ABCMdb

ABCG2 p.Gln126*

ClinVar:

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[hide] Pharmacogenomics of the human ABC transporter ABCG... Naturwissenschaften. 2005 Oct;92(10):451-63. Ishikawa T, Tamura A, Saito H, Wakabayashi K, Nakagawa H
Pharmacogenomics of the human ABC transporter ABCG2: from functional evaluation to drug molecular design.
Naturwissenschaften. 2005 Oct;92(10):451-63., [PMID:16160819]

Abstract [show]
In the post-genome-sequencing era, emerging genomic technologies are shifting the paradigm for drug discovery and development. Nevertheless, drug discovery and development still remain high-risk and high-stakes ventures with long and costly timelines. Indeed, the attrition of drug candidates in preclinical and development stages is a major problem in drug design. For at least 30% of the candidates, this attrition is due to poor pharmacokinetics and toxicity. Thus, pharmaceutical companies have begun to seriously re-evaluate their current strategies of drug discovery and development. In that light, we propose that a transport mechanism-based design might help to create new, pharmacokinetically advantageous drugs, and as such should be considered an important component of drug design strategy. Performing enzyme- and/or cell-based drug transporter, interaction tests may greatly facilitate drug development and allow the prediction of drug-drug interactions. We recently developed methods for high-speed functional screening and quantitative structure-activity relationship analysis to study the substrate specificity of ABC transporters and to evaluate the effect of genetic polymorphisms on their function. These methods would provide a practical tool to screen synthetic and natural compounds, and these data can be applied to the molecular design of new drugs. In this review article, we present an overview on the genetic polymorphisms of human ABC transporter ABCG2 and new camptothecin analogues that can circumvent AGCG2-associated multidrug resistance of cancer.

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105 The variant Q126stop (c.376C>T) was consistently observed in certain Japanese cohorts; however, it was absent in Caucasian and African American groups (Imai et al. 2002; Itoda et al. 2003; Kobayashi et al. 2005). Login to comment
118 For this purpose, we have created variant forms of ABCG2 (V12M, G51C, Q126stop, Q141K, T153M, Q166E, I206L, E334stop, N590Y, D620N, R482G, and R482T) by site-directed mutagenesis. Login to comment
132 No MTX-transport activity was observed in the Q126stop and E334stop variants, as well as in acquired mutation variants (R482G and R482T). Login to comment

[hide] Genetic polymorphisms of ATP-binding cassette tran... Expert Opin Pharmacother. 2005 Nov;6(14):2455-73. Sakurai A, Tamura A, Onishi Y, Ishikawa T
Genetic polymorphisms of ATP-binding cassette transporters ABCB1 and ABCG2: therapeutic implications.
Expert Opin Pharmacother. 2005 Nov;6(14):2455-73., [PMID:16259577]

Abstract [show]
Pharmacogenomics, the study of the influence of genetic factors on drug action, is increasingly important for predicting pharmacokinetics profiles and/or adverse reactions to drugs. Drug transporters, as well as drug metabolism play pivotal roles in determining the pharmacokinetic profiles of drugs and their overall pharmacological effects. There is an increasing number of reports addressing genetic polymorphisms of drug transporters. However, information regarding the functional impact of genetic polymorphisms in drug transporter genes is still limited. Detailed functional analysis in vitro may provide clear insight into the biochemical and therapeutic significance of genetic polymorphisms. This review addresses functional aspects of the genetic polymorphisms of human ATP-binding cassette transporters, ABCB1 and ABCG2, which are critically involved in the pharmacokinetics of drugs.

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213 Some of the above sequence variations showed an allele frequency of ~ 1% in distinct populations, Q126stop and F489L in the Japanese and N590Y in the Caucasian population [129-131,134,135], whereas most of the mutations were only detected in single individuals (e.g., I206L, F431L, S441N, D620N). Login to comment
238 The variant Q126stop (c.376C > T) was consistently observed in certain Japanese cohorts; however, it was absent in two different Caucasian and African-American groups [129,134,135]. Login to comment
250 COOH H2N N590Y V12M G51C Q126stop Q141K T153M Q166E I206L F208S S248P E334stop F431L F489L D620N R482G R482T S441N F571I EXTRACELLULAR INTRACELLULAR R160Q R575stop ATP-binding site (transient or stable expression), the copy number of cDNA incorporated in genomic DNA or other cellular determinants may variably affect the cellular processing and sorting of these proteins. Login to comment
255 For this purpose, variant forms of ABCG2 (V12M, G51C, Q126stop, Q141K, T153M, Q166E, I206L, E334stop, N590Y, D620N, R482G and R482T) were created by site-directed mutagenesis (Figure 3). Login to comment
269 No MTX-transport activity was observed in the Q126stop and E334stop variants, as well as in acquired mutation variants (R482G and R482T). Login to comment

[hide] Functional SNPs of the breast cancer resistance pr... Cancer Lett. 2006 Mar 8;234(1):73-80. Epub 2005 Nov 21. Yanase K, Tsukahara S, Mitsuhashi J, Sugimoto Y
Functional SNPs of the breast cancer resistance protein-therapeutic effects and inhibitor development.
Cancer Lett. 2006 Mar 8;234(1):73-80. Epub 2005 Nov 21., 2006-03-08 [PMID:16303243]

Abstract [show]
Breast cancer resistance protein (BCRP) is a half-molecule ATP-binding cassette transporter that pumps out various anticancer agents such as 7-ethyl-10-hydroxycamptothecin, topotecan and mitoxantrone. We have previously identified three polymorphisms within the BCRP gene, G34A (substituting Met for Val-12), C376T (substituting a stop codon for Gln-126) and C421A (substituting Lys for Gln-141). C421A BCRP-transfected murine fibroblast PA317 cells showed markedly decreased protein expression and low-level drug resistance when compared with wild-type BCRP-transfected cells. In contrast, G34A BCRP-transfected PA317 cells showed a similar protein expression and drug resistance profile to wild-type. The C376T polymorphism would be expected to have a considerable impact as active BCRP protein will not be expressed from a T376 allele. Hence, people with C376T and/or C421A polymorphisms may express low levels of BCRP, resulting in hypersensitivity of normal cells to BCRP-substrate anticancer agents. Estrogens, estrone and 17beta-estradiol, were previously found to restore drug sensitivity levels in BCRP-transduced cells by increasing the cellular accumulation of anticancer agents. BCRP transports sulfated estrogens but not free estrogens and in a series of screening experiments for synthesized and natural estrogenic compounds, several tamoxifen derivatives and phytoestrogens/flavonoids were identified that effectively circumvent BCRP-mediated drug resistance. The kinase inhibitors gefitinib and imatinib mesylate also interact with BCRP. Gefitinib, an inhibitor of epidermal growth factor receptor-tyrosine kinase, inhibits its transporter function and reverses BCRP-mediated drug resistance both in vitro and in vivo. BCRP-transfected human epidermoid carcinoma A431 cells and BCRP-transfected human non-small cell lung cancer PC-9 cells show gefitinib resistance. Imatinib, an inhibitor of BCR-ABL tyrosine kinase, also inhibits BCRP-mediated drug transport. Hence, both functional SNPs and inhibitors of BCRP reduce its transporter function and thus modulate substrate pharmacokinetics and pharmacodynamics.

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64 C376T (Q126stop)-BCRP SNP Another of the BCRP gene SNPs, C376T, substitutes a stop codon for Gln-126 (Q126stop), and was found in 3/124 of our general Japanese samples as a heterozygosity [23]. Login to comment
92 Therefore, we first Table 3 SNPs within the BCRP gene Variation Region Effect Domain A-1379G 50 -flanking (promoter) - D-654-651 50 -flanking (promoter) - G-286C 50 -flanking (promoter) - T-476C Exon 1 (50 - UTR) - D-235A Exon 1 (50 - UTR) - A-113G Exon 1 (50 - UTR) - A-29G Exon 1 (50 - UTR) - G34A Exon 2 V12M N-terminal T114C Exon 2 No change N-terminal G151T Exon 2 G51C N-terminal C369T Exon 4 No change NBD C376T Exon 4 Q126stop NBD C421A Exon 5 Q141K NBD C458T Exon 5 T153M NBD C474T Exon 5 No change NBD C496G Exon 5 Q166E NBD A564G Exon 6 No change NBD A616C Exon 6 I206L NBD T623C Exon 6 F208S NBD T742C Exon 7 S248P Linker G1000T Exon 9 E334stop Linker G1098A Exon 9 No change Linker T1291C Exon 11 F431L TMD A1425G Exon 12 No change TMD T1465C Exon 12 F489L TMD A1768T Exon 15 N590Y TMD G1858A Exon 16 D620N TMD G2237T Exon 16 (30 - UTR) - G2393T Exon 16 (30 - UTR) - Abbreviations: UTR, untranslated region; NBD, nucleotide-binding domain; TMD, transmembrane domain. Login to comment

[hide] The role of the human ABCG2 multidrug transporter ... Cancer Lett. 2006 Mar 8;234(1):62-72. Epub 2005 Dec 7. Cervenak J, Andrikovics H, Ozvegy-Laczka C, Tordai A, Nemet K, Varadi A, Sarkadi B
The role of the human ABCG2 multidrug transporter and its variants in cancer therapy and toxicology.
Cancer Lett. 2006 Mar 8;234(1):62-72. Epub 2005 Dec 7., 2006-03-08 [PMID:16337740]

Abstract [show]
The human multidrug resistance ABC transporters provide a protective function in our body against a large number of toxic compounds. These proteins, residing in the plasma membrane, perform an active, ATP-dependent extrusion of such xenobiotics. However, the same proteins are also used by the tumor cells to fight various anticancer agents. ABCG2 is an important member of the multidrug resistance proteins, an 'ABC half transporter', which functions as a homodimer in the cell membrane. In this review, we provide a basic overview of ABCG2 function in physiology and drug metabolism, but concentrate on the discussion of mutations and polymorphisms discovered in this protein. Interestingly, a single nucleotide mutation, changing amino acid 482 from arginine to threonine or glycine in ABCG2, results in a major increase in the catalytic activity and a wider drug recognition by this protein. Still, this mutation proved to be an in vitro artifact, produced only in heavily drug-selected cell lines. In contrast, at least two, but possibly more polymorphic variants of ABCG2 were found to be present in large human populations with different ethnic background. However, currently available experimental data regarding the cellular expression, localization and function of these ABCG2 variants are strongly contradictory. Since, the proteins produced by these variant alleles may differently modulate cancer treatment, general drug absorption and toxicity, may represent risk factors in fetal toxicity, or alter the differentiation of stem cells, their exact characterization is a major challenge in this field.

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109 To date, altogether eight non-synonymous (V12M, Q141K, I206L, F431L, S441N, F489L, N590Y, D620N), five synonymous (silent) (c.114TOC, c.369COT, c.474COT, c.1098GOA, c.1425AOG) missense mutations, one nonsense (Q126X), and one frameshift (c.1515delC) mutations were identified in the coding region of ABCG2 in healthy individuals or in patients [43-46,49,63-65]. Login to comment
112 Some of the above sequence variations showed an allele frequency of about 1% in distinct populations (Q126X, F489L in the Japanese and N590Y in the Caucasian population [45-47,49,64]), while most of the mutations were only detected in single individuals (missense mutations: I206L, F431L, S441N, D620N, and a frameshift mutation: c.1515delC [44-46,49]). Login to comment
118 An interesting sequence variant Q126X (c.376CO T), affecting the coding region and leading to premature termination of protein synthesis, was consistently observed in certain Japanese cohorts, however, it was absent in two different Caucasian and African American groups [45,46,64]. Login to comment
123 On the basis of definitive molecular haplotype analyses (PCR-RFLP) for the three major variants [c.34GOA (V12M), c.376COT (Q126X), c.421COA (Q141K)] in a Japanese population, four haplotypes were identified G-C-C (V-Q-Q), G-C-A (V-Q-K), A-CC (M-Q-Q), and G-T-C (V-X-Q). Login to comment
127 The above results collectively suggest that the V12M, Q126X, and Q141K variants are likely to occur on separate chromosomes. Login to comment
134 g.34GOA (exon 2) c.34GOA V12M Caucasian 150 27 2 10.3G3.5 [47] Caucasian 150 11 0 3.7G2.2 [46] Caucasian 86 n.a n.a 2.0Gn.a [49] Swedish 60 2 0 1.7G2.3 [43] Total Caucasian 360 40 2 6.1G1.8 Japanese 220 61 8 17.5G3.6 [46] Japanese 29 9 1 19.0G10.3 [64] Total Japanese 249 70 9 17.7G3.4 African-American 150 17 1 6.3G2.8 [46] g.8191COT (exon 4) c.376COT Q126X Caucasian 150 0 0 0.0 [46] Caucasian 150 0 0 0.0 [47] Total Caucasian 300 0 0 0.0 Japanese 220 4 0 0.9G0.9 [46] Japanese 124 3 0 1.2G1.4 [64] Japanese 60 2 0 1.7G2.3 [45] Total Japanese 404 9 0 1.1G0.7 African-American 150 0 0 0.0 [46] g.8825CO A (exon 5) c.421COA Q141K Caucasian 172 33 3 11.3G3.4 [63] Caucasian 150 25 4 11.0G3.6 [46] Caucasian 150 22 2 8.7G3.2 [47] Caucasian 85 n.a n.a 14.0Gn.a [49] Swedish 60 10 1 10.0G5.5 [43] Total Caucasian 532 90 10 10.3G1.9 Japanese 220 90 27 32.7G4.5 [46] Japanese 124 48 9 26.6G5.6 [64] Chinese 95 43 11 34.2G6.9 [63] Total Asian 439 181 47 31.3G3.1 African, Sub-Saharan 938 14 1 0.9G0.4 [63] African-American 150 5 1 2.3G1.7 [46] African-American 94 8 1 5.3G3.3 [63] Total Africanc 1182 27 3 1.4G0.5 g.40645AO T (exon 12) c.1465TOC F489L Japanese 100 1 0 0.5G1.0 [46] Japanese 60 1 0 0.8G1.7 [45] Total Japanese 160 2 0 0.6G0.9 g.45367AO T (exon 15) c.1768AOT N590Y Caucasian 150 1 0 0.3G0.7 [47] Caucasian 65 1 0 0.8G1.5 [49] Total Caucasian 215 2 0 0.5G0.7 Only those cDNA SNPs were listed that were detected in at least two independent studies. Login to comment

[hide] High-speed screening of human ATP-binding cassette... Methods Enzymol. 2005;400:485-510. Ishikawa T, Sakurai A, Kanamori Y, Nagakura M, Hirano H, Takarada Y, Yamada K, Fukushima K, Kitajima M
High-speed screening of human ATP-binding cassette transporter function and genetic polymorphisms: new strategies in pharmacogenomics.
Methods Enzymol. 2005;400:485-510., [PMID:16399366]

Abstract [show]
Drug transporters represent an important mechanism in cellular uptake and efflux of drugs and their metabolites. Hitherto a variety of drug transporter genes have been cloned and classified into either solute carriers or ATP-binding cassette (ABC) transporters. Such drug transporters are expressed in various tissues such as the intestine, brain, liver, kidney, and, importantly, cancer cells, where they play critical roles in the absorption, distribution, and excretion of drugs. We developed high-speed functional screening and quantitative structure-activity relationship analysis methods to study the substrate specificity of ABC transporters and to evaluate the effect of genetic polymorphisms on their function. These methods would provide powerful and practical tools for screening synthetic and natural compounds, and the deduced data can be applied to the molecular design of new drugs. Furthermore, we demonstrate a new "SNP array" method to detect genetic polymorphisms of ABC transporters in human samples.

