New genetic cause of primary lymphedema identified

The lymphatic system is an extensive network of vessels, nodes and ducts throughout the body. It serves to drain fluid (called lymph) that has leaked into tissue, back into the blood stream. In primary lymphedema (PL), the lymphatic system is defectively developed or does not function well. This leads to swelling, mostly in the limbs, but may with time also lead to increased fat accumulation, inflammation and fibrosis. PL can develop in utero, but can also appear later in life, during puberty or adulthood. For about 30% of the cases a genetic cause has been identified.

The lab of Miikka Vikkula has identified a new genetic cause of PL. They found that, in a number of patients with late on-set of the disease, it is caused by mutations of a gene called TIE1. The gene encodes for the TIE1 receptor, a transmembrane molecule that is present on cells that form the inner layer of lymphatic vessels.

The work, mainly performed by Pascal Brouillard, started from genetic research on samples of 755 patients with late on-set of the disease. The researchers found the presence of three specific mutations in the TIE1 genes of patients. With bioinformatic algorithms, in vitro and in vivo experiments, they subsequently proved that these mutations indeed cause lymphedema.

The TIE1 receptor binds, together with its brother TIE2, to angiopoietins, molecules that regulate the formation and remodelling of blood and lymphatic vessels. Earlier the Vikkula lab demonstrated that mutations in one of the angiopoietins (angiopoietin-2) can also cause PL. These results therefore emphasize the important role of this signaling pathway in the functioning of the lymphatic system.

Primary lymphedema is distinguished from secondary lymphedema by its onset. Whereas PL results from an error in lymphatic development, secondary lymphedema is acquired and caused by injury to a normally developed lymphatic system. “This study shows that also late onset lymphedema can be genetic, and thus blurs the distinction that primary and secondary lymphedema are very different. It might rather be that most people who develop secondary lymphedema, for example after surgery, also have a genetic predisposition”, explains Miikka Vikkula.

Article describing this research

Loss-of-function mutations of the TIE1 receptor tyrosine kinase cause late-onset primary lymphedema.

Brouillard P, Murtomäki A, Leppänen VM, Hyytiäinen M, Mestre S, Potier L, Boon LM, Revencu N, Greene AK, Anisimov A, Salo MH, Hinttala R, Eklund L, Quéré I, Alitalo K, Vikkula M.

J Clin Invest. 2024 May 30