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Algorithmic assessment of missense mutation severity in the Von-Hippel Lindau protein

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  • Francisco R Fields
  • Niraja Suresh
  • Morgan Hiller
  • Stefan D Freed
  • Kasturi Haldar
  • Shaun W Lee

Abstract

Von Hippel-Lindau disease (VHL) is an autosomal dominant rare disease that causes the formation of angiogenic tumors. When functional, pVHL acts as an E3 ubiquitin ligase that negatively regulates hypoxia inducible factor (HIF). Genetic mutations that perturb the structure of pVHL result in dysregulation of HIF, causing a wide array of tumor pathologies including retinal angioma, pheochromocytoma, central nervous system hemangioblastoma, and clear cell renal carcinoma. These VHL-related cancers occur throughout the lifetime of the patient, requiring frequent intervention procedures, such as surgery, to remove the tumors. Although VHL is classified as a rare disease (1 in 39,000 to 1 in 91,000 affected) there is a large heterogeneity in genetic mutations listed for observed pathologies. Understanding how these specific mutations correlate with the myriad of observed pathologies for VHL could provide clinicians insight into the potential severity and onset of disease. Using a select set of 285 ClinVar mutations in VHL, we developed a multiparametric scoring algorithm to evaluate the overall clinical severity of missense mutations in pVHL. The mutations were assessed according to eight weighted parameters as a comprehensive evaluation of protein misfolding and malfunction. Higher mutation scores were strongly associated with pathogenicity. Our approach establishes a novel in silico method by which VHL-specific mutations can be assessed for their severity and effect on the biophysical functions of the VHL protein.

Suggested Citation

  • Francisco R Fields & Niraja Suresh & Morgan Hiller & Stefan D Freed & Kasturi Haldar & Shaun W Lee, 2020. "Algorithmic assessment of missense mutation severity in the Von-Hippel Lindau protein," PLOS ONE, Public Library of Science, vol. 15(11), pages 1-19, November.
  • Handle: RePEc:plo:pone00:0234100
    DOI: 10.1371/journal.pone.0234100
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    References listed on IDEAS

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    1. Patrick H. Maxwell & Michael S. Wiesener & Gin-Wen Chang & Steven C. Clifford & Emma C. Vaux & Matthew E. Cockman & Charles C. Wykoff & Christopher W. Pugh & Eamonn R. Maher & Peter J. Ratcliffe, 1999. "The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis," Nature, Nature, vol. 399(6733), pages 271-275, May.
    2. Wai-Ching Hon & Michael I. Wilson & Karl Harlos & Timothy D. W. Claridge & Christopher J. Schofield & Christopher W. Pugh & Patrick H. Maxwell & Peter J. Ratcliffe & David I. Stuart & E. Yvonne Jones, 2002. "Structural basis for the recognition of hydroxyproline in HIF-1α by pVHL," Nature, Nature, vol. 417(6892), pages 975-978, June.
    3. Krastyu G Ugrinov & Stefan D Freed & Clayton L Thomas & Shaun W Lee, 2015. "A Multiparametric Computational Algorithm for Comprehensive Assessment of Genetic Mutations in Mucopolysaccharidosis Type IIIA (Sanfilippo Syndrome)," PLOS ONE, Public Library of Science, vol. 10(3), pages 1-18, March.
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