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Naturally-Occurring Rare Mutations Cause Mild to Catastrophic Effects in the Multifunctional and Cancer-Associated NQO1 Protein
dc.contributor.author | Pacheco García, Juan Luis | |
dc.contributor.author | Cano Muñoz, Mario | |
dc.contributor.author | Sánchez Ramos, Isabel | |
dc.contributor.author | Salido, Eduardo | |
dc.contributor.author | Pey Rodríguez, Ángel Luis | |
dc.date.accessioned | 2021-02-15T12:25:34Z | |
dc.date.available | 2021-02-15T12:25:34Z | |
dc.date.issued | 2020-11-03 | |
dc.identifier.citation | Pacheco-García, J. L., Cano-Muñoz, M., Sánchez-Ramos, I., Salido, E., & Pey, A. L. (2020). Naturally-Occurring Rare Mutations Cause Mild to Catastrophic Effects in the Multifunctional and Cancer-Associated NQO1 Protein. Journal of personalized medicine, 10(4), 207. [doi:10.3390/jpm10040207] | es_ES |
dc.identifier.uri | http://hdl.handle.net/10481/66577 | |
dc.description.abstract | 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 e ects on NQO1 stability and function. Importantly, some mutations perturb functional features located structurally far from the mutated site. These e ects 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 e ects 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. | es_ES |
dc.description.sponsorship | ERDF/Spanish Ministry of Science, Innovation and Universities-State Research Agency RTI2018-096246-B-I00 SAF2015-69796 | es_ES |
dc.description.sponsorship | Junta de Andalucía P18-RT-2413 | es_ES |
dc.language.iso | eng | es_ES |
dc.publisher | Mdpi | es_ES |
dc.rights | Atribución 3.0 España | * |
dc.rights.uri | http://creativecommons.org/licenses/by/3.0/es/ | * |
dc.subject | Missense mutation | es_ES |
dc.subject | Genetic diseases | es_ES |
dc.subject | Protein structure-function | es_ES |
dc.subject | Genotype-phenotype correlations | es_ES |
dc.subject | Multifunctional proteins | es_ES |
dc.title | Naturally-Occurring Rare Mutations Cause Mild to Catastrophic Effects in the Multifunctional and Cancer-Associated NQO1 Protein | es_ES |
dc.type | info:eu-repo/semantics/article | es_ES |
dc.rights.accessRights | info:eu-repo/semantics/openAccess | es_ES |
dc.identifier.doi | 10.3390/jpm10040207 | |
dc.type.hasVersion | info:eu-repo/semantics/publishedVersion | es_ES |