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

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 expre...

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Autores principales: Zámbó, Boglárka, Bartos, Zsuzsa, Mózner, Orsolya, Szabó, Edit, Várady, György, Poór, Gyula, Pálinkás, Márton, Andrikovics, Hajnalka, Hegedűs, Tamás, Homolya, László, Sarkadi, Balázs
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5945641/
https://www.ncbi.nlm.nih.gov/pubmed/29749379
http://dx.doi.org/10.1038/s41598-018-25695-z
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author Zámbó, Boglárka
Bartos, Zsuzsa
Mózner, Orsolya
Szabó, Edit
Várady, György
Poór, Gyula
Pálinkás, Márton
Andrikovics, Hajnalka
Hegedűs, Tamás
Homolya, László
Sarkadi, Balázs
author_facet Zámbó, Boglárka
Bartos, Zsuzsa
Mózner, Orsolya
Szabó, Edit
Várady, György
Poór, Gyula
Pálinkás, Márton
Andrikovics, Hajnalka
Hegedűs, Tamás
Homolya, László
Sarkadi, Balázs
author_sort Zámbó, Boglárka
collection PubMed
description 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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spelling pubmed-59456412018-05-14 Clinically relevant mutations in the ABCG2 transporter uncovered by genetic analysis linked to erythrocyte membrane protein expression Zámbó, Boglárka Bartos, Zsuzsa Mózner, Orsolya Szabó, Edit Várady, György Poór, Gyula Pálinkás, Márton Andrikovics, Hajnalka Hegedűs, Tamás Homolya, László Sarkadi, Balázs Sci Rep Article 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. Nature Publishing Group UK 2018-05-10 /pmc/articles/PMC5945641/ /pubmed/29749379 http://dx.doi.org/10.1038/s41598-018-25695-z Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Zámbó, Boglárka
Bartos, Zsuzsa
Mózner, Orsolya
Szabó, Edit
Várady, György
Poór, Gyula
Pálinkás, Márton
Andrikovics, Hajnalka
Hegedűs, Tamás
Homolya, László
Sarkadi, Balázs
Clinically relevant mutations in the ABCG2 transporter uncovered by genetic analysis linked to erythrocyte membrane protein expression
title 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_short 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
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5945641/
https://www.ncbi.nlm.nih.gov/pubmed/29749379
http://dx.doi.org/10.1038/s41598-018-25695-z
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