Clinically relevant mutations in the ABCG2 transporter uncovered by genetic analysis linked to erythrocyte membrane protein expression
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 AB...
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doaj-985b89481f7e46d08466e8eaf2a472db2020-12-08T03:40:12ZengNature Publishing GroupScientific Reports2045-23222018-05-018111310.1038/s41598-018-25695-zClinically relevant mutations in the ABCG2 transporter uncovered by genetic analysis linked to erythrocyte membrane protein expressionBoglárka Zámbó0Zsuzsa Bartos1Orsolya Mózner2Edit Szabó3György Várady4Gyula Poór5Márton Pálinkás6Hajnalka Andrikovics7Tamás Hegedűs8László Homolya9Balázs Sarkadi10Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of SciencesInstitute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of SciencesInstitute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of SciencesInstitute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of SciencesInstitute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of SciencesNational Institute of Rheumatology and PhysiotherapyNational Institute of Rheumatology and PhysiotherapyNational Blood ServiceDepartment of Biophysics and Radiation Biology, Semmelweis UniversityInstitute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of SciencesInstitute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of SciencesAbstract 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.https://doi.org/10.1038/s41598-018-25695-z |
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DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Boglárka Zámbó Zsuzsa Bartos Orsolya Mózner Edit Szabó György Várady Gyula Poór Márton Pálinkás Hajnalka Andrikovics Tamás Hegedűs László Homolya Balázs Sarkadi |
spellingShingle |
Boglárka Zámbó Zsuzsa Bartos Orsolya Mózner Edit Szabó György Várady Gyula Poór Márton Pálinkás Hajnalka Andrikovics Tamás Hegedűs László Homolya Balázs Sarkadi Clinically relevant mutations in the ABCG2 transporter uncovered by genetic analysis linked to erythrocyte membrane protein expression Scientific Reports |
author_facet |
Boglárka Zámbó Zsuzsa Bartos Orsolya Mózner Edit Szabó György Várady Gyula Poór Márton Pálinkás Hajnalka Andrikovics Tamás Hegedűs László Homolya Balázs Sarkadi |
author_sort |
Boglárka Zámbó |
title |
Clinically relevant mutations in the ABCG2 transporter uncovered by genetic analysis linked to erythrocyte membrane protein expression |
title_short |
Clinically relevant mutations in the ABCG2 transporter uncovered by genetic analysis linked to erythrocyte membrane protein expression |
title_full |
Clinically relevant mutations in the ABCG2 transporter uncovered by genetic analysis linked to erythrocyte membrane protein expression |
title_fullStr |
Clinically relevant mutations in the ABCG2 transporter uncovered by genetic analysis linked to erythrocyte membrane protein expression |
title_full_unstemmed |
Clinically relevant mutations in the ABCG2 transporter uncovered by genetic analysis linked to erythrocyte membrane protein expression |
title_sort |
clinically relevant mutations in the abcg2 transporter uncovered by genetic analysis linked to erythrocyte membrane protein expression |
publisher |
Nature Publishing Group |
series |
Scientific Reports |
issn |
2045-2322 |
publishDate |
2018-05-01 |
description |
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. |
url |
https://doi.org/10.1038/s41598-018-25695-z |
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