Germline Loss-of-Function Mutations in EPHB4 Cause a Second Form of Capillary Malformation-Arteriovenous Malformation (CM-AVM2) Deregulating RAS-MAPK Signaling

Abstract

We found <i>EPHB4</i> mutations in patients with multifocal CMs associated with AVMs. The phenotype, CM-AVM2, mimics <i>RASA1</i>-related CM-AVM1 and also hereditary hemorrhagic telangiectasia. <i>RASA1</i>-encoded p120RASGAP is a direct effector of EPHB4. Our data highlight the pathogenetic importance of this interaction and indicts EPHB4-RAS-ERK signaling pathway as a major cause for AVMs.