Structural bioinformatics mutation analysis reveals genotype-phenotype correlations in von Hippel-Lindau disease and suggests molecular mechanisms of tumorigenesis

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Item Type:	Article
Title:	Structural bioinformatics mutation analysis reveals genotype-phenotype correlations in von Hippel-Lindau disease and suggests molecular mechanisms of tumorigenesis
Creators Name:	Forman, J.R., Worth, C.L., Bickerton, G.R.J., Eisen, T.G. and Blundell, T.L.
Abstract:	Mutations in the VHL gene lead to von Hippel-Lindau (VHL) disease, a clinically heterogeneous cancer syndrome. Here, we use software and database tools to understand and predict the phenotypes associated with missense mutations in the VHL gene product, pVHL. The protein product pVHL is known to interact with elongin B, elongin C, and the HIF substrate. By analyzing known and predicted interaction sites and predictions of thermodynamic stability change upon mutation, we generate new hypotheses regarding the molecular etiology of renal cell carcinoma (RCC) and pheochromocytoma (PCC) in VHL disease. We find that the molecular causes of RCC and PCC appear to be decoupled. RCC may arise through two distinct mechanisms: disruption of HIF interactions or binding at the elongin B interface. PCC is triggered by mutations which disrupt interactions at the elongin C binding site. These findings have important implications for VHL disease and for nonfamilial RCC, because most cases of clear cell RCC are linked with VHL inactivation. Additionally, predicting effects of genetic variation will be critical as genetic sequencing accelerates; the analytical strategy presented here may elucidate other systems as further data on genetic variation become available.
Keywords:	Bioinformatics, Biocomputing, Mutation, Cancer, Genotype-Phenotype, VHL
Source:	Proteins
ISSN:	0887-3585
Publisher:	Wiley
Volume:	77
Number:	1
Page Range:	84-96
Date:	October 2009
Official Publication:	https://doi.org/10.1002/prot.22419
PubMed:	View item in PubMed

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