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dc.contributor.authorPacheco García, Juan Luis 
dc.contributor.authorCano Muñoz, Mario
dc.contributor.authorSánchez Ramos, Isabel
dc.contributor.authorSalido, Eduardo
dc.contributor.authorPey Rodríguez, Ángel Luis
dc.identifier.citationPacheco-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.description.abstractThe 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.sponsorshipERDF/Spanish Ministry of Science, Innovation and Universities-State Research Agency RTI2018-096246-B-I00 SAF2015-69796es_ES
dc.description.sponsorshipJunta de Andalucía P18-RT-2413es_ES
dc.rightsAtribución 3.0 España*
dc.subjectMissense mutationes_ES
dc.subjectGenetic diseaseses_ES
dc.subjectProtein structure-functiones_ES
dc.subjectGenotype-phenotype correlationses_ES
dc.subjectMultifunctional proteinses_ES
dc.titleNaturally-Occurring Rare Mutations Cause Mild to Catastrophic Effects in the Multifunctional and Cancer-Associated NQO1 Proteines_ES

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Atribución 3.0 España
Except where otherwise noted, this item's license is described as Atribución 3.0 España