@misc{10481/66577,
year = {2020},
month = {11},
url = {http://hdl.handle.net/10481/66577},
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.},
organization = {ERDF/Spanish Ministry of Science, Innovation and Universities-State Research Agency 	
RTI2018-096246-B-I00
SAF2015-69796},
organization = {Junta de Andalucía

P18-RT-2413},
publisher = {Mdpi},
keywords = {Missense mutation},
keywords = {Genetic diseases},
keywords = {Protein structure-function},
keywords = {Genotype-phenotype correlations},
keywords = {Multifunctional proteins},
title = {Naturally-Occurring Rare Mutations Cause Mild to Catastrophic Effects in the Multifunctional and Cancer-Associated NQO1 Protein},
doi = {10.3390/jpm10040207},
author = {Pacheco García, Juan Luis and Cano Muñoz, Mario and Sánchez Ramos, Isabel and Salido, Eduardo and Pey Rodríguez, Ángel Luis},
}