A mutation in ARAF was discovered by US researchers as the genetic cause of a very rare and complex lymphatic anomaly and then served as the basis for developing a therapeutic approach. In Nature Medicine, the scientists report on the missense mutation in the ARAF gene, encoding a serine/threonine kinase, which they found in two patients. One of their patients, a 12-year-old boy, showed an advanced anomalous lymphatic disease with severe accumulation of lymphatic fluid in his chest, pericardium, abdomen, lower extremities and genitalia. He presented also with shortness of breath and exercise intolerance.

Further functional investigations revealed that the identified gain-of-function mutation led to elevated MEK-ERK1/2 activity, increased lymphangiogenic capacity, and alterations in actin skeleton architecture and VE-cadherin junctions. These effects were rescued in transfected cells and in a zebrafish model by using the MEK inhibitor trametinib. The researchers then obtained clearance for off-label use of trametinib, an approved cancer drug, in the patient. At twelve months of therapy, the boy showed dramatic clinical improvement with remodeling of lymphatic vasculature, resolution of lymphatic edema and near normalization of regular daily activities.