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. 2021 Feb 1:8:620793.
doi: 10.3389/fmolb.2021.620793. eCollection 2021.

Protein Stability Perturbation Contributes to the Loss of Function in Haploinsufficient Genes

Giovanni Birolo  1 , Silvia Benevenuta  1 , Piero Fariselli  1 , Emidio Capriotti  2 , Elisa Giorgio  3 , Tiziana Sanavia  1
Affiliations

Protein Stability Perturbation Contributes to the Loss of Function in Haploinsufficient Genes

Giovanni Birolo et al. Front Mol Biosci. .

Abstract

Missense variants are among the most studied genome modifications as disease biomarkers. It has been shown that the "perturbation" of the protein stability upon a missense variant (in terms of absolute ΔΔG value, i.e., |ΔΔG|) has a significant, but not predictive, correlation with the pathogenicity of that variant. However, here we show that this correlation becomes significantly amplified in haploinsufficient genes. Moreover, the enrichment of pathogenic variants increases at the increasing protein stability perturbation value. These findings suggest that protein stability perturbation might be considered as a potential cofactor in diseases associated with haploinsufficient genes reporting missense variants.

Keywords: haploinsuffciency; protein mutation; protein stability; protein stability prediction; variant effect prediction.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Barplots displaying the performance (AUC) of all the ΔΔG predictors and the consensus (orange) of the best two performing methods (FoldX5.0 and INPS3D). The bars represent the mean AUC obtained by averaging balanced subsets (the available pathogenic variants were matched with a random sample with the same number of benign variants for one hundred times).
FIGURE 2
FIGURE 2
Performance of top performing predictors, (i.e. FoldX 5.0 and INPS3D, Rosetta and PoPMuSiC along with the combined scores of the first two) split by haploinsufficient, dominant without haploinsufficiency and recessive genes. P-values of the pairwise comparison between each gene group and its complement by the Mann-Whitney U test are reported at the bottom of the x-axis.
FIGURE 3
FIGURE 3
Precision (y-axis) of the protein stability-based methods in predicting pathogenicity at different |ΔΔG| values, defined as the ratio of truly pathogenic over all the variants reporting predicted |ΔΔG| values above a specific threshold (x-axis). Solid and dashed lines are computed on variants in haploinsufficient and non-haploinsufficient genes, respectively. INPS3D and PoPMuSiC lines stop earlier since the methods do not provide predictions with |ΔΔG| values greater than the reported thresholds.
See this image and copyright information in PMC

References

    1. Alford R. F., Leaver-Fay A., Jeliazkov J. R., O'Meara M. J., DiMaio F. P., Park H., et al. (2017). The Rosetta all-atom energy function for macromolecular modeling and design. J. Chem. Theor. Comput. 13 (6), 3031–3048. 10.1021/acs.jctc.7b00125 - DOI - PMC - PubMed
    1. Capriotti E., Fariselli P., Casadio R. (2005). I-Mutant2.0: predicting stability changes upon mutation from the protein sequence or structure. Nucleic Acids Res. 33, W306–W310. 10.1093/nar/gki375 - DOI - PMC - PubMed
    1. Casadio R., Vassura M., Tiwari S., Fariselli P., Luigi Martelli P. (2011). Correlating disease-related mutations to their effect on protein stability: a large-scale analysis of the human proteome. Hum. Mutat. 32 (10), 1161–1170. 10.1002/humu.21555 - DOI - PubMed
    1. Dehouck Y., Kwasigroch J. M., Gilis D., Rooman M. (2011). PoPMuSiC 2.1: a web server for the estimation of protein stability changes upon mutation and sequence optimality. BMC Bioinf. 12, 151 10.1186/1471-2105-12-151 - DOI - PMC - PubMed
    1. Delgado J., Radusky L. G., Cianferoni D., Serrano L. (2019). FoldX 5.0: working with RNA, small molecules and a new graphical interface. Bioinformatics 35 (20), 4168–4169. 10.1093/bioinformatics/btz184 - DOI - PMC - PubMed