Aliases for VHL Gene
External Ids for VHL Gene
Previous GeneCards Identifiers for VHL Gene
Von Hippel-Lindau syndrome (VHL) is a dominantly inherited familial cancer syndrome predisposing to a variety of malignant and benign tumors. A germline mutation of this gene is the basis of familial inheritance of VHL syndrome. The protein encoded by this gene is a component of the protein complex that includes elongin B, elongin C, and cullin-2, and possesses ubiquitin ligase E3 activity. This protein is involved in the ubiquitination and degradation of hypoxia-inducible-factor (HIF), which is a transcription factor that plays a central role in the regulation of gene expression by oxygen. RNA polymerase II subunit POLR2G/RPB7 is also reported to be a target of this protein. Alternatively spliced transcript variants encoding distinct isoforms have been observed. [provided by RefSeq, Jul 2008]
Von Hippel-Lindau (VHL) disease is characterized by heterozygous germline mutation in VHL gene on chromosome 3p. Patients are predisposed to developing hemangioblastomas of the brain, spinal cord, and retina; renal cysts and clear cell renal cell carcinoma; pheochromocytoma, pancreatic cysts and neuroendocrine tumors; endolymphatic sac tumors; and epididymal and broad ligament cysts. Cerebellar hemangioblastomas may be associated with headache, vomiting, gait disturbances, or ataxia. Spinal hemangioblastomas and related syrinx usually present with pain. Sensory and motor loss may develop with cord compression. Retinal hemangioblastomas may be the initial manifestation of VHL disease and can cause vision loss. Renal cell carcinoma occurs in about 70% of individuals with VHL and is the leading cause of mortality. Pheochromocytomas can be asymptomatic but may cause sustained or episodic hypertension. Pancreatic lesions often remain asymptomatic and rarely cause endocrine or exocrine insufficiency. Endolymphatic sac tumors can cause hearing loss of varying severity, which can be a presenting symptom. Cystadenomas of the epididymis are relatively common. They rarely cause problems, unless bilateral, in which case they may result in infertility. The VHL gene product encodes pVHL, which binds to elongin C, elongin B, cullin-2 and Rbx1. This complex catalyzes the polyubiquitinylation of specific proteins and targets them for degradation by proteosomes. For example, under normoxic conditions, hydroxylated hypoxia-inducble factor alpha subunits (HIFα) binds pVHL targets HIFα for degradation. Under hypoxic conditions, HIF1α is not hydroxylated, pVHL does not bind, and HIF1α subunits accumulate. HIF1α forms heterodimers with HIF1β and activates transcription of a variety of hypoxia-inducible genes (i.e., VEGF, EPO, TGFα, PDGFβ). Likewise, when pVHL is absent or mutated, HIF1α subunits accumulate, resulting in cell proliferation and the neovascularization of tumors characteristic of VHL disease. Pathogenic variants in VHL either prevent its expression (i.e., deletions, frameshifts, nonsense mutations, and splice site mutations) or lead to the expression of an abnormal protein (i.e., missense mutations). Missense mutations that destabilize packing of the alpha-helical domains, decrease the stability of the alpha-beta domain interface, interfere with binding of elongin C and HIF1α, or disrupt hydrophobic core residues result in loss of HIF regulation and are more likely to result in VHL type 1 (no predisposition to pheochromocytoma). Missense mutations that result in pVHL that is normal with respect to HIF regulation are more likely to be associated with VHL with clinical pheochromocytoma. Acquired somatic pathogenic variants in VHL may give rise to sporadic VHL-type tumors (i.e., clear cell RCC and hemangioblastoma) without other associated tumors characteristic of the hereditary disease. It should be noted that >90% of the most common form of kidney cancer (clear cell renal cell carcinoma) are associated with bi-allelic somatic mutation in the VHL gene, and is the rationale for the anti-angiogenic therapy for RCC patients.
GeneCards Summary for VHL Gene
VHL (Von Hippel-Lindau Tumor Suppressor) is a Protein Coding gene. Diseases associated with VHL include Von Hippel-Lindau Syndrome and Erythrocytosis, Familial, 2. Among its related pathways are ERK Signaling and Class I MHC mediated antigen processing and presentation. Gene Ontology (GO) annotations related to this gene include enzyme binding and ubiquitin-protein transferase activity. An important paralog of this gene is VHLL.
UniProtKB/Swiss-Prot Summary for VHL Gene
Involved in the ubiquitination and subsequent proteasomal degradation via the von Hippel-Lindau ubiquitination complex. Seems to act as a target recruitment subunit in the E3 ubiquitin ligase complex and recruits hydroxylated hypoxia-inducible factor (HIF) under normoxic conditions. Involved in transcriptional repression through interaction with HIF1A, HIF1AN and histone deacetylases. Ubiquitinates, in an oxygen-responsive manner, ADRB2.