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Article

Rare Human Missense Variants can affect the Function of Disease-Relevant Proteins by Loss and Gain of Peroxisomal Targeting Motifs

1
Bioinformatics Institute, Agency for Science, Technology and Research (A*STAR), Singapore 138671, Singapore
2
National University of Singapore Graduate School for Integrative Sciences and Engineering (NGS), National University of Singapore, Singapore 119077, Singapore
3
Medical University of Vienna, Center for Brain Research, Department of Pathobiology of the Nervous System, 1090 Vienna, Austria
4
Medical University of Vienna, Center for Physiology and Pharmacology, Institute for Vascular Biology and Thrombosis Research, 1090 Vienna, Austria
5
Department of Neurology, Medical University of Vienna, 1090 Vienna, Austria
6
Institute of Human Genetics, Technical University Munich, 81675 Munich, Germany
7
Department of Biological Sciences, National University of Singapore, Singapore 117558, Singapore
8
Innovations in Food and Chemical Safety Programme (IFCS), Agency for Science, Technology and Research (A*STAR), Singapore 138671, Singapore
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Int. J. Mol. Sci. 2019, 20(18), 4609; https://doi.org/10.3390/ijms20184609
Received: 23 July 2019 / Revised: 6 September 2019 / Accepted: 14 September 2019 / Published: 17 September 2019
(This article belongs to the Special Issue Peroxisomes under the Spotlight: Collaboration is the Way to Go)
Single nucleotide variants (SNVs) resulting in amino acid substitutions (i.e., missense variants) can affect protein localization by changing or creating new targeting signals. Here, we studied the potential of naturally occurring SNVs from the Genome Aggregation Database (gnomAD) to result in the loss of an existing peroxisomal targeting signal 1 (PTS1) or gain of a novel PTS1 leading to mistargeting of cytosolic proteins to peroxisomes. Filtering down from 32,985 SNVs resulting in missense mutations within the C-terminal tripeptide of 23,064 human proteins, based on gene annotation data and computational prediction, we selected six SNVs for experimental testing of loss of function (LoF) of the PTS1 motif and five SNVs in cytosolic proteins for gain in PTS1-mediated peroxisome import (GoF). Experimental verification by immunofluorescence microscopy for subcellular localization and FRET affinity measurements for interaction with the receptor PEX5 demonstrated that five of the six predicted LoF SNVs resulted in loss of the PTS1 motif while three of five predicted GoF SNVs resulted in de novo PTS1 generation. Overall, we showed that a complementary approach incorporating bioinformatics methods and experimental testing was successful in identifying SNVs capable of altering peroxisome protein import, which may have implications in human disease. View Full-Text
Keywords: peroxisomal targeting signal 1; PEX5; peroxisome; protein transport; missense variant; mistargeting; gnomAD; disease peroxisomal targeting signal 1; PEX5; peroxisome; protein transport; missense variant; mistargeting; gnomAD; disease
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MDPI and ACS Style

Chong, C.-S.; Kunze, M.; Hochreiter, B.; Krenn, M.; Berger, J.; Maurer-Stroh, S. Rare Human Missense Variants can affect the Function of Disease-Relevant Proteins by Loss and Gain of Peroxisomal Targeting Motifs. Int. J. Mol. Sci. 2019, 20, 4609. https://doi.org/10.3390/ijms20184609

AMA Style

Chong C-S, Kunze M, Hochreiter B, Krenn M, Berger J, Maurer-Stroh S. Rare Human Missense Variants can affect the Function of Disease-Relevant Proteins by Loss and Gain of Peroxisomal Targeting Motifs. International Journal of Molecular Sciences. 2019; 20(18):4609. https://doi.org/10.3390/ijms20184609

Chicago/Turabian Style

Chong, Cheng-Shoong, Markus Kunze, Bernhard Hochreiter, Martin Krenn, Johannes Berger, and Sebastian Maurer-Stroh. 2019. "Rare Human Missense Variants can affect the Function of Disease-Relevant Proteins by Loss and Gain of Peroxisomal Targeting Motifs" International Journal of Molecular Sciences 20, no. 18: 4609. https://doi.org/10.3390/ijms20184609

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