Naturally-Occurring Rare Mutations Cause Mild to Catastrophic Effects in the Multifunctional and Cancer-Associated NQO1 Protein
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Pacheco García, Juan Luis; Cano Muñoz, Mario; Sánchez Ramos, Isabel; Salido, Eduardo; Pey Rodríguez, Ángel LuisEditorial
Mdpi
Materia
Missense mutation Genetic diseases Protein structure-function Genotype-phenotype correlations Multifunctional proteins
Date
2020-11-03Referencia bibliográfica
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]
Sponsorship
ERDF/Spanish Ministry of Science, Innovation and Universities-State Research Agency RTI2018-096246-B-I00 SAF2015-69796; Junta de Andalucía P18-RT-2413Abstract
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.