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115 For this purpose, variant forms (V12M, G51C, Q126stop, Q141K, T153M, Q166E, I206L, E334stop, N590Y, D620N, R482G, and R482T) have been created by site‐ directed mutagenesis with the QuikChange site‐directed mutagensis kit (Stratagene, La Jolla, CA). Login to comment
125 No MTX transport activity was observed in the variants Q126stop, E334stop, R482G, and R482T. Login to comment
233 Figure 13 shows the result of SNP array detection where nonsynonymous polymorphisms of ABCG2, that is, Q126stop and Q141K, were analyzed. Login to comment
249 Detection of nonsynonymous polymorphisms (Q126stop and Q141K) of ABCG2 with the SNP array. Login to comment

[hide] Functional validation of the genetic polymorphisms... Mol Pharmacol. 2006 Jul;70(1):287-96. Epub 2006 Apr 11. Tamura A, Watanabe M, Saito H, Nakagawa H, Kamachi T, Okura I, Ishikawa T
Functional validation of the genetic polymorphisms of human ATP-binding cassette (ABC) transporter ABCG2: identification of alleles that are defective in porphyrin transport.
Mol Pharmacol. 2006 Jul;70(1):287-96. Epub 2006 Apr 11., [PMID:16608919]

Abstract [show]
The ATP-binding cassette (ABC) transporter ABCG2 has been implicated to play a significant role in the response of patients to medication and/or the risk of diseases. To clarify the possible physiological or pathological relevance of ABCG2 polymorphisms, we have functionally validated single nucleotide polymorphisms (SNP) of ABCG2. In the present study, based on the currently available data on SNPs and acquired mutations, we have created a total of 18 variant forms of ABCG2 (V12M, G51C, Q126stop, Q141K, T153M, Q166E, I206L, F208S, S248P, E334stop, F431L, S441N, R482G, R482T, F489L, F571I, N590Y, and D620N) by site-directed mutagenesis and expressed them in insect cells. Because porphyrins are considered to be endogenous substrates for ABCG2, we have investigated the porphyrin transport activity of those variant forms in vitro. We herein provide evidence that the variants Q126stop, F208S, S248P, E334stop, and S441N are defective in porphyrin transport, whereas F489L exhibited impaired transport, approximately 10% of the activity observed for the wild type. Furthermore, Flp-In-293 cells expressing those variants were photosensitive. Thus, among those genetic polymorphisms of ABCG2, at least the hitherto validated alleles of Q126stop, S441N, and F489L are suggested to be of clinical importance related to the potential risk of porphyria.

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2 In the present study, based on the currently available data on SNPs and acquired mutations, we have created a total of 18 variant forms of ABCG2 (V12M, G51C, Q126stop, Q141K, T153M, Q166E, I206L, F208S, S248P, E334stop, F431L, S441N, R482G, R482T, F489L, F571I, N590Y, and D620N) by site-directed mutagenesis and expressed them in insect cells. Login to comment
4 We herein provide evidence that the variants Q126stop, F208S, S248P, E334stop, and S441N are defective in porphyrin transport, whereas F489L exhibited impaired transport, approximately 10% of the activity observed for the wild type. Login to comment
6 Thus, among those genetic polymorphisms of ABCG2, at least the hitherto validated alleles of Q126stop, S441N, and F489L are suggested to be of clinical importance related to the potential risk of porphyria. Login to comment
36 We herein provide evidence that the variants Q126stop, F208S, S248P, E334stop, S441N, and F489L are defective or impaired in the transport of porphyrins, suggesting that those genetic polymorphisms in the ABCG2 gene may be related to the risk of certain diseases resulting from disruption of porphyrin homeostasis. Login to comment
82 GC indicates the percentage of guanine and cytosine contents in the PCR primer set. Tm shows the melting temperature (Tm) for each PCR primer set. Variant and Primers Primer Sequence (5Ј 3 3Ј) Primer Length GC Tm bases % °C V12M 33 39 55 Forward CGAAGTTTTTATCCCAATGTCACAAGGAAACAC Reverse GTGTTTCCTTGTGACATTGGGATAAAAACTTCG G51C 42 35 59 Forward ATCGAGTAAAACTGAAGAGTTGCTTTCTACCTTGTAGAAAAC Reverse GTTTTCGACAAGGTAGAAAGCAACTCTTCAGTTTTACTCGAT Q126stop 40 40 62 Forward GTAATTCAGGTTACGTGGTATAAGATGATGTTGTGATGGG Reverse CCCATCACAACATCATCTTATACCACGTAACCTGAATTAC Q141K 35 42 55 Forward CGGTGAGAGAAAACTTAAAGTTCTCAGCAGCTCTT Reverse AAGAGCTGCTGAGAACTTTAAGTTTTCTCTCACCG T153M 42 40 60 Forward CGGCTTGCAACAACTATGATGAATCATGAAAAAAACGAACGG Reverse CCGTTCGTTTTTTTCATGATTCATCATAGTTGTTGCAAGCCG Q166E 35 42 55 Forward GGATTAACAGGGTCATTGAAGAGTTAGGTCTGGAT Reverse ATCCAGACCTAACTCTTCAATGACCCTGTTAATCC I206L 36 44 59 Forward CTTATCACTGATCCTTCCCTCTTGTTCTTGGATGAG Reverse CTCATCCAAGAACAAGAGGGAAGGATCAGTGATAAG F208S 35 45 55 Forward TGATCCTTCCATCTTGTCCTTGGATGAGCCTACAA Reverse TTGTAGGCTCATCCAAGGACAAGATGGAAGGATCA S248P 35 40 55 Forward TTCATCAGCCTCGATATCCCATCTTCAAGTTGTTT Reverse AAACAACTTGAAGATGGGATATCGAGGCTGATGAA E334stop 35 31 55 Forward TCATAGAAAAATTAGCGTAGATTTATGTCAACTCC Reverse GGAGTTGACATAAATCTACGCTAATTTTTCTATGA F431L 28 60 62 Forward AGCTGGGGTTCTCCTCTTCCTGACGACC Reverse GGTCGTCAGGAAGAGGAGAACCCCAGCT S441N 34 47 59 Forward AACCAGTGTTTCAGCAATGTTTCAGCCGTGGAAC Reverse GTTCCACGGCTGAAACATTGCTGAAACACTGGTT F489L 46 34 62 Forward GAGGATGTTACCAAGTATTATACTTACCTGTATAGTGTACTTCATG Reverse CATGAAGTACACTATACAGGTAAGTATAATACTTGGTAACATCCTC F571I 36 47 61 Forward GTCATGGCTTCAGTACATCAGCATTCCACGATATGG Reverse CCATATCGTGGAATGCTGATGTACTGAAGCCATGAC N590Y 42 38 62 Forward CATAATGAATTTTTGGGACAATACTTCTGCCCAGGACTCAAT Reverse ATTGAGTCCTGGGCAGAAGTATTGTCCCAAAAATTCATTATG D620N 32 56 62 Forward GGTAAAGCAGGGCATCAATCTCTCACCCTGGG Reverse CCCAGGGTGAGAGATTGATGCCCTGCTTTACC veloped by using Western Lighting Chemiluminescent Reagent Plus (PerkinElmer Life and Analytical Sciences, Boston, MA) and detected by Lumino Imaging Analyzer FAS-1000 (Toyobo Engineering, Osaka, Japan). Login to comment
144 For this purpose, based on the currently available data on SNPs and acquired mutations, we generated variant forms (i.e., V12M, G51C, Q126stop, Q141K, T153M, Q166E, I206L, F208S, S248P, E334stop, F431L, S441N, R482G, R482T, F489L, F571I, N590Y, and D620N) by site-directed mutagenesis. Login to comment
148 For Q126stop and E334stop, however, that treatment created truncated proteins (Fig. 4A). Login to comment
164 It is important to note that the variants Q126stop, F208S, S248P, E334stop, and S441N substantially lack transport activity for both hematoporphyrin and methotrexate. Login to comment
214 In the present study, based on the currently available data on SNPs and acquired mutations, we have created a total of 18 variant forms of ABCG2 (V12M, G51C, Q126stop, Q141K, T153M, Q166E, I206L, F208S, S248P, E334stop, F431L, S441N, R482G, R482T, F489L, F571I, N590Y, and D620N) by site-directed mutagenesis and expressed them in insect cells. Login to comment
215 We provide evidence that the variants Q126stop, F208S, S248P, E334stop, and S441N are defective in the transport of hematoporphyrin (Fig. 5). Login to comment
219 The frequencies of the Q126stop, S441N, and F489L alleles are relatively low (less than 2%) compared with those of the V12M and Q141K alleles. Login to comment
220 The variant Q126stop was consistently observed in certain Japanese cohorts; however, it was absent in two different Caucasian and African-American groups (Imai et al., 2002; Itoda et al., 2003; Mizuarai et al., 2004; Kobayashi et al., 2005; for a recent review, see Ishikawa et al., 2005) for recent review. Login to comment
224 Potential Risk Amino Acid Transport Allele Frequency cDNA Position Located on Exon Allele Data Sourcea Hemato MTX Wild-Type Allele % V12M ϩϩ ϩϩ 2.0-90.0 34 2 G A 1, 2, 4, 5, 7, 8 ૽૽ Q126stop - - 0.0-1.7 376 4 C T 1, 3, 5, 7 Q141K ϩϩ ϩϩ 0.0-35.5 421 5 C A 1, 2, 4, 5, 6, 7, 8 T153M ϩϩ ϩϩ 3.3 458 5 C T 5 R160Q N.D. N.D. 0.5 479 5 G A 8 Q166E ϩϩ ϩϩ N.D. 496 5 C G NCBI dbSNP rs1061017 I206L ϩϩ ϩϩ 10.0 616 6 A C 2 ૽૽ F208S - - N.D. 623 6 T C NCBI dbSNP rs1061018 ૽૽ S248P - - N.D. 742 7 T C NCBI dbSNP rs3116448 ૽૽ E334stop - - N.D. 1000 9 G T NCBI dbSNP rs3201997 F431L ϩϩ - 0.8 1291 11 T C 3 ૽૽ S441N - - 0.5 1322 11 G A 7 ૽ F489L ϩ - 0.5-0.8 1465 12 T C 3, 7 F571L ϩϩ ϩϩ 0.5 1711 14 T A NCBI dbSNP rs9282571 (૽૽) R575stop N.D. N.D. 0.5 1723 14 C T 8 N590Y ϩϩ ϩϩ 0.0-1.0 1768 15 A T 2, 5 D620N ϩϩ ϩϩ 0.5 1858 16 G A 8 Hemato, hematoporphyrin; NCBI, National Center for Biotechnology Information; N.D., not determined; ૽, risk of porphyria; (૽), potential risk is assumed as the lack of transport activity being as a result of a truncated protein. Login to comment
240 Therefore, at least, the validated alleles such as Q126stop, S441N, and F489L with a loss of porphyrin transport activity are at potential risk of diseases. Login to comment

[hide] Role of pharmacogenetics of ATP-binding cassette t... Pharmacol Ther. 2006 Nov;112(2):457-73. Cascorbi I
Role of pharmacogenetics of ATP-binding cassette transporters in the pharmacokinetics of drugs.
Pharmacol Ther. 2006 Nov;112(2):457-73., [PMID:16766035]

Abstract [show]
Interindividual differences of drug response are an important cause of treatment failures and adverse drug reactions. The identification of polymorphisms explaining distinct phenotypes of drug metabolizing enzymes contributed in part to the understanding of individual variations of drug plasma levels. However, bioavailability also depends on a major extent from the expression and activity of drug transport across biomembranes. In particular efflux transporters of the ATP-binding cassette (ABC) family such as ABCB1 (P-glycoprotein, P-gp), the ABCC (multidrug resistance-related protein, MRP) family and ABCG2 (breast cancer resistance protein, BCRP) have been identified as major determinants of chemoresistance in tumor cells. They are expressed in the apical membranes of many barrier tissue such as the intestine, liver, blood-brain barrier, kidney, placenta, testis and in lymphocytes, thus contributing to plasma, liquor, but also intracellular drug disposition. Since expression and function exhibit a broad variability, it was hypothesized that hereditary variances in the genes of membrane transporters could explain at least in part interindividual differences of pharmacokinetics and clinical outcome of a variety of drugs. This review focuses on the functional significance of single nucleotide polymorphisms (SNP) of ABCB1, ABCC1, ABCC2, and ABCG2 in in vitro systems, in vivo tissues and drug disposition, as well as on the clinical outcome of major indications.

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917 0.005 Exon 4 c. 376 C>T Q126stop 0.01 Lack of function 0.00a 0.00b Exon 5 c. 421 C>A Q141K 0.35 Reduced activity (Mizuarai et al., 2004; Kobayashi et al., 2005; Sparreboom et al., 2005) 0.11a 0.02b IVS 5-16 A>G ? Login to comment

[hide] Multidrug resistance: retrospect and prospects in ... Curr Med Chem. 2006;13(16):1859-76. Perez-Tomas R
Multidrug resistance: retrospect and prospects in anti-cancer drug treatment.
Curr Med Chem. 2006;13(16):1859-76., [PMID:16842198]

Abstract [show]
Conventional cancer chemotherapy is seriously limited by the multidrug resistance (MDR) commonly exhibited by tumour cells. One mechanism by which a living cell can achieve multiple resistances is via the active efflux of a broad range of anticancer drugs through the cellular membrane by MDR proteins. Such drugs are exported in both ATP-dependent and -independent manners, and can occur despite considerable concentration gradients. To the ATP-dependent group belongs the ATP-binding cassette (ABC) transporter family, which includes P-gp, MRP, BCRP, etc. Another protein related to MDR, though not belonging to the ABC transporter family, is lung resistance-related protein (LRP). All of these proteins are involved in diverse physiological processes, and are responsible for the uptake and efflux of a multitude of substances from cancer cells. Many inhibitors of MDR transporters have been identified over the years. Firstly, MDR drugs were not specifically developed for inhibiting MDR; in fact, they had other pharmacological properties, as well as a relatively low affinity for MDR transporters. They included compounds of diverse structure and function, such as verapamil and cyclosporine, and caused side effects. Secondly, the new drugs were more inhibitor-specific, in terms of MDR transport, and were designed to reduce such side effects (e.g., R-verapamil, dexniguldipine, etc.). Unfortunately, they displayed poor response in clinical studies. Recently, new compounds obtained from drug development programs conducted by the pharmaceutical industry are characterized by a high affinity to MDR transporters and are efficient at nanomolar concentrations. Some of these compounds (e.g., MS-209) are currently under clinical trials for specific forms of advanced cancers. We aim to provide an overview of the properties associated with those mammalian MDR transporters known to mediate significant transport of relevant drugs in cancer treatments. We also summarize recent advances concerning resistance to cancer drug therapies with respect to the function and overexpression of ABC and LRP multidrug transporters.

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219 The results showed three BCRP-coding SNPs [G34A (V12M), C376T (Q126stop) and C421A (Q141K)] (Fig. 6). Login to comment

[hide] Human ABC transporter ABCG2 in xenobiotic protecti... Drug Metab Rev. 2006;38(3):371-91. Wakabayashi K, Tamura A, Saito H, Onishi Y, Ishikawa T
Human ABC transporter ABCG2 in xenobiotic protection and redox biology.
Drug Metab Rev. 2006;38(3):371-91., [PMID:16877258]

Abstract [show]
Human ATP-binding cassette (ABC) transporter ABCG2 (BCRP/MXR/ABCP) is regarded as a member of the phase III system of xenobiotic metabolism. This efflux pump is suggested to be responsible for protecting the body from toxic xenobiotics and for removing toxic metabolites. The aim of this review article is to address new aspects of ABCG2 related to redox biology, namely the posttranslational modification (intra- and intermolecular disulfide bond formation) of ABCG2 protein and the transport of porphyrin and chlorophyll metabolites, as well as the high-speed screening and QSAR analysis method to evaluate ABCG2-drug interactions.

