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

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 dysregul...

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Autores principales: Fields, Francisco R., Suresh, Niraja, Hiller, Morgan, Freed, Stefan D., Haldar, Kasturi, Lee, Shaun W.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7644048/
https://www.ncbi.nlm.nih.gov/pubmed/33151962
http://dx.doi.org/10.1371/journal.pone.0234100
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author Fields, Francisco R.
Suresh, Niraja
Hiller, Morgan
Freed, Stefan D.
Haldar, Kasturi
Lee, Shaun W.
author_facet Fields, Francisco R.
Suresh, Niraja
Hiller, Morgan
Freed, Stefan D.
Haldar, Kasturi
Lee, Shaun W.
author_sort Fields, Francisco R.
collection PubMed
description 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.
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spelling pubmed-76440482020-11-16 Algorithmic assessment of missense mutation severity in the Von-Hippel Lindau protein Fields, Francisco R. Suresh, Niraja Hiller, Morgan Freed, Stefan D. Haldar, Kasturi Lee, Shaun W. PLoS One Research Article 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. Public Library of Science 2020-11-05 /pmc/articles/PMC7644048/ /pubmed/33151962 http://dx.doi.org/10.1371/journal.pone.0234100 Text en © 2020 Fields et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Fields, Francisco R.
Suresh, Niraja
Hiller, Morgan
Freed, Stefan D.
Haldar, Kasturi
Lee, Shaun W.
Algorithmic assessment of missense mutation severity in the Von-Hippel Lindau protein
title Algorithmic assessment of missense mutation severity in the Von-Hippel Lindau protein
title_full Algorithmic assessment of missense mutation severity in the Von-Hippel Lindau protein
title_fullStr Algorithmic assessment of missense mutation severity in the Von-Hippel Lindau protein
title_full_unstemmed Algorithmic assessment of missense mutation severity in the Von-Hippel Lindau protein
title_short Algorithmic assessment of missense mutation severity in the Von-Hippel Lindau protein
title_sort algorithmic assessment of missense mutation severity in the von-hippel lindau protein
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7644048/
https://www.ncbi.nlm.nih.gov/pubmed/33151962
http://dx.doi.org/10.1371/journal.pone.0234100
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