Cellular expression and function of naturally occurring variants of the human ABCG2 multidrug transporter

Abstract

The human ABCG2 multidrug transporter plays a crucial role in the absorption and excretion of xeno-and endobiotics; thus the relatively frequent polymorphic and mutant ABCG2 variants in the population may significantly alter disease conditions and pharmacological effects. Low-level or non-functional ABCG2 expression may increase individual drug toxicity, reduce cancer drug resistance, and result in hyperuricemia and gout. In the present work we have studied the cellular expression, trafficking, and function of nine naturally occurring polymorphic and mutant variants of ABCG2. A comprehensive analysis of the membrane localization, transport, and ATPase activity, as well as retention and degradation in intracellular compartments was performed. Among the examined variants, R147W and R383C showed expression and/or protein folding defects, indicating that they could indeed contribute to ABCG2 functional deficiency. These studies and the applied methods should significantly promote the exploration of the medical effects of these personal variants, promote potential therapies, and help to elucidate the specific role of the affected regions in the folding and function of the ABCG2 protein. Keywords ABCG2 • BCRP • MXR • Membrane transporter • Natural variants Cellular and Molecular Life Sciences Boglárka Zámbó and Orsolya Mózner contributed equally to this work.

Comprehensive Analysis of ABCG2 Genetic Variation in the Polish Population and Its Inter-Population Comparison

“…Although the significance of c.34G>A (p.Val12Met) remains unclear, c.421C>A (p.Gln141Lys) has often been reported to be associated with altered protein functionality. Generally, lower levels of mRNA maturation, protein folding and membrane trafficking were observed compared to the wild-type protein expression in the cellular membrane [ 43 ] but this also occurred as a result of ubiquitination-mediated proteasomal degradation, which the protein undergoes when it is recognized as misfolded [ 44 ]. This processes probably occur as an effect of an amino acid change located within the functionally important ATP-binding region between the Walker A and B motifs of the protein which likely affects its ATPase activity levels [ 6 ].…”

“…Furthermore, a number of studies of different ethnic populations, including genome-wide association (GWA) studies, have also indicated c.421C>A (p.Gln141Lys) to be the major risk factor for gout and hyperuricemia, which is correlated with increased urate concentration [ 13 , 51 , 52 , 53 ]. Regarding SNP c.34G>A (p.Val12Met), although it did not alter the protein expression and urate transport activity [ 43 ], some high-throughput studies [ 41 , 54 ], supported by meta-analysis results [ 38 ], suggest that it plays a protective role against gout. Thus, determining the appropriate frequency of both of these ABCG2 variants in each particular population appears to be an important step in determining the full clinical implications of the gene.…”

Interactions of anti-COVID-19 drug candidates with multispecific ABC and OATP drug transporters

“…These cells were sorted for similar levels of eGFP, and ABCG2 expression was examined by a monoclonal (5D3) antibody-based flow cytometry assay (Q141K-ABCG2 cell surface expression was approximately 80% of the wild type ABCG2 expression. For details see Zámbó et al [45]).…”

Impact of Variants in Atp-Binding Cassette Transporters on Breast Cancer Treatment

“…In this study the authors found an association between Q141K (rs2231142) and improved response, as well as a link between V12M (rs2231137) and increased overall survival in hormone receptor positive breast cancer patients after postoperative anthracycline-based chemotherapy with hazard ratios (HRs) between 0.5 and 0.7 (Table 3). Experimental evidence suggests that V12M is functionally neutral, whereas Q141K results in reduced expression levels [57][58][59][60]. Furthermore, Q141K but not V12M have been consistently implicated in differences in the pharmacokinetics of BCRP substrates, such as statins, camptothecins and mitoxantrone [61,62].…”