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176 Based on the currently available data on SNPs and acquired mutations, we have created a total of 18 variant forms of ABCG2 (V12M, G51C, Q126stop, Q141K, T153M, Q166E, I206L, F208S, S248P, E334stop, F431L, S441N, R482G, R482T, F489L, F571I, N590Y, and D620N) by site-directed mutagenesis and expressed them in Sf9 insect cells. Login to comment
177 The variants Q126stop, F208S, S248P, E334stop, and S441N were found to be defective in the transport of hematoporphyrin (Tamura et al., 2006) (Table 2). Login to comment

[hide] Human multidrug resistance ABCB and ABCG transport... Physiol Rev. 2006 Oct;86(4):1179-236. Sarkadi B, Homolya L, Szakacs G, Varadi A
Human multidrug resistance ABCB and ABCG transporters: participation in a chemoimmunity defense system.
Physiol Rev. 2006 Oct;86(4):1179-236., [PMID:17015488]

Abstract [show]
In this review we give an overview of the physiological functions of a group of ATP binding cassette (ABC) transporter proteins, which were discovered, and still referred to, as multidrug resistance (MDR) transporters. Although they indeed play an important role in cancer drug resistance, their major physiological function is to provide general protection against hydrophobic xenobiotics. With a highly conserved structure, membrane topology, and mechanism of action, these essential transporters are preserved throughout all living systems, from bacteria to human. We describe the general structural and mechanistic features of the human MDR-ABC transporters and introduce some of the basic methods that can be applied for the analysis of their expression, function, regulation, and modulation. We treat in detail the biochemistry, cell biology, and physiology of the ABCB1 (MDR1/P-glycoprotein) and the ABCG2 (MXR/BCRP) proteins and describe emerging information related to additional ABCB- and ABCG-type transporters with a potential role in drug and xenobiotic resistance. Throughout this review we demonstrate and emphasize the general network characteristics of the MDR-ABC transporters, functioning at the cellular and physiological tissue barriers. In addition, we suggest that multidrug transporters are essential parts of an innate defense system, the "chemoimmunity" network, which has a number of features reminiscent of classical immunology.

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1002 1425AϾG) mutations, one nonsense (Q126X, c. Login to comment
1005 The sequence variant Q126X, leading to premature termination of protein synthesis, was consistently observed in certain Japanese cohorts, while absent in different Caucasian and African American groups (145, 148, 185). Login to comment

[hide] Involvement of breast cancer resistance protein (B... Drug Metab Dispos. 2007 Feb;35(2):209-14. Epub 2006 Nov 8. Enokizono J, Kusuhara H, Sugiyama Y
Involvement of breast cancer resistance protein (BCRP/ABCG2) in the biliary excretion and intestinal efflux of troglitazone sulfate, the major metabolite of troglitazone with a cholestatic effect.
Drug Metab Dispos. 2007 Feb;35(2):209-14. Epub 2006 Nov 8., [PMID:17093005]

Abstract [show]
Troglitazone sulfate (TGZS) is the major metabolite of troglitazone (TGZ), an antidiabetic agent, and thought to be a cause of the cholestasis induced by TGZ. The aim of the present study is to elucidate the involvement of breast cancer resistance protein (BCRP/ABCG2) in the hepatic disposition of TGZS. The basal-to-apical transport of TGZS was enhanced in organic anion transporting polypeptide 1B1-expressing Madin-Darby canine kidney II cells by infection of recombinant adenovirus harboring human BCRP and mouse Bcrp cDNA. TGZS was given to wild-type and Bcrp (-/-) mice by constant infusion. Biliary excretion is the predominant elimination pathway of TGZS in wild-type mice, and the biliary excretion clearance of TGZS with regard to the hepatic concentration was reduced to 30% of the control in Bcrp (-/-) mice. However, plasma and hepatic concentrations were unchanged, suggesting induction of compensatory mechanisms in Bcrp (-/-) mice for the elimination of TGZS. Involvement of BCRP in the intestinal efflux transport of TGZS was examined using everted sacs. The mucosal efflux clearance of TGZS showed only a slight reduction (15% reduction) in Bcrp (-/-) mice. Our results suggest that BCRP plays a major role in the biliary excretion but a minor role in the intestinal transport of TGZS.

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192 BCRP has some functional single nucleotide polymorphisms (SNP), such as C376T (Q126stop), C421A (Q141K), and G1322A (S441N). Login to comment

[hide] Pharmacogenetics/genomics of membrane transporters... Cancer Metastasis Rev. 2007 Mar;26(1):183-201. Huang Y
Pharmacogenetics/genomics of membrane transporters in cancer chemotherapy.
Cancer Metastasis Rev. 2007 Mar;26(1):183-201., [PMID:17323126]

Abstract [show]
Inter-individual variability in drug response and the emergence of adverse drug reactions are main causes of treatment failure in cancer therapy. Recently, membrane transporters have been recognized as an important determinant of drug disposition, thereby affecting chemosensitivity and -resistance. Genetic factors contribute to inter-individual variability in drug transport and targeting. Therefore, pharmacogenetic studies of membrane transporters can lead to new approaches for optimizing cancer therapy. This review discusses genetic variations in efflux transporters of the ATP-binding cassette (ABC) family such as ABCB1 (MDR1, P-glycoprotein), ABCC1 (MRP1), ABCC2 (MRP2) and ABCG2 (BCRP), and uptake transporters of the solute carrier (SLC) family such as SLC19A1 (RFC1) and SLCO1B1 (SLC21A6), and their relevance to cancer chemotherapy. Furthermore, a pharmacogenomic approach is outlined, which using correlations between the growth inhibitory potency of anticancer drugs and transporter gene expression in multiple human cancer cell lines, has shown promise for determining the relevant transporters for any given drugs and predicting anticancer drug response.

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124 Moreover, Letourneau et al. examined 10 non-synonymous ABCC1 SNPs to determine Table 2 Summary of genetic variants in ABC transporters ABCB1, ABCC1, ABCC2 and ABCG2 involved in cancer chemotherapy Variants (location, effect) Phenotype Drug Sample Reference ABCB1 +103T>C (5'flanking, non-coding) Increased transcription Doxorubicin vincristine osteosarcoma Stein et al., 1994 [19] +8T>C (5'flanking, non-coding) Unknown Leukemia Rund et al., 1999 [21] 1236C>T (exon12, synonymous) Higher expression AML blasts Illmer et al., 2002 [47] Lower clearance Irinotecan Cancer patients Sai et al., 2003 [44] Higher exposure Irinotecan, SN-38 Cancer patients Mathijssen et al., 2003 [45] 2677G>T/A (exon21, A893S/T) Lower expression placenta Tanabe et al., 2001 [42] Lower expression placenta Hitzl et al., 2004 [37] Higher expression AML blasts Illmer et al., 2002 [47] Allele specific expression Cell lines, lymphoma Mickley et al., 1998 [22] Lower clearance Irinotecan Cancer patients Sai et al., 2003 [44] Survival leukemia Illmer et al., 2002 [47] Survival leukemia van den Heuvel-Eibrink et al., 2001 [48] Worse survival AML blasts Kim et al., 2006 [10] Higher efficacy Paclitaxel Ovarian cancer Green et al., 2006 [50] 2995G>A (exon24, A999T) None Cell lines, lymphoma Mickley et al., 1998 [22] 3435C>T (exon26, synonymous) Lower expression Duodenal protein Hoffmeyer et al., 2000 [26] Lower expression placenta Hitzl et al., 2004 [37] Higher expression Intestine mRNA Nakamura et al., 2002 [32] Higher expression AML blasts Illmer et al., 2002 [47] Lower clearance Irinotecan Cancer patients Sai et al., 2003 [44] Lower efflux Digoxin CD56+ NK cells Hitzl et al., 2001 [27] Higher plasma level Digoxin Healthy volunteers Hoffmeyer et al., 2000 [26] Higher AUC Cyclosporin transplant patients Bonhomme-Faivre et al., 2004 [36] Lower CNS relapse Cancer patients Stanulla et al., 2005 [46] Better survival leukemia Illmer et al., 2002 [47] Higher efficacy Breast cancer Kafka et al., 2003 [49] Higher activity, worse survival AML Kim et al., 2006 [10] Better survival Platinums Esophageal cancer Wu et al., 2006 [43] No difference Docetaxel patients Puisset et al., 2004 [41] No difference Irinotecan Cancer patients Mathijssen et al., 2004 [39] No difference Vincristine patients Plasschaert et al., 2004 [40] No difference colon Taniguchi et al., 2003 [24] ABCC1 -260G>C (5'flanking, non-coding) Higher activity Transfected cell line Wang et al., 2005 [62] Table 2 (Continued) Variants (location, effect) Phenotype Drug Sample Reference 128G>C (exon2, C43S) Reduced resistance Vincristine, arsenite Transfected cell line Leslie et al., 2003 [60] 1299G>T (exon10, R433S) Reduced transport of LTC4, increased resistance to doxorubicin Leukotriene C4, doxorubicin Transfected cell line Conrad et al., 2002 [59] 2012G>T (exon16, G671V) No change in activityLeukotriene C4 Transfected cell line Conrad et al., 2001 [58] Heart toxicity Doxorubicin nLon-Hodgkin lymphoma Wojnowski et al., 2005 [63] 2965G>A (exon22, A989T) Reduced transport Estradiol 17β-glucuronide Transfected cell line Letourneau et al., 2005 [61] ABCC2 1271A>G (exon10, R421G) Reduced drug elimination, increased nephrotoxicity Methotrexate One lymphoma patient Hulot et al., 2005 [79] 3972C>T (exon28, nonsynonymous) Reduced drug clearance Irinotecan Cancer patients Innocenti et al., 2004 [80] ABCG2 376C>T (exon4, Q126stop) Reduced transport Porphyrin Trensfected cell Tamura et al., 2006 [104] 421C>A (exon5, Q141K) Lower expression Transfected cell lines Imai et al., 2002 [94] Lower expression Transfected cell lines Kondo et al., 2004 [95] Lower expression Placenta Kobayashi et al., 2005 [98] Reduced ATPase activity Trensfected cell lines Mizuarai et al., 2004 [97] Higher plasma levels Diflomotecan patients Sparreboom et al., 2004 [100] Increased bioavailability Topotecan patients Sparreboom et al., 2005 [101] Increased bioavailability 9-Aminocamptothecin patients Zamboni et al., 2006 [81] Increased drug accumulation Imatinib Transfected cell lines Gardner et al., 2006 [96] Increased drug accumulation Topotecan Trensfected cell lines Imai et al., 2002 [94] No difference Imatinib patients Gardner et al., 2006 [96] No difference intestine Zamber et al., 2003 [99] No difference MTX Trensfected cell lines Kondo et al., 2004 [95] the effects on expression and function of this transporter in transfected HEK293T cells [61]. Login to comment
187 Another polymorphism, 376C>T, substitutes a stop codon for Gln (Q126stop) and causes the absence of active ABCG2 protein from the T allele [95, 99]. Login to comment
189 It was recently demonstrated that in vitro the Q126stop protein was defective in porphyrin transport [104]. Login to comment

[hide] The effect of ABCG2 V12M, Q141K and Q126X, known f... Br J Clin Pharmacol. 2007 Nov;64(5):645-54. Epub 2007 May 17. Kim HS, Sunwoo YE, Ryu JY, Kang HJ, Jung HE, Song IS, Kim EY, Shim JC, Shon JH, Shin JG
The effect of ABCG2 V12M, Q141K and Q126X, known functional variants in vitro, on the disposition of lamivudine.
Br J Clin Pharmacol. 2007 Nov;64(5):645-54. Epub 2007 May 17., [PMID:17509035]

Abstract [show]
AIMS: To evaluate the effects of three ABCG2 variants (Q141K, V12M and Q126X), which are known to have altered transport properties in vitro, on the disposition of lamivudine in healthy subjects. METHODS: To evaluate whether lamivudine is a substrate of ABCG2, intracellular accumulation and vectorial transport of 3H-lamivudine were determined in MDCK-ABCG2 cells. The pharmacokinetic parameters of lamivudine were compared among subjects with four different ABCG2 genotypes, including wild type (seven subjects), K141/K141 (six subjects), Q126/Stop126 (four subjects) and M12/M12 (five subjects) after a single oral dose of 100 mg lamivudine. RESULTS: The intracellular accumulation of lamivudine in MDCK-ABCG2 cells was significantly lower than that in MDCK-mock cells, but fumitremorgin C reversed the intracellular lamivudine concentration to that of MDCK-mock cells. The ABCG2-mediated transport of lamivudine was saturable and the values of Km and Vmax were 216.5 +/- 58 microm and 20.42 +/- 2.9 nmol h(-1) per 10(6) cells, respectively. After lamivudine administration to healthy subjects, the AUC of lamivudine showed no difference among subjects with different ABCG2 genotypes; 2480 +/- 502, 2207 +/- 1019, 2422 +/- 239, 2552 +/- 698 ng h(-1) ml(-1) for wild type, K141/K141, Q126/Stop126 and M12/M12 genotype, respectively (P = 0.85). The estimated 95% confidence intervals for the mean difference between K141/K141, Q126/Stop126, M12/M12 and wild as reference were (-1053, 507), (-555, 439) and (-552, 696), respectively. No other pharmacokinetic parameters were estimated to be significantly different among four different ABCG2 genotypes tested. CONCLUSIONS: Lamivudine appeared to be a substrate of ABCG2 in vitro, but the disposition of lamivudine was not significantly influenced by known in vitro functional variants of ABCG2, Q141K, V12M and Q126X in healthy subjects.

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0 The effect of ABCG2 V12M, Q141K and Q126X, known functional variants in vitro, on the disposition of lamivudine Ho-Sook Kim,1 Yu Eun Sunwoo,1 Ji Young Ryu,1 Ho-Jin Kang,1 Hye-Eun Jung,1 Im-Sook Song,1 Eun-Young Kim,1,2 Joo-Cheol Shim,1,3 Ji-Hong Shon1,2 & Jae-Gook Shin1,2 1 Department of Pharmacology and Pharmacogenomics Research Centre, Inje University College of Medicine, 2 Department of Clinical Pharmacology and 3 Department of Psychiatry, Inje University Busan Paik Hosptial, Busan, Korea Correspondence Jae-Gook Shin, MD, PhD, Department of Pharmacology and Clinical Pharmacology, Pharmacogenomics Research Centre, Inje University College of Medicine, 633-165 Gaegum-dong, Jin-gu, Busan 614-735, Korea. Login to comment
2 Received 19 September 2006 Accepted 15 March 2007 Published OnlineEarly 17 May 2007 Aims To evaluate the effects of three ABCG2 variants (Q141K, V12M and Q126X), which are known to have altered transport properties in vitro, on the disposition of lamivudine in healthy subjects. Login to comment
10 Conclusions Lamivudine appeared to be a substrate of ABCG2 in vitro, but the disposition of lamivudine was not significantly influenced by known in vitro functional variants of ABCG2, Q141K, V12M and Q126X in healthy subjects. Login to comment
85 After washing Table 2 Sequences of primers used for the amplification and sequencing analysis of ABCG2 genotype and the denaturation temperatures used in the PCR Name Primer sequence (5Ј,3Ј) Size PCR ( Tm; °C) ABCG2 V12M F: Biotin-CTCTCCAGATGTCTTCCAGTAATG 278 54 R: GCCAAAACCTGTGAGGTTCA S: CATTGGTGTTTCCTTGTGA ABCG2 Q126X F: GTCTTAGCTGCAAGGAAAGATCCA 174 54.5 R: Biotin-ACTATCAGCCAAAGCACTTACCC S: AATGTAATTCAGGTTACGTG ABCG2 Q141K F: TGATGTTGTGATGGGCACTC 69 54 R: Biotin-GTTGCAAGCCGAAGAGCTG S: GACGGTGAGAGAAAACTT F, forward primer; R, reverse primer; S, sequencing primer; Tm, melting temperature; PCR, polymerase chain reaction. Login to comment

[hide] ABC multidrug transporters: structure, function an... Pharmacogenomics. 2008 Jan;9(1):105-27. Sharom FJ
ABC multidrug transporters: structure, function and role in chemoresistance.
Pharmacogenomics. 2008 Jan;9(1):105-27., [PMID:18154452]

Abstract [show]
Three ATP-binding cassette (ABC)-superfamily multidrug efflux pumps are known to be responsible for chemoresistance; P-glycoprotein (ABCB1), MRP1 (ABCC1) and ABCG2 (BCRP). These transporters play an important role in normal physiology by protecting tissues from toxic xenobiotics and endogenous metabolites. Hydrophobic amphipathic compounds, including many clinically used drugs, interact with the substrate-binding pocket of these proteins via flexible hydrophobic and H-bonding interactions. These efflux pumps are expressed in many human tumors, where they likely contribute to resistance to chemotherapy treatment. However, the use of efflux-pump modulators in clinical cancer treatment has proved disappointing. Single nucleotide polymorphisms in ABC drug-efflux pumps may play a role in responses to drug therapy and disease susceptibility. The effect of various genotypes and haplotypes on the expression and function of these proteins is not yet clear, and their true impact remains controversial.

