Clinically relevant mutations in the ABCG2 transporter uncovered by genetic analysis linked to erythrocyte membrane protein expression

Scientific Reports
Boglárka ZámbóBalázs Sarkadi

Abstract

The ABCG2 membrane protein is a key xeno- and endobiotic transporter, modulating the absorption and metabolism of pharmacological agents and causing multidrug resistance in cancer. ABCG2 is also involved in uric acid elimination and its impaired function is causative in gout. Analysis of ABCG2 expression in the erythrocyte membranes of healthy volunteers and gout patients showed an enrichment of lower expression levels in the patients. By genetic screening based on protein expression, we found a relatively frequent, novel ABCG2 mutation (ABCG2-M71V), which, according to cellular expression studies, causes reduced protein expression, although with preserved transporter capability. Molecular dynamics simulations indicated a stumbled dynamics of the mutant protein, while ABCG2-M71V expression in vitro could be corrected by therapeutically relevant small molecules. These results suggest that personalized medicine should consider this newly discovered ABCG2 mutation, and genetic analysis linked to protein expression provides a new tool to uncover clinically important mutations in membrane proteins.

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Citations

Oct 1, 2020·Vox Sanguinis·Willy Albert FlegelWilliam Douglas Figg
Jun 30, 2019·Cellular and Molecular Life Sciences : CMLS·Boglárka ZámbóBalázs Sarkadi
Oct 6, 2020·FEBS Letters·Balázs SarkadiTamás Hegedűs
Jan 14, 2020·Drug Resistance Updates : Reviews and Commentaries in Antimicrobial and Anticancer Chemotherapy·A ToliosT Mohr
Feb 27, 2021·Frontiers in Cell and Developmental Biology·Zsuzsa Bartos, László Homolya
Apr 4, 2021·International Journal of Molecular Sciences·László Homolya
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Sep 30, 2021·Cellular and Molecular Life Sciences : CMLS·Samiksha KukalRitushree Kukreti
Dec 3, 2021·PloS One·Edit SzabóGyörgy Várady

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Methods Mentioned

BETA
flow cytometry
transfection
glycosylation
confocal microscopy
FACS

Software Mentioned

MDAnalysis Python
ImageJ
STATISTICA
GROMACS
ZEN
OPM
VMD Network Wizard Plugin

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