Identification of EPHB4 variants in dilated cardiomyopathy patients

Cardiac homeostasis relies on the appropriate provision of nutrients to the working myocardium. EPHB4 is required for the maintenance of vascular integrity and correct fatty acid transport uptake in the heart via regulating the caveolar trafficking of the fatty acid receptor CD36. In the mouse, endothelial specific loss-of-function of the receptor EphB4, or its ligand ephrin-B2, induces Dilated Cardiomyopathy (DCM) like defects. Now, we have identified six newEPHB4variants with deleterious potential in a cohort of 573 DCM patients. Similar to the EphB4 mutant mice,EPHB4variants carrying patients show an altered expression pattern of CD36 and CAV1 in the heart. For the first time, our data identifies EPHB4 mutations in DCM patients. This observation supports the notion that the Eph-ephrin signalling pathway, and in particular the receptor EPHB4, plays a role in the development of DCM in human patients.