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355 Over 80 SNPs, missense, nonsense and frameshift mutations in the ABCG2 gene have been identified in different ethnic groups [23,170], including V12M (N-terminal cytosolic region), Q141K (NBD) and Q126stop (in which no active protein is produced). Login to comment
368 A recent study characterized the activity of 18 ABCG2 variants, and concluded that Q126stop, F208S, S248P, E334stop, S441N and F489L are defective in hematoporphyrin transport [170], which may increase the risk of disease in individuals carrying these polymorphisms. Login to comment

[hide] In vitro evaluation of photosensitivity risk relat... Drug Metab Pharmacokinet. 2007 Dec;22(6):428-40. Tamura A, Onishi Y, An R, Koshiba S, Wakabayashi K, Hoshijima K, Priebe W, Yoshida T, Kometani S, Matsubara T, Mikuriya K, Ishikawa T
In vitro evaluation of photosensitivity risk related to genetic polymorphisms of human ABC transporter ABCG2 and inhibition by drugs.
Drug Metab Pharmacokinet. 2007 Dec;22(6):428-40., [PMID:18159130]

Abstract [show]
Since porphyrins are regarded as endogenous substrates for the ATP-binding cassette (ABC) transporter ABCG2, it is hypothesized that functional impairment owing to genetic polymorphisms or inhibition of ABCG2 by drugs may result in a disruption of cellular porphyrin homeostasis. In the present study, we expressed ABCG2 genetic variants, i.e., V12M, Q141K, S441N, and F489L, as well as the wild type (WT) in Flp-In-293 cells to examine the hypothesis. Cells expressing S441N and F489L variants exhibited high levels of both cellularly accumulated pheophorbide a and photosensitivity, when those cells were incubated with pheophorbide a and irradiated with visible light. To further elucidate the significance of ABCG2 in cellular porphyrin homeostasis, we observed cellular accumulation and compartmentation of porphyrin and pheophorbide a by means of a new fluorescence microscopy technology, and found that accumulation of porphyrin and pheophorbide a in the cytoplasm compartment was maintained at low levels in Flp-In-293 cells expressing ABCG2 WT, V12M, or Q141K. When ABCG2 was inhibited by imatinib or novobiocin, however, those cells became sensitive to light. Based on these results, it is strongly suggested that certain genetic polymorphisms and/or inhibition of ABCG2 by drugs can enhance the potential risk of photosensitivity.

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22 By using plasma membrane vesicles and a high-speed screening system, we precisely evaluated functional changes associated with genetic polymorphisms in vitro.24) Since porphyrins are considered to be endogenous substrates for ABCG2, we have investigated the transport of porphyrins with a total of 18 variant forms of human ABCG2 in the plasma membrane vesicle system.4) As a result, we found that the variants Q126stop, F208S, S248P, E334stop, S441N, and F489L are defective or impaired in the transport of porphyrins. Login to comment
199 Indeed, we reported that the variants Q126stop, F208S, S248P, E334stop, and S441N are defective in the transport of hematoporphyrin.4) The F489L variant showed impaired transport activity. Login to comment

[hide] Ubiquitin-mediated proteasomal degradation of non-... Biochem J. 2008 May 1;411(3):623-31. Nakagawa H, Tamura A, Wakabayashi K, Hoshijima K, Komada M, Yoshida T, Kometani S, Matsubara T, Mikuriya K, Ishikawa T
Ubiquitin-mediated proteasomal degradation of non-synonymous SNP variants of human ABC transporter ABCG2.
Biochem J. 2008 May 1;411(3):623-31., 2008-05-01 [PMID:18237272]

Abstract [show]
Clinical relevance is implicated between the genetic polymorphisms of the ABC (ATP-binding cassette) transporter ABCG2 (ABC subfamily G, member 2) and the individual differences in drug response. We expressed a total of seven non-synonymous SNP (single nucleotide polymorphism) variants in Flp-In-293 cells by using the Flp (flippase) recombinase system. Of these, ABCG2 F208S and S441N variants were found to be expressed at markedly low levels, whereas their mRNA levels were equal to those of the other SNP variants and ABCG2 WT (wild-type). Interestingly, protein expression levels of the ABCG2 F208S and S441N variants increased 6- to 12-fold when Flp-In-293 cells were treated with MG132, a proteasome inhibitor. Immunoprecipitation followed by immunoblot analysis showed that the ABCG2 F208S and S441N variant proteins were endogenously ubiquitinated in Flp-In-293 cells, and treatment with MG132 significantly enhanced the level of these ubiquitinated variants. Immunofluorescence microscopy demonstrated that MG132 greatly affected the ABCG2 F208S and S441N variants in terms of both protein levels and intracellular distribution. Immunoblot analysis revealed that those variants were N-glycosylated; however, their oligosaccharides were immature compared with those present on ABCG2 WT. The ABCG2 F208S and S441N variant proteins do not appear to be processed in the Golgi apparatus, but undergo ubiquitin-mediated protein degradation in proteasomes, whereas ABCG2 WT is sorted to the plasma membrane and then degraded via the lysosomal pathway. The present study provides the first evidence that certain genetic polymorphisms can affect the protein stability of ABCG2. Control of proteasomal degradation of ABCG2 would provide a novel approach in cancer chemotherapy to circumvent multidrug resistance of human cancers.

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26 The ABCG2 non-synonymous SNP variants Q126stop, F208S, S248P, E334stop, S441N and F489L were defective in the active transport of methotrexate and haematoporphyrin [18]. Login to comment

[hide] Homology modeling of breast cancer resistance prot... J Struct Biol. 2008 Apr;162(1):63-74. Epub 2007 Dec 15. Hazai E, Bikadi Z
Homology modeling of breast cancer resistance protein (ABCG2).
J Struct Biol. 2008 Apr;162(1):63-74. Epub 2007 Dec 15., [PMID:18249138]

Abstract [show]
BCRP (also known as ABCG2, MXR, and ABC-P) is a member of the ABC family that transports a wide variety of substrates. BCRP is known to play a key role as a xenobiotic transporter. Since discovering its role in multidrug resistance, considerable efforts have been made in order to gain deeper understanding of BCRP structure and function. The recent study was aimed at predicting BCRP structure by creating a homology model. Based on sequence similarity with known structures of full-length, NB and TM domain of ABC transporters, TM, NB, and linker regions of BCRP were defined. The NB domain of BCRP was modeled using MalK as a template. Based on secondary structure prediction of BCRP and comparison of the transmembrane connecting regions of known structures of ABC transporters, the TM domain arrangement of BCRP was established and was found to resemble to that of the recently published crystal structure of Sav1866. Thus, an initial alignment of TM domain of BCRP was established using Sav1866 as a template. This alignment was subsequently refined using constrains derived from secondary structure and TM predictions and the final model was built. Finally, the complete homodimer ABCG2 model was generated using Sav1866 as template. Furthermore, known ligands of BCRP were docked to our model in order to define possible binding sites. The results of molecular dockings of known BCRP substrates to the BCRP model were in agreement with recently published experimental data indicating multiple binding sites in BCRP.

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245 However, in our model, R482 cannot form interaction with rhodamine, but L484 is in interacting distance Table 3 Mutations on BCRP and their effect on its function Mutation Effect/results Reference V12M Did not effect Hemato and MTX transport Tamura et al. (2006) G51C Did not effect Hemato and MTX transport Tamura et al. (2006) K86M Inactivates transporter (dominant negative effect on ATPase activity); alters subcellular distribution Henriksen et al. (2005a) K86M Transporter inactive, but still able to bind ATP Ozvegy et al. (2002) Q126stop Defective porphyrin transport Tamura et al. (2006) Q141K Did not effect Hemato and MTX transport Tamura et al. (2006) T153M Did not effect Hemato and MTX transport Tamura et al. (2006) Q166E Did not effect Hemato and MTX transport Tamura et al. (2006) I206L Did not effect Hemato and MTX transport Tamura et al. (2006) F208S Defective porphyrin transport Tamura et al. (2006) S248P Defective porphyrin transport Tamura et al. (2006) E334stop Defective porphyrin transport Tamura et al. (2006) F431L Effects MTX transport Tamura et al. (2006) S441N Defective porphyrin transport Tamura et al. (2006) E446-mutants No drug resistance Miwa et al. (2003) R482G, R482T Effects MTX transport Tamura et al. (2006) R482T Substrate drug transport and inhibitor efficiency is not mediated by changes in drug-binding Pozza et al. (2006) R482G, R482T Substitution influence the substrate specificity of the transporter Ozvegy et al. (2002) R482G, R482T Altered substrate specificity Honjo et al. (2001) R482G Methotrexate not transported Chen et al. (2003b) Mitomo et al. (2003) R482G Resistance to hydrophilic antifolates in vitro, G482-ABCG2 mutation confers high-level resistance to various hydrophilic antifolates Shafran et al., (2005) R482G Three distinct drug, binding sites Clark et al. (2006) R482G Altered substrate specificity, granulocyte maturation uneffected Ujhelly et al. (2003) R482 mutants Higher resistance to mitoxantrone and doxorubicin than wt Miwa et al. (2003) R482X Affects substrate transport and ATP hydrolysis but not substrate binding Ejendal et al. (2006) F489L Impaired porphyrin transport Tamura et al. (2006) G553L; G553E Impaired trafficing, expression, and N-linked glycosylation Polgar et al. (2006) L554P Dominant negative effect on drug sensitivity Kage et al. (2002) N557D Resistance to MTX, but decreased transport of SN-38; N557E no change in transport compared to wt Miwa et al. (2003) F571I Did not effect Hemato and MTX transport Tamura et al. (2006) N590Y Did not effect Hemato and MTX transport Tamura et al. (2006) C592A Impaired function and expression Henriksen et al. (2005b) C592A/C608A Restored plasma mb expression; MTX transport normal, BODIPY-prazosin impaired Henriksen et al. (2005b) C603A Disulfide bridge; no functional or membrane targeting change Henriksen et al. (2005b) C608A Impaired function and expression Henriksen et al. (2005b) D620N Did not effect Hemato and MTX transport Tamura et al. (2006) H630X No change in transport Miwa et al. (2003) Cand N-terminal truncated Impaired trafficing Takada et al. (2005) with the ligand. Login to comment

[hide] Drug-induced phototoxicity evoked by inhibition of... Expert Opin Drug Metab Toxicol. 2008 Mar;4(3):255-72. Tamura A, An R, Hagiya Y, Hoshijima K, Yoshida T, Mikuriya K, Ishikawa T
Drug-induced phototoxicity evoked by inhibition of human ABC transporter ABCG2: development of in vitro high-speed screening systems.
Expert Opin Drug Metab Toxicol. 2008 Mar;4(3):255-72., [PMID:18363541]

Abstract [show]
BACKGROUND: Photosensitivity depends on both genetic and environmental factors. Pheophorbide a, present in various plant-derived foods and food supplements, can be absorbed by the small intestine. Accumulation of pheophorbide a and porphyrins in the systemic blood circulation can result in phototoxic lesions on light-exposed skin. OBJECTIVE: As the human ATP-binding cassette (ABC) transporter ABCG2 has been suggested to be critically involved in porphyrin-mediated photosensitivity, we aimed to develop in vitro screening systems for drug-induced phototoxicity. CONCLUSION: Functional impairment owing to inhibition of ABCG2 by drugs or its genetic polymorphisms can lead to the disruption of porphyrin homeostasis. This review article provides an overview on drug-induced photosensitivity, as well as our hypothesis on a potential role of ABCG2 in phototoxicity.

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230 Plasma membrane Outside Inside ATP-binding cassette H2 N COOH V12M G51C Q126stop Q141K T153M R160Q Q166E I206L F208S S248P E334stop F431L F489L S441N R482G R482T F571I R575stop N590Y D620N T542A A528T D296H P269S A. Login to comment
231 0.0 0.1 0.2 0.3 0.4 0.5 Mock WT V12M G51C Q126stop Q141K T153M Q166E I206L F208S S248P E334stop F431L S441N F489L F571I N590Y D620N R482G R482T ATP-dependenthematoporphyrintransport (nmol/min/mgprotein) B. interactions should also take into consideration the presence of multiple flavonoids. Login to comment
245 Based on the presently available data on SNPs and acquired mutations, we have created a total of 18 variant forms of ABCG2 (V12M, G51C, Q126stop, Q141K, T153M, Q166E, I206L, F208S, S248P, E334stop, F431L, S441N, R482G, R482T, F489L, F571I, N590Y, and D620N) by site-directed mutagenesis and expressed them in insect cells. Login to comment
246 The variants Q126stop, F208S, S248P, E334stop, and S441N were defective in the transport of hematoporphyrin (Figure 9). Login to comment
252 Amino acid Porphyrin transport* Allele frequency (%)‡ cDNA position Location Wild-type allele Variant alllele V12M ++ 2.0 - 90.0 34 Exon 2 G A Q126stop - 0.0 - 1.7 376 Exon 4 C T Q141K ++ 0.0 - 35.5 421 Exon 5 C A T153M ++ 3.3 458 Exon 5 C T Q166E ++ N.D. 496 Exon 5 C G I206L ++ 10.0 616 Exon 6 A C F208S - N.D. 623 Exon 6 T C S248P - N.D. 742 Exon 7 T C E334stop - N.D. 1000 Exon 9 G T F431L ++ 0.8 1291 Exon 11 T C S441N - 0.5 1322 Exon 11 G A F489L + 0.5 - 0.8 1465 Exon 12 T C F571L ++ 0.5 1711 Exon 14 T A N590Y ++ 0.0 - 1.0 1768 Exon 15 A T D620N ++ 0.5 1858 Exon 16 G A *Transport of hematoporphyrin is indicated by either '+` (positive) or '-' (negative). Login to comment

[hide] Human ABC transporters ABCG2 (BCRP) and ABCG4. Xenobiotica. 2008 Jul;38(7-8):863-88. Koshiba S, An R, Saito H, Wakabayashi K, Tamura A, Ishikawa T
Human ABC transporters ABCG2 (BCRP) and ABCG4.
Xenobiotica. 2008 Jul;38(7-8):863-88., [PMID:18668433]

Abstract [show]
1. The human ABC transporter ABCG2 is regarded as a member of the phase III system for xenobiotic metabolism, and it has been suggested that this efflux pump is responsible for protecting the body from toxic xenobiotics and for removing metabolites. 2. This review paper will address the new aspects of ABCG2 in terms of post-translational modifications (i.e., disulfide bond formation, ubiquitination, and endoplasmic reticulum-associated degradation) of ABCG2 protein, high-speed screening, and quantitative structure-activity relationship (QSAR) analysis to evaluate ABCG2-drug interactions, and genetic polymorphisms potentially associated with photosensitivity. 3. In addition, new aspects of human ABCG4 and mouse Abcg4 are presented with respect to their molecular properties and potential physiological roles. Considering a high sequence similarity between ABCG1 and ABCG4, both Abcg4 and ABCG4 may be involved in the transport of cholesterol from neurons and astrocytes. Furthermore, high expression of the mouse Abcg4 protein in the testis implicates its involvement in transport of certain sex hormones.

