Von Hippel Lindau disease is a rare, autosomal syndrome caused by mutations in the VHL tumour suppressor gene on chromosome 3p25.3. The predominant phenotype is the development of hemangioblastomas in the central nervous system and retina, whilst other symptoms include renal angioma, renal cell carcinoma and pheochromocytomas (tumours originating from adrenal glands).
The renal carcinoma phenotype appears to be the biggest similarity between BHD syndrome and VHL disease. The development of cutaneous hemangiomas in VHL might seem similar to the development of fibrofolliculomas in BHD at first glance, but this does not seem to be a predominant phenotype in VHL and so I put this facet on the back burner for now. Can we learn anything from the similarities in the renal phenotype between these two disorders?
Several lines of evidence suggest that HIF is the critical downstream target of VHL with respect to tumourigenesis: Firstly, VHL mutants associated with hemangioblastoma and renal cell carcinoma have, when tested, been defective with respect to HIF polyubiquitylation. Second, VHL tumor suppressor activity can be neutralized by peptides that bind to the VHL domain. Both of these observations suggest that HIF, or perhaps some other substrate recognized by the domain, is an important VHL target. The importance of HIF per se with respect to renal carcinogenesis is underscored by the finding that a HIF1 variant that escapes recognition by VHL can override VHL’s tumor suppressor activity in vitro, whereas a similar HIF2 variant can override VHL’s tumor suppressor activity in vivo. Thus, in the context of renal cell carcinoma, inhibition of HIF is necessary for tumour suppression by VHL.
But how does this tie in to BHD? Weppler et al (2008) utilised a stable FLCN knock-down in vitro model to show that BHD patients may have aberrant HIF2 activity and Kim et al (2006) carried out histopathological examination of patient tumour samples and showed that HIF expression was greatly enhanced and these tumours suggesting that aberrant folliculin function is associated with HIF up-regulation. These results suggest that the development of skin and kidney tumors in BHD may proceed in a HIF-dependent mechanism and definitely merits further investigation!