Von hippel-lindau disease

Abstract

A germline mutation in the Von-Hippel Lindau (VHL) gene predisposes carriers to development of abundantly vascularised tumours in the retina, cerebellum, spine, kidney, adrenal gland and pancreas. Most VHL patients die from the consequences of cerebellar haemangioblastoma or renal cell carcinoma. The VHL gene is a tumour suppressor gene and is involved in angiogenesis by regulation of the activity of hypoxia-inducible factor 1-alpha (HIF1-alpha). Clinical diagnosis of VHL can be confirmed by molecular genetic analysis of the VHL gene, which is informative in virtually all VHL families. A patient with (suspicion for) VHL is an indication for genetic counselling and periodical examination.

Figure 1

Tumours in VHL disease.

Figure 2

Functional domains of the VHL protein and distribution of germline mutations (from VHL database) [22]. Hotspots for mutations are readily visible at amino acids 67-117, hypoxia-inducible factor (HIF)-1α binding domain (in the β-domain) and 157-170, Elongin C (EloC) binding domain (in the α-domain). Copyright 2003, The Endocrine Society [16]

Figure 3

The VHL protein and oxygen-dependent ubiquitination of the hypoxia-inducible factor (HIF)-1α. The VHL protein contains two functional domains: alpha (α) and beta (β). The α-domain of the VHL protein binds to Elongin C, which is connected with Elongin B in a multi-protein complex consisting of Cul2, Rbx1 and E2 ubiquitin conjugating enzyme (E2). The β-domain directly binds the substrate, HIF-1α. The VHL protein directs, depending on the amount of available oxygen, the breakdown (ubiquitination) of HIF-1α in the proteasome. In normoxic circumstances, HIF-1α is hydroxylated and binds to an intact VHL protein and is ubiquitinated in the proteasome (left). During hypoxic circumstances HIF-1α is not hydroxylated. The non-hydroxylated HIF-1α does not bind to the VHL protein and accumulates (right). In the case of a defect or absent VHL protein, HIF-1α also accumulates. Subsequently, genes that are regulated by HIF-1α, like vascular endothelial growth factor (VEGF) and erythropoietin (Epo), are upregulated, leading to (neo) angiogenesis and tumour growth. Copyright 2003, The Endocrine Society [16]