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225 Based on the currently available data on SNPs and acquired mutations, a total of 18 variant forms of ABCG2 (V12M, G51C, Q126stop, Q141K, T153M, Q166E, I206L, F208S, S248P, E334stop, F431L, S441N, R482G, R482T, F489L, F571I, N590Y, and D620N) were created by site-directed mutagenesis and expressed in Sf9 insect cells (Tamura et al. 2006, 2007). Login to comment
232 S. Koshiba et al. variants Q126stop, F208S, S248P, E334stop, and S441N substantially lack transport activity for both haematoporphyrin and methotrexate. Login to comment

[hide] Major SNP (Q141K) variant of human ABC transporter... Pharm Res. 2009 Feb;26(2):469-79. Epub 2008 Oct 29. Furukawa T, Wakabayashi K, Tamura A, Nakagawa H, Morishima Y, Osawa Y, Ishikawa T
Major SNP (Q141K) variant of human ABC transporter ABCG2 undergoes lysosomal and proteasomal degradations.
Pharm Res. 2009 Feb;26(2):469-79. Epub 2008 Oct 29., [PMID:18958403]

Abstract [show]
PURPOSE: Single nucleotide polymorphisms (SNPs) of the ATP-binding cassette (ABC) transporter ABCG2 gene have been suggested to be a significant factor in patients' responses to medication and/or the risk of diseases. We aimed to evaluate the impact of the major non-synonymous SNP Q141K on lysosomal and proteasomal degradations. METHODS: ABCG2 WT and the Q141K variant were expressed in Flp-In-293 cells by using the Flp recombinase system. Their expression levels and cellular localization was measured by immunoblotting and immunofluorescence microscopy, respectively. RESULTS: The protein level of the Q141K variant expressed in Flp-In-293 cells was about half that of ABCG2 WT, while their mRNA levels were equal. The protein expression level of the Q141K variant increased about two-fold when Flp-In-293 cells were treated with MG132. In contrast, the protein level of ABCG2 WT was little affected by the same treatment. After treatment with bafilomycin A1, the protein levels of ABCG2 WT and Q141K increased 5- and 2-fold in Flp-In-293 cells, respectively. CONCLUSIONS: The results strongly suggest that the major non-synonymous SNP Q141K affects the stability of the ABCG2 protein in the endoplasmic reticulum and enhances its susceptibility to ubiquitin-mediated proteasomal degradation.

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174 The nonsynonymous SNP variants of Q126stop, F208S, S248P, E334stop, S441N, and F489L were defective in the active transport of methotrexate and hematoporphyrin (42). Login to comment

[hide] Functions of the breast cancer resistance protein ... Adv Drug Deliv Rev. 2009 Jan 31;61(1):26-33. Epub 2008 Dec 3. Noguchi K, Katayama K, Mitsuhashi J, Sugimoto Y
Functions of the breast cancer resistance protein (BCRP/ABCG2) in chemotherapy.
Adv Drug Deliv Rev. 2009 Jan 31;61(1):26-33. Epub 2008 Dec 3., 2009-01-31 [PMID:19111841]

Abstract [show]
The breast cancer resistance protein, BCRP/ABCG2, is a half-molecule ATP-binding cassette transporter that facilitates the efflux of various anticancer agents from the cell, including 7-ethyl-10-hydroxycamptothecin, topotecan and mitoxantrone. The expression of BCRP can thus confer a multidrug resistance phenotype in cancer cells, and its transporter activity is involved in the in vivo efficacy of chemotherapeutic agents. Thus, the elucidation of the substrate preferences and structural relationships of BCRP is essential to understanding its in vivo functions during chemotherapeutic treatments. Single nucleotide polymorphisms (SNPs) have also been found to be key factors in determining the efficacy of chemotherapeutics, and those therapeutics that inhibit BCRP activity, such as the SNP that results in a C421A mutant, may result in unexpected side effects of the BCRP- anticancer drugs interaction even at normal dosages. In order to modulate the BCRP activity during chemotherapy, various compounds have been tested as inhibitors of this protein. Estrogenic compounds including estrone, several tamoxifen derivatives in addition to phytoestrogens and flavonoids have been shown to reverse BCRP-mediated drug resistance. Intriguingly, recently developed molecular targeted cancer drugs, such as the tyrosine kinase inhibitors imatinib mesylate, gefitinib and others, can also interact with BCRP. Since both functional SNPs and inhibitory agents of BCRP modulate the in vivo pharmacokinetics and pharmacodynamics of its substrate drugs, BCRP activity is an important consideration in the development of molecular targeted chemotherapeutics.

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228 C376T (Q126stop)-BCRP SNP . Login to comment
865 C376T (Q126stop)-BCRP SNP We have identified another SNP within the BCRP gene, C376T, which substitutes a stop codon for Gln-126 (Q126stop) and is present at a low frequency in samples from healthy Japanese individuals as a heterozygote (reported frequencies of 3/124 and 2/120 in two studies, respectively) [54,60]. Login to comment
874 Among these SNPs, with the exception of C376T and C421A, only a few have been studied Table 1 Identified SNPs within the BCRP gene Variation Effect Domain A-1379G - Δ-654/-651 - G-286C - T-476C - Δ-235A - A-113G - A-29G - G34A V12M N-terminal T114C No change N-terminal G151T G51C N-terminal C369T No change NBD C376T Q126stop NBD C421A Q141K NBD C458T T153M NBD C474T No change NBD C496G Q166E NBD A564G No change NBD A616C I206L NBD T623C F208S NBD T742C S248P Linker G1000T E334stop Linker G1098A No change Linker T1291C F431L TMD A1425G No change TMD T1465C F489L TMD A1768T N590Y TMD G1858A D620N TMD G2237T - G2393T - NBD, nucleotide-binding domain; TMD, transmembrane domain. Login to comment

[hide] Quality control of human ABCG2 protein in the endo... Adv Drug Deliv Rev. 2009 Jan 31;61(1):66-72. Epub 2008 Dec 11. Wakabayashi-Nakao K, Tamura A, Furukawa T, Nakagawa H, Ishikawa T
Quality control of human ABCG2 protein in the endoplasmic reticulum: ubiquitination and proteasomal degradation.
Adv Drug Deliv Rev. 2009 Jan 31;61(1):66-72. Epub 2008 Dec 11., 2009-01-31 [PMID:19111842]

Abstract [show]
Human ATP-binding cassette (ABC) transporter ABCG2 (BCRP/MXR/ABCP) is a plasma membrane protein carrying intra- and inter-molecular disulfide bonds and an N-linked glycan. Both disulfide bond formation and N-glycosylation are critical check points determining the stability and degradation fate of ABCG2 protein in the endoplasmic reticulum (ER). Misfolded ABCG2 protein without those post-translational modifications is removed from the ER by retrotranslocation to the cytosol compartment, ubiquitination by ubiquitin ligase, and finally degradation by proteasomes. Certain non-synonymous SNP variants of ABCG2 undergo such ER-associated degradation (ERAD).

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950 The non-synonymous SNP variants Q126stop, F208S, S248P, E334stop, S441N, and F489L were defective in the active transport of methotrexate and hematoporphyrin [54]. Login to comment

[hide] Additive effects of drug transporter genetic polym... Cancer Chemother Pharmacol. 2010 May;66(1):95-105. Epub 2009 Sep 22. Sai K, Saito Y, Maekawa K, Kim SR, Kaniwa N, Nishimaki-Mogami T, Sawada J, Shirao K, Hamaguchi T, Yamamoto N, Kunitoh H, Ohe Y, Yamada Y, Tamura T, Yoshida T, Matsumura Y, Ohtsu A, Saijo N, Minami H
Additive effects of drug transporter genetic polymorphisms on irinotecan pharmacokinetics/pharmacodynamics in Japanese cancer patients.
Cancer Chemother Pharmacol. 2010 May;66(1):95-105. Epub 2009 Sep 22., [PMID:19771428]

Abstract [show]
PURPOSE: Effects of genetic polymorphisms/variations of ABCB1, ABCC2, ABCG2 and SLCO1B1 in addition to "UGT1A1*28 or *6" on irinotecan pharmacokinetics/pharmacodynamics in Japanese cancer patients were investigated. METHODS: Associations between transporter haplotypes/variations along with UGT1A1*28 or *6 and SN-38 area under the time-concentration curve (AUC) or neutropenia were examined in irinotecan monotherapy (55 patients) and irinotecan-cisplatin-combination therapy (62 patients). RESULTS: Higher SN-38 AUC values were observed in ABCB1 2677G>T (A893S) (*2 group) for both regimens. Associations of grade 3/4 neutropenia were observed with ABCC2 -1774delG (*1A), ABCG2 421C>A (Q141K) and IVS12 + 49G>T ((#) IIB) and SLCO1B1 521T>C (V174A) (*15 x 17) in the irinotecan monotherapy, while they were evident only in homozygotes of ABCB1*2, ABCG2 (#) IIB, SLCO1B1*15 x 17 in the cisplatin-combination therapy. With combinations of haplotypes/variations of two or more genes, neutropenia incidence increased, but their prediction power for grade 3/4 neutropenia is still unsatisfactory. CONCLUSIONS: Certain transporter genotypes additively increased irinotecan-induced neutropenia, but their clinical importance should be further elucidated.

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107 These variations include an amino acid substitution leading to reduced in vitro activity, ABCG2 1465T[C (F489L) [36], and the stop codons, ABCG2 376C[T (Q126X) and 1723C[T (R575X) [28]. Login to comment
118 It was noted that the additive effect of g1 [ABCG2 376C[T (Q126X)] was not observed in the heterozygotes (g1/-), but was evident in the compound heterozygotes with another ABCG2 genetic polymorphism, # IIB, (G/g1) (Fig. 2a, b). Login to comment
124 patients who experienced grade 4 neutropenia ID Gene Genetic variation Nucleotide change (amino acid substitution) Haplotypea b1 ABCB1 304G[C (G102R) Block 1 *3 b2(B)b 1804G[A (D602N) Block 2 *12 b3(B)b 1342G[A (E448K) Block 2 *14 b4 3043A[G (T1015A) Block 2 *16 b5 3751G[A (V1251I) Block 3 *2 c1 ABCC2 1177C[T (R393W) *7 g1 ABCG2 376C[T (Q126X) Block 1 *4 g2 1465T[C (F489L) Block 2 *2 g3 1723C[T (R575X) Block 2 *5 s1(S)c SLCO1B1 1007C[G (P336R) s2 311T[A (M104K) u1 UGT1A1 -3279T[G, 1941C[G # 60-# IB (?/?) Login to comment

[hide] Human ABC transporter ABCG2 in cancer chemotherapy... J Exp Ther Oncol. 2009;8(1):5-24. Ishikawa T, Nakagawa H
Human ABC transporter ABCG2 in cancer chemotherapy and pharmacogenomics.
J Exp Ther Oncol. 2009;8(1):5-24., [PMID:19827267]

Abstract [show]
The ability of cancer cells to acquire resistance to multiple anticancer agents, termed multidrug resistance, is often mediated by overexpression of ATP-binding cassette (ABC) transporters that remove drugs out of the cell against a concentration gradient. ABCG2, or breast cancer resistance protein (BCRP), is an ABC transporter that has been the subject of intense study since its discovery a decade ago. While ABCG2 overexpression has been demonstrated in cancer cells after in vitro drug treatment, endogenous ABCG2 expression in certain cancers is considered as a reflection of the differentiated phenotype of the cell of origin and likely contributes to intrinsic drug resistance. Notably, ABCG2 is often expressed in stem cell populations, where it plays a critical role in cellular protection. ABCG2 exhibits a broad range of substrate specificity. New technologies of high-speed screening and quantitative structure-activity-relationship (QSAR) analysis have been developed to analyze the interactions of drugs with ABCG2. As ABCG2 reportedly transports porphyrins, its contribution to photodynamic therapy of human cancer is also implicated. Protein expression levels of ABCG2 in cancer cells are regulated by both transcriptional activation and protein degradation. The ABCG2 protein undergoes endosomal and/or ubiquitin-mediated proteasomal degradations. Furthermore, genetic polymorphisms in the ABCG2 gene are important factors in cancer chemotherapy to circumvent adverse effects and/or to enhance the efficacy of anticancer drugs. The present review article addresses recent advances in molecular pharmacology and pharmacogenomics of ABCG2 and provides novelideas to improve cancer chemotherapy.

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222 COOH H2N N590Y V12M G51C Q126stop Q141K T153M Q166E I206L F208S S248P E334stop F431L F489L D620N R482G R482T S441N F571I OUT IN R160Q R575stop ATP-binding site Figure 7. Continued A 005-024 pp JETO-0900616-TI (Review).indd 8/7/2009 3:59:50 19 Q141K has been associated with lower levels of protein expression and impaired transport in vitro (Imai et al., 2002; Kobayashi et al., 2005; Misuarai et al., 2004; Zamber et al., 2003; Morisaki et al., 2008; Kondo et al., 2004). Login to comment
227 The non-synonymous SNP variants Q126stop, F208S, S248P, E334stop, S441N, and F489L were defective in the active transport of methotrexate and hematoporphyrin (Tamura et al., 2006) (Fig. 7C). Login to comment
232 It is known that, in the ER, the N-linked glycans play pivotal roles in protein fold- 0.0 0.5 1.0 1.5 Mock WT V12M G51C Q126stop Q141K T153M Q166E I206L F208S S248P E334stop F431L S441N F489L F571I N590Y D620N R482G R482T Methotrexatetransport (nmol/min/mgprotein) Methotrexate 0.0 0.5 1.0 1.5 0.0 0.5 1.0 1.5 Mock WT V12M G51C Q126stop Q141K T153M Q166E I206L F208S S248P E334stop F431L S441N F489L F571I N590Y D620N R482G R482T Methotrexatetransport (nmol/min/mgprotein) MethotrexateMethotrexate Porphyrintransport (nmol/min/mgprotein) 0.0 0.1 0.2 0.3 0.4 0.5 0.0 0.1 0.2 0.3 0.4 0.5 Porphyrin Figure 7. Login to comment

[hide] Pharmacogenetics of ATP-binding cassette transport... Methods Mol Biol. 2010;596:95-121. Cascorbi I, Haenisch S
Pharmacogenetics of ATP-binding cassette transporters and clinical implications.
Methods Mol Biol. 2010;596:95-121., [PMID:19949922]

Abstract [show]
Drug resistance is a severe limitation of chemotherapy of various malignancies. In particular efflux transporters of the ATP-binding cassette family such as ABCB1 (P-glycoprotein), the ABCC (multidrug resistance-associated protein) family, and ABCG2 (breast cancer resistance protein) have been identified as major determinants of chemoresistance in tumor cells. Bioavailability depends not only on the activity of drug metabolizing enzymes but also to a major extent on the activity of drug transport across biomembranes. They are expressed in the apical membranes of many barrier tissues such as the intestine, liver, blood-brain barrier, kidney, placenta, testis, and in lymphocytes, thus contributing to plasma, liquor, but also intracellular drug disposition. Since expression and function exhibit a broad variability, it was hypothesized that hereditary variances in the genes of membrane transporters could explain at least in part interindividual differences of pharmacokinetics of a variety of anticancer drugs and many others contributing to the clinical outcome of certain leukemias and further malignancies.

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242 0.005 c. 376 C>T Q126stop 0.01 0.00a 0.00b Lack of function c. 421 C>A Q141K 0.35 0.11a 0.02b Reduced activity [120, 124, 137] IVS 5 -16 A>G ? Login to comment

[hide] What lies behind serum urate concentration? Insigh... Genome Med. 2009 Dec 29;1(12):118. Ichida K
What lies behind serum urate concentration? Insights from genetic and genomic studies.
Genome Med. 2009 Dec 29;1(12):118., [PMID:20090896]

Abstract [show]
Many factors, including genetic components and acquired factors such as obesity and alcohol consumption, influence serum uric acid (urate) concentrations. Since serum urate concentrations are determined by the balance between renal urate excretion and the volume of urate produced via purine metabolism, urate transporter genes as well as genes coding for enzymes involved in purine metabolism affect serum urate concentrations. URAT1 was the first transporter affecting serum urate concentrations to be identified. Using the characterization of this transporter as an indicator, several transporters have been shown to transport urate, allowing the construction of a synoptic renal urate transport model. Notable re-absorptive urate transporters are URAT1 at apical membranes and GLUT9 at basolateral membranes, while ABCG2, MRP4 (multidrug resistance protein 4) and NPT1 are secretive transporters at apical membranes. Recent genome-wide association studies have led to validation of the in vitro model constructed from each functional analysis of urate transporters, and identification of novel candidate genes related to urate metabolism and transport proteins, such as glucokinase regulatory protein (GKRP), PDZK1 and MCT9. However, the function and physiologic roles of several candidates, as well as the influence of acquired factors such as obesity, foods, or alcoholic beverages, remain unclear.

