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,” explained Kari Alitalo, MD, research professor 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 study is published in Science Translational Medicine in an article titled, “Characterization of ANGPT2 mutations associated with 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.

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.

A new model of ANGPT2-mediated TIE2 and TIE1 clustering and activation at atomic resolution.
[Reprinted by permission of VM Leppanen et al.]

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

“ANGPT2 has previously been shown to influence lymphatic development in mice, but this is the first time when mutations in this gene were found to cause lymphedema in humans,” noted Alitalo.

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 “have a dominant-negative effect on ANGPT2 signaling.”

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.

A model of the angiopoietin 2 growth factor secretion from lymphatic endothelial cells and the effect of ANGPT2 mutations on the development of lymphedema. Reduced secretion of the ANGPT2 mutants results in decreased receptor dimerization and activation, leading to swelling of the leg.
[Alitalo Lab]

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.

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

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