominant-negative effect. The fourth one is hyper-active, inducing increased proliferation of dilated lymphatic vessels in a mouse ear model. This mutant more specifically demonstrated altered integrin binding. Whether they induce development of too few or too many lymphatic vessels, these mutations result in primary lymphedema in patients.

In Europe, over a million people are affected by lymphedema. Therapy is limited to repeated manual lymphatic drainage and use of compressive garments. In some cases, surgery may be helpful. No cure exists and only in a minority of cases it resolves or ameliorates with time.

The team of the de Duve Institute has previously identified several disease-causative genes for primary lymphedema, and demonstrated that mutations can be dominant, recessive or even de novo. Some cause a much wider fetal lymphatic dysfunction (hydrops fetalis) or a syndrome, enlarging diagnostic testing indications. For many patients however, the cause of the disease is still unknown. Until now, 28 genes have been found to cause primary lymphedema and/or predispose to the secondary form, but these account only for less than a third of the patients, each gene explaining a defined percentage of cases. Identifying the genetic causes is crucial for a 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. It also leads to insight in the underlying cellular mechanisms, which may be targets for the development of new therapies.

Source : de Duve Institute (UCLouvain)
Illustration : Pr. L. Boon (UCLouvain)
References: Leppänen and Brouillard et al, Science Translational Medicine 2020

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