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91 Q126X shows stronger effects on gout development than Q141K, conferring an odds ratio of 5.97 [44]. Login to comment

[hide] The rs2231142 variant of the ABCG2 gene is associa... Rheumatology (Oxford). 2010 Aug;49(8):1461-5. Epub 2010 Apr 25. Yamagishi K, Tanigawa T, Kitamura A, Kottgen A, Folsom AR, Iso H
The rs2231142 variant of the ABCG2 gene is associated with uric acid levels and gout among Japanese people.
Rheumatology (Oxford). 2010 Aug;49(8):1461-5. Epub 2010 Apr 25., [PMID:20421215]

Abstract [show]
OBJECTIVES: Recent genome-wide association and functional studies have shown that the ABCG2 gene encodes for a urate transporter, and a common causal ABCG2 variant, rs2231142, leads to elevated uric acid levels and prevalent gout among Whites and Blacks. We examined whether this finding is observed in a Japanese population, since Asians have a high reported prevalence of the T-risk allele. METHODS: A total of 3923 Japanese people from the Circulatory Risk in Communities Study aged 40-90 years were genotyped for rs2231142. Associations of the rs2231142 variant with serum uric acid levels and prevalence of gout and hyperuricaemia were examined. RESULTS: The frequency of the T-risk allele was 31% in this Japanese sample. Multivariable adjusted mean uric acid levels were 7-9 micromol/l higher for TG and TT than GG carriers (P-additive = 0.0006). The multivariable-adjusted odds ratio (OR) of prevalent gout was 1.37 (95% CI 0.68, 2.76) for TG and 4.37 (95% CI 1.98, 9.62) for TT compared with the GG carriers (P-additive = 0.001). When evaluating the combined outcome of hyperuricaemia and gout, the respective ORs were 1.40 (95% CI 1.04, 1.87) for TG and 1.88 (95% CI 1.23, 2.89) for TT carriers. The population attributable risk was 29% for gout and 19% for gout and/or hyperuricaemia. CONCLUSIONS: The association of the causal ABCG2 rs2231142 variant with uric acid levels and gout was confirmed in a sample of Japanese ancestry. Our study emphasizes the importance of this common causal variant in a population with a high risk allele frequency, especially as more Japanese adopt a Western lifestyle with a concomitant increase in mean serum uric acid levels.

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86 A recent functional and association study of Japanese people [8] has identified another causal SNP of ABCG2, Q126X, with less frequency of minor allele (1.8% among control), but stronger effect on gout/hyperuricaemia than presently analysed ABCG2 (Q141K). Login to comment

[hide] A 'complexity' of urate transporters. Kidney Int. 2010 Sep;78(5):446-52. Epub 2010 Jul 7. Wright AF, Rudan I, Hastie ND, Campbell H
A 'complexity' of urate transporters.
Kidney Int. 2010 Sep;78(5):446-52. Epub 2010 Jul 7., [PMID:20613716]

Abstract [show]
Genetic variation in the SLC2A9 gene is a new genetic risk factor for low fractional excretion of uric acid, hyperuricemia, and gout. Its gene product, GLUT9, was previously known as a type II glucose/fructose transporter but is now known to function as a high-capacity uric acid transporter that is expressed in kidney, liver, and several other tissues. Follow-up meta-analyses, including one with data from 28,141 individuals, implicated a total of nine additional loci influencing serum urate concentrations, including six other membrane transporters (SLC17A1, SLC17A3, SLC22A11, SLC22A12, SLC16A9, and ABCG2). Variants in these genes together account for about 5% of the variance in serum urate, two-thirds of which is due to SLC2A9. Using these variants in 'Mendelian randomization' analyses provides a powerful means of dissecting the role of urate in cardiovascular and metabolic diseases, where cause-and-effect influences are difficult to discern due to potential confounding. The results highlight the complex interplay of membrane transporters involved in urate metabolism. They also show how variants of weak effect identified by genome-wide association studies can still be important in identifying novel pathways, including a 'complexity' of new and potentially druggable targets for modifying urate transport.

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36 Other loss-of-function variants have been identified in the Japanese population (for example, Q126X in 5% of Japanese) so that variants at the ABCG2 locus have been estimated to account for about 10% of gout cases in both Caucasian and Japanese populations.21,22 The equivalent 'population attributable risk`-the proportional reduction in disease incidence if the associated variants could be removed from the population- for SLC2A9 is 55% of gout cases, because a very common SLC2A9 allele (frequency B77%) is associated with raised serum urate and the odds ratio for gout is similar to ABCG2, at 1.4 per allele.8 Population attributable risk figures are multiplicative, so that the combined reduction in gout due to these two loci would be 41% (0.9 Â 0.45). Login to comment

[hide] Structure and function of the human breast cancer ... Curr Drug Metab. 2010 Sep;11(7):603-17. Ni Z, Bikadi Z, Rosenberg MF, Mao Q
Structure and function of the human breast cancer resistance protein (BCRP/ABCG2).
Curr Drug Metab. 2010 Sep;11(7):603-17., [PMID:20812902]

Abstract [show]
The human breast cancer resistance protein (BCRP/ABCG2) is the second member of the G subfamily of the large ATP-binding cassette (ABC) transporter superfamily. BCRP was initially discovered in multidrug resistant breast cancer cell lines where it confers resistance to chemotherapeutic agents such as mitoxantrone, topotecan and methotrexate by extruding these compounds out of the cell. BCRP is capable of transporting non-chemotherapy drugs and xenobiotiocs as well, including nitrofurantoin, prazosin, glyburide, and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine. BCRP is frequently detected at high levels in stem cells, likely providing xenobiotic protection. BCRP is also highly expressed in normal human tissues including the small intestine, liver, brain endothelium, and placenta. Therefore, BCRP has been increasingly recognized for its important role in the absorption, elimination, and tissue distribution of drugs and xenobiotics. At present, little is known about the transport mechanism of BCRP, particularly how it recognizes and transports a large number of structurally and chemically unrelated drugs and xenobiotics. Here, we review current knowledge of structure and function of this medically important ABC efflux drug transporter.

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249 A systematic study of 18 natural variants of BCRP expressed in insect cells showed that the variants Q126stop, F208S, S248P, E334stop, and S441N were defective in porphyrin transport, whereas F489L displayed approximately 10% of the transport activity of wild-type BCRP [120]. Login to comment

[hide] A strong role for the ABCG2 gene in susceptibility... Hum Mol Genet. 2010 Dec 15;19(24):4813-9. Epub 2010 Sep 21. Phipps-Green AJ, Hollis-Moffatt JE, Dalbeth N, Merriman ME, Topless R, Gow PJ, Harrison AA, Highton J, Jones PB, Stamp LK, Merriman TR
A strong role for the ABCG2 gene in susceptibility to gout in New Zealand Pacific Island and Caucasian, but not Maori, case and control sample sets.
Hum Mol Genet. 2010 Dec 15;19(24):4813-9. Epub 2010 Sep 21., 2010-12-15 [PMID:20858603]

Abstract [show]
Genetic variation in ABCG2 (rs2231142, Q141K), encoding a uric acid transporter, is associated with gout in diverse populations. The aim of this study was to examine a role for ABCG2 in gout susceptibility in New Zealand Maori, Pacific Island and Caucasian samples. Patients (n = 185, 173 and 214, for Maori, Pacific Island and Caucasian, respectively) satisfied the American College of Rheumatology gout classification criteria. The comparison samples comprised 284, 129 and 562 individuals, respectively, without gout. rs2231142 was genotyped and stratification accounted for using genomic control markers. Association of the minor allele of rs2231142 with gout was observed in the Pacific Island samples (OR = 2.80, P(STRAT) < 0.001 after accounting for effects of population structure), but not in the Maori samples (OR = 1.08, P(STRAT)= 0.70), with heterogeneity in association evident between the Maori and Pacific Island datasets (P(HET) = 0.001). A similar dichotomy in association was observed when samples were stratified into Western (Tonga, Samoa, Niue, Tokelau) versus Eastern Polynesian (Maori, Cook Island) origin (OR = 2.59, P(STRAT) < 0.001; OR = 1.12, P(STRAT)= 0.48, respectively; P(HET) = 0.005). Association with gout was observed in the Caucasian samples (OR = 2.20, P = 3.2 x 10(-8)). Unlike SLC2A9, which is a strong risk factor for gout in both Maori and Pacific Island people, ABCG2 rs2231142 has a strong effect only in people of Western Polynesian ancestry. Our results emphasize the need to account for sub-population differences when undertaking biomedical genetic research in a group defined by a geographical region and shared ancestry but characterized by migratory events that create bottlenecks and altered genetic structure in the founder populations.

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108 However, this needs to be confirmed by re-sequencing ABCG2 in this population group and genotyping all variants in gout cases and controls, in a fashion analogous to that done previously in a Japanese sample set (9), in which a genetically independent variant (Q126X; rs72552713) also confers risk to gout (OR ¼ 4.25). Login to comment

[hide] In vitro and in vivo evidence for the importance o... Handb Exp Pharmacol. 2011;(201):325-71. Meyer zu Schwabedissen HE, Kroemer HK
In vitro and in vivo evidence for the importance of breast cancer resistance protein transporters (BCRP/MXR/ABCP/ABCG2).
Handb Exp Pharmacol. 2011;(201):325-71., [PMID:21103975]

Abstract [show]
The breast cancer resistance protein (BCRP/ABCG2) is a member of the G-subfamiliy of the ATP-binding cassette (ABC)-transporter superfamily. This half-transporter is assumed to function as an important mechanism limiting cellular accumulation of various compounds. In context of its tissue distribution with localization in the sinusoidal membrane of hepatocytes, and in the apical membrane of enterocytes ABCG2 is assumed to function as an important mechanism facilitating hepatobiliary excretion and limiting oral bioavailability, respectively. Indeed functional assessment performing mouse studies with genetic deletion or chemical inhibition of the transporter, or performing pharmacogenetic studies in humans support this assumption. Furthermore the efflux function of ABCG2 has been linked to sanctuary blood tissue barriers as described for placenta and the central nervous system. However, in lactating mammary glands ABCG2 increases the transfer of substrates into milk thereby increasing the exposure to potential noxes of a breastfed newborn. With regard to its broad substrate spectrum including various anticancer drugs and environmental carcinogens the function of ABCG2 has been associated with multidrug resistance and tumor development/progression. In terms of cancer biology current research is focusing on the expression and function of ABCG2 in immature stem cells. Recent findings support the notion that the physiological function of ABCG2 is involved in the elimination of uric acid resulting in higher risk for developing gout in male patients harboring genetic variants. Taken together ABCG2 is implicated in various pathophysiological and pharmacological processes.

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251 To date there are 26 nonsynonymous, five synonymous (c.114T>C, c.369C>T, c.474C>T, c.1098G>A, and c.1425A>G) polymorphisms, three nonsense mutations (Q126X, E334X, and R575X), and one frameshift mutation (c.1515delC) described in healthy individuals or patients (compare Table 3). Login to comment

[hide] Key Role of Human ABC Transporter ABCG2 in Photody... Adv Pharmacol Sci. 2010;2010:587306. Epub 2010 Jul 8. Ishikawa T, Nakagawa H, Hagiya Y, Nonoguchi N, Miyatake S, Kuroiwa T
Key Role of Human ABC Transporter ABCG2 in Photodynamic Therapy and Photodynamic Diagnosis.
Adv Pharmacol Sci. 2010;2010:587306. Epub 2010 Jul 8., [PMID:21188243]

Abstract [show]
Accumulating evidence indicates that ATP-binding cassette (ABC) transporter ABCG2 plays a key role in regulating the cellular accumulation of porphyrin derivatives in cancer cells and thereby affects the efficacy of photodynamic therapy and photodynamic diagnosis. The activity of porphyrin efflux can be affected by genetic polymorphisms in the ABCG2 gene. On the other hand, Nrf2, an NF-E2-related transcription factor, has been shown to be involved in oxidative stress-mediated induction of the ABCG2 gene. Since patients have demonstrated individual differences in their response to photodynamic therapy, transcriptional activation and/or genetic polymorphisms of the ABCG2 gene in cancer cells may affect patients' responses to photodynamic therapy. Protein kinase inhibitors, including imatinib mesylate and gefitinib, are suggested to potentially enhance the efficacy of photodynamic therapy by blocking ABCG2-mediated porphyrin efflux from cancer cells. This review article provides an overview on the role of human ABC transporter ABCG2 in photodynamic therapy and photodynamic diagnosis.

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167 Based on the currently available data on SNPs and acquired mutations, we have created a total of 18 variant forms of ABCG2 (V12M, G51C, Q126stop, Q141K, T153M, Q166E, I206L, F208S, S248P, E334stop, F431L, S441N, R482G, R482T, F489L, F571I, N590Y, and D620N) by site-directed mutagenesis and expressed them in insect cells [41, 90]. Login to comment
168 The variants Q126stop, F208S, S248P, E334stop, and S441N are defective in the transport of hematoporphyrin (Figure 4(b)). Login to comment
177 Gefitinib and imatinib are new anticancer drugs Outside Plasma membrane Inside H2N COOH V12M G51C Q126stop Q141K T153M R160Q Q166E I206L F208S S248P E334stop F431L F489L S441N R482G R482T F571I R575stop N590Y D620N T542A A528T D296H P269S ATP-binding cassette (a) 0 0.1 0.3 0.4 0.2 0.5 Mock WT V12M G51C Q126stop Q141K T153M Q166E I206L F208S S248P E334stop F431L S441N F489L F571I N590Y D620N R482G R482T ATP-dependenthematoporphyrin transport(nmol/min/mgprotein) (b) Figure 4: (a) Schematic illustration of human ABCG2 and its nonsynonymous polymorphisms. Login to comment

[hide] Significant association of serum uric acid levels ... Mol Genet Metab. 2011 Aug;103(4):378-82. Epub 2011 Apr 8. Hamajima N, Okada R, Kawai S, Hishida A, Morita E, Yin G, Wakai K, Matsuo H, Inoue H, Takada Y, Asai Y, Mori A, Naito M
Significant association of serum uric acid levels with SLC2A9 rs11722228 among a Japanese population.
Mol Genet Metab. 2011 Aug;103(4):378-82. Epub 2011 Apr 8., [PMID:21511506]

Abstract [show]
Genome-wide association studies identified that SLC2A9 (GLUT9) gene polymorphisms were associated with serum uric acid (SUA) levels. Among the Japanese, a C/T polymorphism in intron 8 (rs11722228) was reported to be highly significant, though the function and strength of association were unknown. This study aimed to confirm the association, estimating the means of SUA according to the genotype, as well as OR of the genotype. Subjects were 5024 health checkup examinees (3413 males and 1611 females) aged 35 to 69 years with creatinine <2.0 mg/dL. Since SLC22A12 258X allele and ABCG2 126X allele are known to influence SUA levels strongly, the subjects with SLC22A12 258WW and ABCG2 126QQ (3082 males and 1453 females, in total 4535 subjects) were selected. The genotype frequency of SLC2A9 rs11722228 was 2184 for CC, 1947 for CT, and 404 for TT, being in Hardy-Weinberg equilibrium (p=0.312). Mean SUA was 6.10 mg/dL for CC, 6.25 mg/dL for CT, and 6.45 mg/dL for TT among males (p=1.5E-6), and 4.34 mg/dL, 4.59 mg/dL, and 4.87 mg/dL among females (p=4.6E-11), respectively. Males with SUA less than 5.0 mg/dL were 14.7% for CC, 10.6% for CT, and 7.8% for TT (p=2.3E-4), and females with SUA less than 4.0 mg/dL were 34.1%, 25.5%, and 15.4% (p=3.7E-6), respectively. This study was the first report to estimate the impact of SLC2A9 rs11722228 on SUA levels. Since the allele frequency of rs11722228 is similar among different ethnic groups, the impact remains to be examined in other ethnic groups.

