In addition to reactive activation of HIF-1, constitutive activation of HIF-1α by loss-of-function mutation of the VHL gene is the causative mutation of von Hippel–Lindau disease, a familial cancer syndrome characterized by renal cell carcinoma, pheochromocytoma, and hemangioblastoma (central nervous system and retina) [29]. This evidence concerns the gene HIF1A and von Hippel-Lindau disease.