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Naturally-Occurring Rare Mutations Cause Mild to Catastrophic Effects in the Multifunctional and Cancer-Associated NQO1 Protein

The functional and pathological implications of the enormous genetic diversity of the human genome are mostly unknown, primarily due to our unability to predict pathogenicity in a high-throughput manner. In this work, we characterized the phenotypic consequences of eight naturally-occurring missense...

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Autores principales: Pacheco-García, Juan Luis, Cano-Muñoz, Mario, Sánchez-Ramos, Isabel, Salido, Eduardo, Pey, Angel L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7711955/
https://www.ncbi.nlm.nih.gov/pubmed/33153185
http://dx.doi.org/10.3390/jpm10040207
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author Pacheco-García, Juan Luis
Cano-Muñoz, Mario
Sánchez-Ramos, Isabel
Salido, Eduardo
Pey, Angel L.
author_facet Pacheco-García, Juan Luis
Cano-Muñoz, Mario
Sánchez-Ramos, Isabel
Salido, Eduardo
Pey, Angel L.
author_sort Pacheco-García, Juan Luis
collection PubMed
description The functional and pathological implications of the enormous genetic diversity of the human genome are mostly unknown, primarily due to our unability to predict pathogenicity in a high-throughput manner. In this work, we characterized the phenotypic consequences of eight naturally-occurring missense variants on the multifunctional and disease-associated NQO1 protein using biophysical and structural analyses on several protein traits. Mutations found in both exome-sequencing initiatives and in cancer cell lines cause mild to catastrophic effects on NQO1 stability and function. Importantly, some mutations perturb functional features located structurally far from the mutated site. These effects are well rationalized by considering the nature of the mutation, its location in protein structure and the local stability of its environment. Using a set of 22 experimentally characterized mutations in NQO1, we generated experimental scores for pathogenicity that correlate reasonably well with bioinformatic scores derived from a set of commonly used algorithms, although the latter fail to semiquantitatively predict the phenotypic alterations caused by a significant fraction of mutations individually. These results provide insight into the propagation of mutational effects on multifunctional proteins, the implementation of in silico approaches for establishing genotype-phenotype correlations and the molecular determinants underlying loss-of-function in genetic diseases.
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spelling pubmed-77119552020-12-04 Naturally-Occurring Rare Mutations Cause Mild to Catastrophic Effects in the Multifunctional and Cancer-Associated NQO1 Protein Pacheco-García, Juan Luis Cano-Muñoz, Mario Sánchez-Ramos, Isabel Salido, Eduardo Pey, Angel L. J Pers Med Article The functional and pathological implications of the enormous genetic diversity of the human genome are mostly unknown, primarily due to our unability to predict pathogenicity in a high-throughput manner. In this work, we characterized the phenotypic consequences of eight naturally-occurring missense variants on the multifunctional and disease-associated NQO1 protein using biophysical and structural analyses on several protein traits. Mutations found in both exome-sequencing initiatives and in cancer cell lines cause mild to catastrophic effects on NQO1 stability and function. Importantly, some mutations perturb functional features located structurally far from the mutated site. These effects are well rationalized by considering the nature of the mutation, its location in protein structure and the local stability of its environment. Using a set of 22 experimentally characterized mutations in NQO1, we generated experimental scores for pathogenicity that correlate reasonably well with bioinformatic scores derived from a set of commonly used algorithms, although the latter fail to semiquantitatively predict the phenotypic alterations caused by a significant fraction of mutations individually. These results provide insight into the propagation of mutational effects on multifunctional proteins, the implementation of in silico approaches for establishing genotype-phenotype correlations and the molecular determinants underlying loss-of-function in genetic diseases. MDPI 2020-11-03 /pmc/articles/PMC7711955/ /pubmed/33153185 http://dx.doi.org/10.3390/jpm10040207 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Pacheco-García, Juan Luis
Cano-Muñoz, Mario
Sánchez-Ramos, Isabel
Salido, Eduardo
Pey, Angel L.
Naturally-Occurring Rare Mutations Cause Mild to Catastrophic Effects in the Multifunctional and Cancer-Associated NQO1 Protein
title Naturally-Occurring Rare Mutations Cause Mild to Catastrophic Effects in the Multifunctional and Cancer-Associated NQO1 Protein
title_full Naturally-Occurring Rare Mutations Cause Mild to Catastrophic Effects in the Multifunctional and Cancer-Associated NQO1 Protein
title_fullStr Naturally-Occurring Rare Mutations Cause Mild to Catastrophic Effects in the Multifunctional and Cancer-Associated NQO1 Protein
title_full_unstemmed Naturally-Occurring Rare Mutations Cause Mild to Catastrophic Effects in the Multifunctional and Cancer-Associated NQO1 Protein
title_short Naturally-Occurring Rare Mutations Cause Mild to Catastrophic Effects in the Multifunctional and Cancer-Associated NQO1 Protein
title_sort naturally-occurring rare mutations cause mild to catastrophic effects in the multifunctional and cancer-associated nqo1 protein
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7711955/
https://www.ncbi.nlm.nih.gov/pubmed/33153185
http://dx.doi.org/10.3390/jpm10040207
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