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0 Significant association of serum uric acid levels with SLC2A9 rs11722228 among a Japanese population Nobuyuki Hamajima a, ⁎, Rieko Okada a , Sayo Kawai a , Asahi Hishida a , Emi Morita a , Guang Yin a , Kenji Wakai a , Hirotaka Matsuo b , Hiroki Inoue b , Yuzo Takada c , Yatami Asai d , Atsuyoshi Mori d , Mariko Naito a a Department of Preventive Medicine, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan b Department of Integrative Physiology and Bio-Nano Medicine, National Defense Medical College, Saitama 359-8513, Japan c Laboratory for Biofunctions, the Central Research Institute, National Defense Medical College, Saitama 359-8513, Japan d Seirei Social Welfare Community, Hamamatsu 433-8558, Japan a b s t r a c ta r t i c l e i n f o Article history: Received 8 March 2011 Received in revised form 3 April 2011 Accepted 3 April 2011 Available online xxxx Keywords: Serum uric acid SLC2A9 rs11722228 ABCG2 Q126X SLC22A12 W258X Polymerase chain reaction with confronting two-pair primers Hypouricemia Genome-wide association studies identified that SLC2A9 (GLUT9) gene polymorphisms were associated with serum uric acid (SUA) levels. Login to comment
13 ATP-binding cassette subfamily G member 2 (ABCG2) gene in chromosome 4q22, coding a uric acid transporter, has a functional polymorphism, Q126X (rs72552713), which was reported to reduce transportation activity, resulting in hyperuricemia [1-3]. Login to comment
52 ABCG2 Q126X and SLC22A12 W258X were genotyped as described in the previous papers [2,18]. Login to comment
65 Among them, examinees with SLC22A12 258X (230 individuals), ABCG2 126X (250 individuals), and/or not genotyped (one for SLC22A12 W258X and thirteen for ABCG2 Q126X) were excluded from the analysis, and 4535 subjects (3082 males and 1453 females) with SLC22A12 258WW and ABCG2 126QQ remained. Login to comment
49 ABCG2 Q126X and SLC22A12 W258X were genotyped as described in the previous papers [2,18]. Login to comment
62 Among them, examinees with SLC22A12 258X (230 individuals), ABCG2 126X (250 individuals), and/or not genotyped (one for SLC22A12 W258X and thirteen for ABCG2 Q126X) were excluded from the analysis, and 4535 subjects (3082 males and 1453 females) with SLC22A12 258WW and ABCG2 126QQ remained. Login to comment

[hide] Genetic polymorphisms of uptake (OATP1B1, 1B3) and... Expert Opin Drug Metab Toxicol. 2009 Jul;5(7):703-29. Ieiri I, Higuchi S, Sugiyama Y
Genetic polymorphisms of uptake (OATP1B1, 1B3) and efflux (MRP2, BCRP) transporters: implications for inter-individual differences in the pharmacokinetics and pharmacodynamics of statins and other clinically relevant drugs.
Expert Opin Drug Metab Toxicol. 2009 Jul;5(7):703-29., [PMID:19442037]

Abstract [show]
Recent pharmacogenomic/pharmacogenetic studies have disclosed important roles of drug transporters in the pharmacokinetic/pharmacodynamic (PK/PD) profiles of some clinically relevant drugs. It has concurrently been explained that variations in the drug transporter genes are associated with not only inter-individual but also inter-ethnic differences in PK/PD profiles of these drugs. This review focuses on two uptake and two efflux transporters. Organic anion transporting polypeptide (OATP) 1B1 and OATP1B3 are uptake transporters, specifically expressed in the liver, and considered important for drugs, particularly as their pharmacological target organ is the liver. Two ATP-binding cassette transporters, multi-drug resistance-associated protein 2 and breast cancer resistance protein, are efflux transporters, expressed in various human tissues, and considered particularly important for intestinal drug absorption and hepatic drug elimination. All 3-hydroxyl-3-methylglutaryl-CoA reductase inhibitors (statins) except fluvastatin are substrates for OATP1B1, but hepatobiliary (canalicular) efflux transporters differ among statins. In this review, we update the pharmacogenomic/pharmacogenetic properties of these transporters and their effects on PK/PD profiles of statins and other clinically relevant drugs. In addition, we describe a physiologically-based pharmacokinetic model for predicting the effects of changes in transporter activities on systemic and hepatic exposure to pravastatin.

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546 Kim HS, Sunwoo YE, Ryu JY, et al. The effect of ABCG2 V12M, Q141K and Q126X, known functional variants in vitro, on the disposition of lamivudine. Login to comment

[hide] Intestinal transporters for endogenic and pharmace... J Pharm Pharmacol. 2012 Nov;64(11):1523-48. doi: 10.1111/j.2042-7158.2012.01505.x. Epub 2012 Mar 30. Grandvuinet AS, Vestergaard HT, Rapin N, Steffansen B
Intestinal transporters for endogenic and pharmaceutical organic anions: the challenges of deriving in-vitro kinetic parameters for the prediction of clinically relevant drug-drug interactions.
J Pharm Pharmacol. 2012 Nov;64(11):1523-48. doi: 10.1111/j.2042-7158.2012.01505.x. Epub 2012 Mar 30., [PMID:23058041]

Abstract [show]
Objectives This review provides an overview of intestinal human transporters for organic anions and stresses the need for standardization of the various in-vitro methods presently employed in drug-drug interaction (DDI) investigations. Key findings Current knowledge on the intestinal expression of the apical sodium-dependent bile acid transporter (ASBT), the breast cancer resistance protein (BCRP), the monocarboxylate transporters (MCT) 1, MCT3-5, the multidrug resistance associated proteins (MRP) 1-6, the organic anion transporting polypetides (OATP) 2B1, 1A2, 3A1 and 4A1, and the organic solute transporter alpha/beta (OSTalpha/beta) has been covered along with an overview of their substrates and inhibitors. Furthermore, the many challenges in predicting clinically relevant DDIs from in-vitro studies have been discussed with focus on intestinal transporters and the various methods for deducting in-vitro parameters for transporters (K(m) /K(i) /IC50, efflux ratio). The applicability of using a cut-off value (estimated based on the intestinal drug concentration divided by the K(i) or IC50) has also been considered. Summary A re-evaluation of the current approaches for the prediction of DDIs is necessary when considering the involvement of other transporters than P-glycoprotein. Moreover, the interplay between various processes that a drug is subject to in-vivo such as translocation by several transporters and dissolution should be considered.

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517 Kim HS et al. The effect of ABCG2 V12M, Q141K and Q126X, known functional variants in vitro, on the disposition of lamivudine. Login to comment

[hide] The genetics of hyperuricaemia and gout. Nat Rev Rheumatol. 2012 Oct;8(10):610-21. doi: 10.1038/nrrheum.2012.144. Epub 2012 Sep 4. Reginato AM, Mount DB, Yang I, Choi HK
The genetics of hyperuricaemia and gout.
Nat Rev Rheumatol. 2012 Oct;8(10):610-21. doi: 10.1038/nrrheum.2012.144. Epub 2012 Sep 4., [PMID:22945592]

Abstract [show]
Gout is a common and very painful inflammatory arthritis caused by hyperuricaemia. This Review provides an update on the genetics of hyperuricaemia and gout, including findings from genome-wide association studies. Most of the genes that associated with serum uric acid levels or gout are involved in the renal urate-transport system. For example, the urate transporter genes SLC2A9, ABCG2 and SLC22A12 modulate serum uric acid levels and gout risk. The net balance between renal urate absorption and secretion is a major determinant of serum uric acid concentration and loss-of-function mutations in SLC2A9 and SLC22A12 cause hereditary hypouricaemia due to reduced urate absorption and unopposed urate secretion. However, the variance in serum uric acid explained by genetic variants is small and their clinical utility for gout risk prediction seems limited because serum uric acid levels effectively predict gout risk. Urate-associated genes and genetically determined serum uric acid levels were largely unassociated with cardiovascular-metabolic outcomes, challenging the hypothesis of a causal role of serum uric acid in the development of cardiovascular disease. Strong pharmacogenetic associations between HLA-B(*)5801 alleles and severe allopurinol-hypersensitivity reactions were shown in Asian and European populations. Genetic testing for HLA-B(*)5801 alleles could be used to predict these potentially fatal adverse effects.

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58 In the liver, GCKR regulates glucokinase75,85 by mediating the phosphorylation of glucose to glucose‑6-phosphate, a precursor of liver glycogen synthesis and of de novo purine synthesis.75,85 A deficiency in the activity of glucose‑6-phosphatase causes glycogen storage disease type 1 (also known as von Gierke disease), which is characterized by hypertriglyceridaemia and hyperuricaemia.75,85 The GCKR SNP rs780094 might affect both serum uric acid and triglyceride levels (which are associated with insulin resistance) via a common mediator.75 Interestingly, GCKR is associated with insulin resistance,32 glucose level, triglyceride level, and C‑reactive protein,86 which are components of metabolic syndrome.75 Table 2 | SLC2A9, ABCG2 and SLC22A12 variants associated with serum uric acid levels, FeUA and gout Variant Location Phenotype Populations SLC2A9 (chromosome 4) rs1014290 Intron 3 SUA, FeUA, gout European ancestry34 rs6449213 Intron 4 SUA, FeUA, gout White,34-37,43 African American51,72 rs16890979 Exon 6 SUA, gout White,37,42,44 African American,72 Amish55 rs734553 Intron 6 SUA, gout White,32,39,44 Icelandic,13 African American72 rs7442295 Intron 6 SUA, gout White 35,38,39,44 rs737267 Intron 7 SUA, FeUA, gout European ancestry34,44 rs6855911 Intron 7 SUA, gout White,35,38,39,44 African American72 rs13129697 Intron 7 SUA, gout White,33,44 African American72 rs2241480 Intron 8 SUA, gout European ancestry72 rs7663032 Intron 9 SUA, gout African American,72 Croatian44 rs3775948 Intron 9 SUA Croatian,44 African American51 rs16890979 Intergenic SUA, gout White,37 Amish,55 Croatian,44 Pacific Islander,42 New Zealander42 rs717615 Intergenic SUA Croatian44 rs6856396 Intergenic SUA African American51 rs10489070 Intergenic Gout Amish55 ABCG2 (chromosome 4) rs2231137 Exon 2 SUA Japanese63 rs72552713 (Q126X) Exon 4 SUA, gout Japanese63 rs2231142 (Q141K) Exon 5 FeUA, SUA, gout White,32,37,39,44,62 African,37,72 Chinese,60 Icelandic,13 Japanese,59,63 Pacific Islander,61 New Zealander31,61 rs2199936 Intergenic SUA White 32,33,44 SLC22A12 (chromosome 11) rs11231825 Exon 1 FeUA, SUA Chinese,70 White,32,68 African American72 rs3825016 Exon 2 FeUA German68 rs12800450 Exon 2 SUA African American72 rs161109885 Intron 3 SUA Chinese73 rs893006 Intron 4 SUA Japanese,67 Chinese71 rs1529909 Intron 4 FeUA, SUA Korean74 rs475688 Intron 4 Gout Chinese,70 Solomon Islander70 rs17300741 Intron 4 SUA European32,75 rs7932775 Exon 8 SUA, FeUA, gout German,68 Chinese,70,73 Solomon Islander70 rs505802 Intergenic SUA European,32,44 African American72 rs11602903 Intergenic FeUA, SUA German,68 Chinese73 Abbreviations: FeUA, fractional excretion of urate; SUA, serum uric acid. Login to comment

[hide] Significant interaction between LRP2 rs2544390 in ... Gene. 2012 Jul 15;503(1):131-6. Epub 2012 Apr 28. Hamajima N, Naito M, Okada R, Kawai S, Yin G, Morita E, Higashibata T, Tamura T, Nakagawa H, Matsuo H, Mori A, Wakai K
Significant interaction between LRP2 rs2544390 in intron 1 and alcohol drinking for serum uric acid levels among a Japanese population.
Gene. 2012 Jul 15;503(1):131-6. Epub 2012 Apr 28., [PMID:22565184]

Abstract [show]
A genome-wide association study identified that LRP2 rs2544390 in intron 1 was associated with serum uric acid (SUA) levels among Japanese, as well as polymorphisms of SLC22A12, ABCG2, and SLC2A9. This study aimed to confirm the association of rs2544390 C/T with SUA, as well as another LRP2 polymorphism (rs3755166 G/A) in the promoter. Subjects were 5016 health checkup examinees (3409 males and 1607 females) aged 35 to 69years with creatinine<2.0mg/dL. The subjects with SLC22A12 258WW, SLC2A9 rs11722228C allele, ABCG2 126QQ and 141Q allele (2546 males and 1199 females) were selected for analysis. Mean SUA was 6.03mg/dL for CC, 6.18mg/dL for CT, and 6.19mg/dL for TT among males (p=0.012), and 4.49mg/dL, 4.45mg/dL, and 4.42mg/dL among females (not significant), respectively. No association was observed for rs3755166. The association with rs2544390 was stronger among male drinkers. The odds ratio of drinking >/=5/week relative to no drinking for hyperuricemia (SUA>/=7mg/dL and/or under medication for hyperuricemia) was 1.11 (95% confidence interval, 0.67-1.84) among CC males, 1.75 (1.22-2.51) among CT males, and 3.13 (1.80-5.43) among TT males. The interaction terms with drinking >/=5/week were 1.56 (p=0.156) for CT and 2.87 (p=0.005) for TT. This was the first report on the interaction between LRP2 genotype and alcohol drinking for SUA. Since the low density lipoprotein-related protein 2 (megalin) encoded by LRP2 is a multi-ligand endocytic receptor expressed in many tissues including the kidney proximal tubules, the association/interaction remained to be confirmed both epidemiologically and biologically.

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31 This study aimed to confirm the association of SUA with LRP2 rs2544390 at intron 1 and rs3755166 at the promoter region in a Japanese population, after eliminating the effects of SLC22A12 W258X SLC2A9 rs11722228 at intron 8, ABCG2 Q126X, and ABCG2 Q141K on SUA (Hamajima et al., 2011a, 2011b; Matsuo et al., 2009; Tabara et al., 2010). Login to comment
110 The difference in the mean SUA between CC and TT was 0.08 mg/dL among males with creatinineb2 mg/dL (G1 in Table 3), which was smaller than those among SLC22A12 W258X, SLC2A9 rs11722228, ABCG2 Q126X, and Q141K. Login to comment

[hide] Decreased extra-renal urate excretion is a common ... Nat Commun. 2012 Apr 3;3:764. doi: 10.1038/ncomms1756. Ichida K, Matsuo H, Takada T, Nakayama A, Murakami K, Shimizu T, Yamanashi Y, Kasuga H, Nakashima H, Nakamura T, Takada Y, Kawamura Y, Inoue H, Okada C, Utsumi Y, Ikebuchi Y, Ito K, Nakamura M, Shinohara Y, Hosoyamada M, Sakurai Y, Shinomiya N, Hosoya T, Suzuki H
Decreased extra-renal urate excretion is a common cause of hyperuricemia.
Nat Commun. 2012 Apr 3;3:764. doi: 10.1038/ncomms1756., [PMID:22473008]

Abstract [show]
ABCG2, also known as BCRP, is a high-capacity urate exporter, the dysfunction of which raises gout/hyperuricemia risk. Generally, hyperuricemia has been classified into urate 'overproduction type' and/or 'underexcretion type' based solely on renal urate excretion, without considering an extra-renal pathway. Here we show that decreased extra-renal urate excretion caused by ABCG2 dysfunction is a common mechanism of hyperuricemia. Clinical parameters, including urinary urate excretion, are examined in 644 male outpatients with hyperuricemia. Paradoxically, ABCG2 export dysfunction significantly increases urinary urate excretion and risk ratio of urate overproduction. Abcg2-knockout mice show increased serum uric acid levels and renal urate excretion, and decreased intestinal urate excretion. Together with high ABCG2 expression in extra-renal tissues, our data suggest that the 'overproduction type' in the current concept of hyperuricemia be renamed 'renal overload type', which consists of two subtypes-'extra-renal urate underexcretion' and genuine 'urate overproduction'-providing a new concept valuable for the treatment of hyperuricemia and gout.

