Algorithmic Assessment of Missense Mutation Severity in the Von-Hippel Lindau Protein

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