- Human pathology

Home > A. Molecular pathology > VHL


Tuesday 23 September 2003

The protein encoded by the VHL gene is a component of the protein complex that includes elongin B, elongin C, and cullin-2, and possesses ubiquitin ligase E3 activity.

This complex is involved in the ubiquitination and degradation of a 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.


The VHL protein forms a complex that function as ubiquitin ligases. A main substrate for this activity is HIF-1 (hypoxia inducible transcription factor 1), which regulates several genes, including VEGF and PDGF. Lack of VHL activity prevents ubiquitination and degradation of HIF-1 and is associated with increased levels of angiogenic growth factors.

VHL is part of an SCF related E3-ubiquitin ligase complex with ’gatekeeper’ function in renal carcinoma.

The von Hippel-Lindau (pVHL) protein plays an important role in hypoxia sensing. It binds to the hydroxylated hypoxia-inducible factor 1 alpha (HIF-1 alpha) and serves as a recognition component of an E3-ubiquitin ligase complex.

In hypoxia or secondary to a mutated VHL gene, the nondegraded HIF-1 alpha forms a heterodimer with HIF-beta and leads to increased transcription of hypoxia-inducible genes, including erythropoietin (EPO).


- Germ line mutations of VHL in the von Hippel Lindau disease

  • The von Hippel Lindau disease is associated with hereditary renal cell cancers, pheochromocytomas, hemangioblastomas of the central nervous system, retinal angiomas, and renal cysts.

- Mutations of the VHL gene have also been noted in sporadic renal cell cancers.

- The autosomal dominant cancer-predisposition von Hippel-Lindau syndrome is due to inheritance of a single mutated allele of VHL.

- Somatic mutations in renal cell carcinoma

- homozygous VHL germline mutation in congenital polycythemia (12844285)

Von Hippel-Lindau (VHL) syndrome is a dominantly inherited familial cancer syndrome caused by mutations in the VHL gene.

VHL syndrome displays marked variation in expression and analysis of genotype-phenotype correlations have led to the concept of four subtypes of VHL syndrome.

Type 2 subtypes of VHL syndrome are characterized by the presence of pheochromocytoma and the three Type 2 subtypes are associated with differing risks of hemangioblastoma and renal cell carcinoma (RCC).

Type 2 VHL syndrome is usually associated with surface missense mutations.

Type 1 VHL syndrome is most commonly caused by germline exon deletions and truncating mutations and is characterized by susceptibility to hemangioblastomas and RCC but not pheochromocytoma.

Recently, it has been suggested that large VHL gene deletions involving C3orf10 (HSPC300) might be associated with a low risk of RCC.

Large VHL gene deletions associated with a contiguous loss of C3orf10 are associated with a significantly lower lifetime risk of RCC than deletions that do not involve C3orf10. (19764026)

The risks of hemangioblastomas are similar in both groups. (19764026)

These results add to the growing body of evidence suggesting that patients with VHL syndrome caused by large VHL deletions that include C3orf10 may be designated as having a specific subtype (Type 1B) of the disorder. (19764026)


- VHL interacting proteins


- Maher ER. Von Hippel-Lindau disease. Curr Mol Med. 2004 Dec;4(8):833-42. PMID: 15579030

- Barry RE, Krek W. The von Hippel-Lindau tumour suppressor: a multi-faceted inhibitor of tumourigenesis. Trends Mol Med. 2004 Sep;10(9):466-72. PMID: 15350900

- George DJ, Kaelin WG Jr. The von Hippel-Lindau protein, vascular endothelial growth factor, and kidney cancer. N Engl J Med. 2003 Jul 31;349(5):419-21. PMID: 12890838

- Kaelin WG Jr. Molecular basis of the VHL hereditary cancer syndrome. Nat Rev Cancer. 2002 Sep;2(9):673-82. PMID: 12209156

- Kaelin WG Jr, Maher ER. The VHL tumour-suppressor gene paradigm. Trends Genet. 1998 Oct;14(10):423-6. PMID: 9820032


- Genotype-phenotype correlations in VHL exon deletions. McNeill A, Rattenberry E, Barber R, Killick P, MacDonald F, Maher ER. Am J Med Genet A. 2009 Oct;149A(10):2147-51. PMID: 19764026