NRAS ^Q61R Expression in Lymphatic Endothelial Cells Causes Enlarged Vessels, Hemorrhagic Chylous Effusions, and High Mortality in a Mouse Model of Kaposiform Lymphangiomatosis

BACKGROUND: ) mutation has been associated with KLA. Existing preclinical models do not recapitulate the thoracic effusions that drive morbidity and mortality in patients. The goal of this study was to develop a genetic mouse model that more closely mimics the clinical phenotype of KLA. PROCEDURE: expression. Survival, effusion incidence, and plasma Ang-2 levels were assessed at 3 weeks. Recombination efficiency and lymphatic vessel structure in the lungs and whole-mounts of the diaphragm and ear were determined. RESULTS: recombination was 93% in the pulmonary lymphatics, which were enlarged and abnormal. Lymphatic vessel diameters were increased in the diaphragm (193%) and ears (152%). CONCLUSIONS: mutant mice closely resemble KLA patients with high mortality, hemorrhagic chylothorax, elevated Ang-2 levels, and enlarged lymphatic vessels. Future studies can utilize this model to elucidate the mechanisms underlying KLA pathogenesis and test novel therapeutics.