ANGPT2 Mutations Associated with Primary Lymphedema

Researchers from the Duve Institute and the University of Helsinki have identified that mutations in ANGPT2 are linked to primary lymphedema. Their findings were published in Science Translational Medicine.

"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 lead researcher Kari Alitalo. Lymphedema can be either primary or secondary, and primary lymphedema is often inherited while secondary lymphedema results from damaged tissue. 

The team collected samples from almost 900 patients—and family members—suffering from primary lymphedema and used whole exome sequencing to study mutations in ANGPT2. Through their analysis, they discovered ANGPT2 mutations in lymphedema patients from five families. Among the mutations identified, one resulted in a deletion of the gene copy, and the other four resulted in amino acid substitutions.

They also identified that the mutations have a dominant-negative effect—three of the mutants are not properly secreted from cells that normally produce the protein, decreasing the secretion of the protein produced from the remaining normal allele. The fourth mutant was hyperactive in inducing increased proliferation of dilated lymphatic vessels. 

"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," Alitalo concludes.