The Human Molecular Genetics laboratory of the de Duve Institute (UCLouvain), headed by Professor Miikka Vikkula, 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. This important discovery, published in Science Translational Medicine, is essential for the proper diagnosis of this disease and opens a novel pathway for developing treatments.
of a novel gene involved in primary lymphedema
Human Molecular Genetics laboratory of the de
(UCLouvain), headed by Professor
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
is essential for the proper
of patients suffering from primary lymphedema, and opens a novel
pathway for developing treatments.
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
team of WELBIO investigator Miikka Vikkula has a large
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.
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.
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
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.
Leppänen and Brouillard et al, Science
WELBIO (Walloon Excellence in Lifesciences and Biotechnology),
F.R.S.-FNRS and Prix Generet (Fondation Roi Baudouin).