RESUMO
IMPACT STATEMENT: The detailed molecular mechanism of orbital venous malformation (OVM) is still not clear. Using whole exome sequencing, 4 types of melanocortin 4 receptor (MC4R) mutation were detected in 7 of 27 patients with OVM, and all types of MC4R mutations resulted in the upregulation of MC4R expression. In vitro study indicated that MC4R has impacts on the proliferation, cell cycle, migration, and tube formation of the endothelial cells. Moreover, MC4R mutations altered the downstream signaling, including cAMP concentration and the expression levels of several PI3K/AKT/mTOR downstream genes, including p21, cyclin B1, ITGA10, and ITGA11. MC4R mutations may lead to the pathogenesis of OVM through modulating the downstream signaling to alter the angiogenic activity of endothelial cells.