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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Autores principales:	Boglárka Zámbó, Zsuzsa Bartos, Orsolya Mózner, Edit Szabó, György Várady, Gyula Poór, Márton Pálinkás, Hajnalka Andrikovics, Tamás Hegedűs, László Homolya, Balázs Sarkadi
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2018
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/985b89481f7e46d08466e8eaf2a472db
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spelling	oai:doaj.org-article:985b89481f7e46d08466e8eaf2a472db2021-12-02T11:41:23ZClinically relevant mutations in the ABCG2 transporter uncovered by genetic analysis linked to erythrocyte membrane protein expression10.1038/s41598-018-25695-z2045-2322https://doaj.org/article/985b89481f7e46d08466e8eaf2a472db2018-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-018-25695-zhttps://doaj.org/toc/2045-2322Abstract 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.Boglárka ZámbóZsuzsa BartosOrsolya MóznerEdit SzabóGyörgy VáradyGyula PoórMárton PálinkásHajnalka AndrikovicsTamás HegedűsLászló HomolyaBalázs SarkadiNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 8, Iss 1, Pp 1-13 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q 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
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.
format	article
author	Boglárka Zámbó Zsuzsa Bartos Orsolya Mózner Edit Szabó György Várady Gyula Poór Márton Pálinkás Hajnalka Andrikovics Tamás Hegedűs László Homolya Balázs Sarkadi
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 Portfolio
publishDate	2018
url	https://doaj.org/article/985b89481f7e46d08466e8eaf2a472db
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Clinically relevant mutations in the ABCG2 transporter uncovered by genetic analysis linked to erythrocyte membrane protein expression

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