VHL

About VHL

VHL Von Hippel Lindau on chromosome 3p25.3 encodes the substrate recognition component of an E3 ubiquitin ligase that targets the alpha subunits of hypoxia inducible factor, HIF, for degradation when oxygen is plentiful. When oxygen is low, or when VHL is lost, HIF accumulates and activates genes for angiogenesis such as VEGF, red cell production such as erythropoietin, glycolysis, and other adaptive responses. Germline VHL variants cause von Hippel Lindau disease, an autosomal dominant tumor syndrome with hemangioblastomas of the cerebellum, spinal cord, and retina, clear cell renal cell carcinoma, pheochromocytoma, pancreatic cysts and neuroendocrine tumors, endolymphatic sac tumors of the inner ear, and epididymal cystadenomas. The condition is named after the German ophthalmologist Eugen von Hippel and the Swedish pathologist Arvid Lindau, who described its features in the early twentieth century, and the gene was identified in 1993. Affected individuals usually undergo long term surveillance. Work on the VHL and HIF pathway earned William Kaelin, Peter Ratcliffe, and Gregg Semenza the 2019 Nobel Prize in Physiology or Medicine. VHL loss drives most sporadic clear cell kidney cancers, explaining why VEGF targeted drugs and the HIF 2 alpha inhibitor belzutifan are effective in this tumor type.