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 Rodríguez, Ángel Luis Missense mutation Genetic diseases Protein structure-function Genotype-phenotype correlations Multifunctional proteins 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. 2021-02-15T12:25:34Z 2021-02-15T12:25:34Z 2020-11-03 info:eu-repo/semantics/article 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] http://hdl.handle.net/10481/66577 10.3390/jpm10040207 eng http://creativecommons.org/licenses/by/3.0/es/ info:eu-repo/semantics/openAccess Atribución 3.0 España Mdpi