Novel Gene Mutation Identified in Generalized Lymph Node Swelling

Mutations in a novel gene, ANGPT2, that is responsible for primary lymphedema, has been identified. These mutations could lead to the dysfunction of ANGPT2 protein that otherwise helps in lymphatic and blood vessel maturation. "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", explains Professor Kari Alitalo.

The study by the Human Molecular Genetics laboratory of the de Duve Institute (UCLouvain), headed by Professor Miikka Vikkula, is published in Science Translational Medicine.

Lymphedema is a chronic, debilitating condition caused by abnormal development or function of the lymphatic system. It is characterized by poor drainage of lymph from tissues that lead to its accumulation in the legs or arms, causing swelling, and fibrosis.

Lymphedema limits mobility and increases the likelihood of infections. Lymphedema can be primary, which has no underlying cause, or secondary, that results from removed or damaged lymph vessels, after surgery, infection, or cancer treatment. Primary lymphedema is often inherited.

So far, there is no cure for lymphedema, and only a handful of cases become manageable with time.

For the study, the research team collected samples from almost 900 patients, and family members suffering from primary lymphedema. They used whole-exome sequencing to identify mutations in ANGPT2 in lymphedema patients from five families. The ANGPT2 encodes the angiopoietin-2 protein, a growth factor that binds to receptors in the blood and lymphatic vessels.

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"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", says Professor Alitalo.

Among the five mutations that were identified, one deletes an entire gene copy, while the other four mutations were amino acid substitutions.

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Among the four, three of the mutants had a dominant-negative effect. They were improperly secreted from cells that normally produce the protein, which decreases the secretion of the protein.

The fourth mutant was hyperactive proliferation of dilated lymphatic vessels. This mutant demonstrated altered integrin binding.

The mutations that resulted in primary lymphedema gives information about 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. As the newly published study shows, research on lymphedema leads to insight in the underlying cellular mechanisms, which may be targeted for the development of new therapies", Professor Alitalo continues.

Source-Medindia