A detailed analysis of von Hippel Lindau (VHL) mutations in sporadic clear cell renal carcinoma (ccRCC), VHL syndrome, and Chuvash polycythaemia.

e15024 Background: Germline mutations in the VHL gene cause VHL syndrome. Functional loss of the VHL gene product, pVHL is also seen in the majority of cases of sporadic ccRCC and homozygosity for the germline R200W VHL mutation causes Chuvash polycythaemia, a benign congenital erythrocytosis. pVHL has many functions including the ability to target hypoxia-inducible factor (HIF) for polyubiquitylation and proteasomal degradation by forming the substrate recognition component of a ubiquitin-ligase complex. The development of ccRCC has been attributed to impaired HIF-α downregulation by pVHL mutants. However many point mutations within VHL which are associated with ccRCC are external to the HIF-α binding site. The structural and functional effects of the R200W mutation are unknown. Methods: We present a detailed biochemical analysis of pVHL mutant proteins identified in patients with sporadic ccRCC, type 2A (low risk of ccRCC) and 2B (high risk of ccRCC) VHL syndrome and Chuvash polycythaemia. Results: Type...