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21 We also showed that common dysfunctional genotype combinations of ABCG2 gene (Q126X (rs72552713) and Q141K) are a major cause of gout21. Login to comment
28 The risk allele frequency of Q126X (risk allele, X) and Q141K (risk allele, K), among 644 male outpatients with hyperuricemia including 575 gout cases, was 4.1 and 45.9%, respectively. Login to comment
29 Those who had Q126X and Q141K variants were 8.1 and 71.9%, respectively, of all patients (Supplementary Table S2). Login to comment
30 Subsequent haplotype frequency analysis revealed that the minor alleles of Q126X and Q141K were in different haplotypes (Supplementary Table S3), which indicated that these variants were independent risks, as reported previously21. Login to comment
31 Therefore, we could estimate urate export function of ABCG2 by the combination of two common variants, non-functional Q126X and half-functional Q141K (Supplementary Fig. S1). Login to comment
82 Estimated transport activity Genotype N Frequency of OP hyperuricemia RR 95% CI P Adjusted RR† Adjusted 95% CI† Adjusted PȂ0; Q126X (rs72552713) Q141K (rs2231142) OP hyperuricemia* Non-OP hyperuricemia* ≤1/4 Function X/X Q/Q 26 3 0.897 2.35 1.86-2.97 3.32×10 - 7 2.30 1.31-3.90 2.65×10 - 3 Q/X Q/K 1/2 Function Q/X Q/Q 96 55 0.636 1.66 1.32-2.10 8.58×10 - 6 1.79 1.25-2.59 1.55×10 - 3 Q/Q K/K 3/4 Function Q/Q Q/K 160 147 0.521 1.36 1.09-1.71 4.55×10 - 3 1.42 1.03-2.00 0.035 Full function Q/Q Q/Q 60 97 0.382 1.00 Abbreviations: CI, confidence interval; OP, overproduction; RR, risk ratio. Login to comment
143 The export function of ABCG2 was then estimated from the combinations of ABCG2 variants, rs72552713 (Q126X) and rs2231142 (Q141K), and divided into four functional groups21; that is, full function, 3/4 function (mild dysfunction), 1/2 function (moderate dysfunction) and ≤1/4 function (severe dysfunction). Login to comment
146 The wild-type human ABCG2 cDNA (GenBank accession number NM_004827) or mutated (Q126X and Q141K) ABCG2 cDNA was inserted into the Nhe I and Apa I sites of pcDNA3.1( + ) vector plasmid, with a myc-tag sequence attached at the 5'-end21. Login to comment

[hide] Functional significance of genetic polymorphisms i... Drug Metab Pharmacokinet. 2012;27(1):85-105. Epub 2011 Nov 29. Ieiri I
Functional significance of genetic polymorphisms in P-glycoprotein (MDR1, ABCB1) and breast cancer resistance protein (BCRP, ABCG2).
Drug Metab Pharmacokinet. 2012;27(1):85-105. Epub 2011 Nov 29., [PMID:22123128]

Abstract [show]
Recent pharmacogenomic/pharmacogenetic (PGx) studies have disclosed important roles for drug transporters in the human body. Changes in the functions of drug transporters due to drug/food interactions or genetic polymorphisms, for example, are associated with large changes in pharmacokinetic (PK) profiles of substrate drugs, leading to changes in drug response and side effects. This information is extremely useful not only for drug development but also for individualized treatment. Among drug transporters, the ATP-binding cassette (ABC) transporters are expressed in most tissues in humans, and play protective roles; reducing drug absorption from the gastrointestinal tract, enhancing drug elimination into bile and urine, and impeding the entry of drugs into the central nervous system and placenta. In addition to PK/pharmacodynamic (PD) issues, ABC transporters are reported as etiologic and prognostic factors (or biomarkers) for genetic disorders. Although a consensus has not yet been reached, clinical studies have demonstrated that the PGx of ABC transporters influences the overall outcome of pharmacotherapy and contributes to the pathogenesis and progression of certain disorders. This review explains the impact of PGx in ABC transporters in terms of PK/PD, focusing on P-glycoprotein and breast cancer resistance protein (BCRP).

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71 Impact of ABCG2 (BCRP) polymorphisms on PK/PD/disorders Gene marker ¤SNPs/haplotype¥ Functional effect of the study Drug Population Disease Ref.Pharmacokinetics Therapeutic efficacy Side effects SNPs assay Others ¤e.g., frequency and susceptibility¥ %15622CgT or ¤1143ChT, %15622ChT¥ haplotype * gefitinib patient NSCLC 68 421ChA * * A771726 HV 223 421ChA ¤141QhK, rs2231142¥ * patient gout 224 421ChA * imatinib patient CML 225 421ChA * patient uric acid 226 421ChA ¤141QhK, rs2231142¥ * patient gout 227 421ChA, 914ChA * methotrexate patient RA 228 421ChA * * sunitinib patient RCC 70 421ChA * rosuvastatin patient myocardial infarction 229 346GhA, 421ChA, 1143ChT, 15994GhA * danusertib patient 230 421ChA * rosuvastatin patient hypercholesterolemia 231 421ChA * patient gout 232 376ChT, 421ChA * gefitinib patient NSCLC 67 421ChA * telatinib patient 233 421ChA * 3 statines HV 234 rs2622604 * irinitecan patient myelosuppression 235 ¤%15622C/T, 1143C/T¥ haplotype * sunitinib patient 127 12VhM, 141QhK * mitoxantrone patient multiple sclerosis 236 421ChA * imatinib patient CML 237 421ChA * sulfasalazine HV 238 421ChA * erlotinib patient SCC 69 421ChA * patient gout 239 421ChA * atorvastatin, rosuvastatin HV 240 12VhM, 141QhK * R-CHOP patient DLBCL 241 12VhM * patient ischemic stroke 242 421ChA * imatinib patient solid malignancies 243 421ChA * patient gout 73 rs2622621, rs1481012 * patient colorectal cancer 244 421ChA * nitrofurantoin HV 245 421ChA * sulfasalazine HV 246 421ChA * doxorubicin patient breast cancer 168 421ChA * sulfasalazine HV 60 Q141K, V12M, Q126X * lamivudine HV 247 34ChA, 421ChA * patient DLBCL 248 421ChA * pitavastatin HV 64 Continued on next page: 141QhK¥ which has been associated with lower BCRP protein expression.52,55¥ Recently, 421ChA was found to greatly affect the stability of BCRP in the endoplasmic reticulum, leading to increased protein degradation via ubiquitination and proteasomal proteolysis.56,57¥ Therefore, 421ChA may lead to increased bioavailability after the oral administration of substrate drugs. Login to comment

[hide] Human ABCG2: structure, function, and its role in ... Int J Biochem Mol Biol. 2012;3(1):1-27. Epub 2011 Mar 30. Mo W, Zhang JT
Human ABCG2: structure, function, and its role in multidrug resistance.
Int J Biochem Mol Biol. 2012;3(1):1-27. Epub 2011 Mar 30., [PMID:22509477]

Abstract [show]
Human ABCG2 is a member of the ATP-binding cassette (ABC) transporter superfamily and is known to contribute to multidrug resistance (MDR) in cancer chemotherapy. Among ABC transporters that are known to cause MDR, ABCG2 is particularly interesting for its potential role in protecting cancer stem cells and its complex oligomeric structure. Recent studies have also revealed that the biogenesis of ABCG2 could be modulated by small molecule compounds. These modulators, upon binding to ABCG2, accelerate the endocytosis and trafficking to lysosome for degradation and effectively reduce the half-life of ABCG2. Hence, targeting ABCG2 stability could be a new venue for therapeutic discovery to sensitize drug resistant human cancers. In this report, we review recent progress on understanding the structure, function, biogenesis, as well as physiological and pathophysiological functions of ABCG2.

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889 The effect of ABCG2 V12M, Q141K and Q126X, known functional variants in vitro, on the disposition of lamivudine. Login to comment
895 The effect of ABCG2 V12M, Q141K and Q126X, known functional variants in vitro, on the disposition of lamivudine. Login to comment

[hide] ABCG2/BCRP dysfunction as a major cause of gout. Nucleosides Nucleotides Nucleic Acids. 2011 Dec;30(12):1117-28. Matsuo H, Takada T, Ichida K, Nakamura T, Nakayama A, Suzuki H, Hosoya T, Shinomiya N
ABCG2/BCRP dysfunction as a major cause of gout.
Nucleosides Nucleotides Nucleic Acids. 2011 Dec;30(12):1117-28., [PMID:22132966]

Abstract [show]
Recent genome-wide association studies showed that serum uric acid (SUA) levels relate to ABCG2/BCRP gene, which locates in a gout-susceptibility locus revealed by a genome-wide linkage study. Together with the ABCG2 characteristics, we hypothesized that ABCG2 transports urate and its dysfunction causes hyperuricemia and gout. Transport assays showed ATP-dependent transport of urate via ABCG2. Kinetic analysis revealed that ABCG2 mediates high-capacity transport of urate (Km: 8.24 +/- 1.44 mM) even under high-urate conditions. Mutation analysis of ABCG2 in 90 Japanese hyperuricemia patients detected six nonsynonymous mutations, including five dysfunctional variants. Two relatively frequent dysfunctional variants, Q126X and Q141K, were then examined. Quantitative trait locus analysis of 739 Japanese individuals showed that Q141K increased SUA as the number of minor alleles of Q141K increased (p = 6.60 x 10(-5)). Haplotype frequency analysis revealed that there is no simultaneous presence of Q126X and Q141K in one haplotype. Becuase Q126X and Q141K are assigned to nonfunctional and half-functional haplotypes, respectively, their genotype combinations are divided into four functional groups. The association study with 161 male gout patients and 865 male controls showed that all of those with dysfunctional ABCG2 increased the gout risk, especially those with </=1/4 function (OR, 25.8; 95% CI, 10.3-64.6; p = 3.39 x 10(-21)). These genotypes were found in 10.1% of gout patients, but in only 0.9% of control. Our function-based clinicogenetic (FBCG) analysis showed that combinations of the two dysfunctional variants are major causes of gout, thereby providing a new approach for prevention and treatment of the gout high-risk population.

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11 Two relatively frequent dysfunctional variants, Q126X and Q141K, were Received 29 May 2011; accepted 17 October 2011. Login to comment
19 Haplotype frequency analysis revealed that there is no simultaneous presence of Q126X and Q141K in one haplotype. Login to comment
20 Becuase Q126X and Q141K are assigned to nonfunctional and half-functional haplotypes, respectively, their genotype combinations are divided into four functional groups. Login to comment
38 1119 ABCG2 : ATP binding casse e G2 SNP : single nucleo de polymorphism QTL : quan ta ve trait locus OR : odds ra o ABCG2 as a urate secre on transporter in humans Gene c analysis Func onal analysis ABCG2 muta on analysis of 90 hyperuricemic cases (all coding regions) ABCG2 muta ons (with amino acid altera ons) 6 muta ons c d Func onal analysis of urate transport via wild type ABCG2 (vesicle studies) a Iden fica on of urate transport ac vi es via ABCG2 b Func onal analysis of urate transport via mutated ABCG2 6 mutants e No effect (V12M) g Dysfunc onal genotype combina ons of ABCG2 as major causes of gout q Dysfunc onal SNP with high frequency (>30%) (Q141K) QTL analysis in 739 Japanese individuals h i j n Gout / hyperuricemia with ABCG2 homozygous, n = 2 heterozygous, n = 24 Loss of func on (Q126X, G268R, S441N, F506Sfs) Reduced func on (~50%) (Q141K) f p Genotype combina on analysis 10.1% of gout with ≤1/4 ABCG2 func on OR = 25.8, p = 3.39×10-21 o Haplotype analysis 13.5% of gout with disease haplotype OR = 5.97, p = 4.10×10-12 Associa on analysis of hyperuricemia (Q126X) OR = 3.61, p = 2.91× 10-7 l m Associa on analysis of gout (Q126X) OR = 4.25, p =3.04 × 10-8 Genotyping of nonfunc onal SNP (Q126X) hyperuricemia, n=228 k FIGURE 1 Flowchart for molecular-function-based clinicogenetic (FBCG) analysis of gout patients with ABCG2 polymorphic variants. Login to comment
53 Using the site-directed mutagenesis technique, we constructed ABCG2 mutants (V12M, Q126X, Q141K, G268R, S441N, and F506SfsX4), which were used for urate transport analysis, on the expression vector for ABCG2. Login to comment
65 The following six nonsynonymous mutations, including three SNPs, were found: V12M, Q126X, Q141K, G268R, S441N, and F506SfsX4 (Figure 2A). Login to comment
76 Maekawa et al.[17] reported that V12M, Q126X, and Q141K are quite common in the Japanese population, and allele frequencies for these SNPs were 31.9% for Q141K, 19.2% for V12M, and 2.8% for Q126X, respectively. Login to comment
77 Using Hardy-Weinberg equilibrium and these data on a Japanese population reported by Maekawa et al.,[17] we estimated that the frequencies of Japanese individuals with these minor alleles were 53.6% for Q141K, 34.7% for V12M, and 5.5% for Q126X. Login to comment
79 Among six mutants, ATP-dependent urate transport was reduced by approximately half (46.7%) in one mutant, Q141K, and was nearly eliminated in four mutants, Q126X, G268R, S441N, and F506SfsX4 (Figure 2B). Login to comment
85 ABCG2 Dysfunction Increases Gout Risk Additional genotyping of ABCG2 SNPs for 228 Japanese men with hyperuricemia (including 161 men with gout) served to identify Q126X homozygous (n = 2) and heterozygous (n = 24) mutations. Login to comment
86 Two patients with Q126X homozygous mutations showed very high SUA (> 10 mg/dl) before they were treated for hyperuricemia/gout. Login to comment
88 Through the association study, Q126X was revealed to increase the risk of hyperuricemia (odds ratio [OR], 3.61; 95% confidence interval [CI], 2.14-6.08; p = 2.91 × 10-7 ). Login to comment
89 Among the 161 gout patients, Q126X homozygous (n = 1) and heterozygous (n = 21) mutations were found, which revealed that Q126X dramatically increased gout risk (OR, 4.25; 95% CI, 2.44-7.38; p = 3.04 × 10-8 ). Login to comment
91 Haplotype frequency analysis revealed no simultaneous presence of the minor alleles of Q126X and Q141K in one haplotype. Login to comment
92 The haplotype with Q126X markedly increased gout risk (OR, 5.97; 95% CI, 3.39-10.51; p = 4.10 × 10-12 ) compared with nonrisk haplotypes. Login to comment
94 Our data also revealed enrichment of the Q126X minor allele in gout or hyperuricemia patients relative to normouricemic subjects (SUA ≤ 7.0 mg/dl). Login to comment
95 Thus, the Q126X mutation of the ABCG2 gene is identified as a major cause of primary gout. Login to comment
96 Together, these findings suggest that nonfunctional variants of ABCG2, such as Q126X, essentially block urate excretion and cause gout. Login to comment
98 Because Q126X and Q141K are assigned to different risk haplotypes, nonfunctional and half-functional, respectively, their genotype combinations are divided into four functional groups on the basis of the estimated ABCG2 transport functions, i.e., full function, 3/4 function, 1/2 function, and ≤1/4 function. Login to comment
106 We also demonstrated that nonfunctional ABCG2 variant Q126X is assigned to the identical haplotype, which increases gout risk, conferring an OR of 5.97. Login to comment
110 Together with P-glycoprotein 21.4% 45.3% 23.3% 10.1% 50.8% 35.6% 12.7% 0.9% other gout risks gout no function Q126X T/T Q141K C/C Full function C/C C/C 3/4 function 1/2 function C/C C/C T/C A/C A/A C/C Gout patients Normal control SUA ≤ 7.0 mg/dl 1/4 function T/C A/C 25.8-fold gout risk ≥3.02-fold gout risk (n = 865) (n = 161) FIGURE 3 ABCG2 transport dysfunction as a major gout risk. Login to comment
111 Genotype combinations of Q126X and Q141K are divided into several groups based on estimated ABCG2 transport functions. Login to comment
125 [14] Our approach (Figure 1) revealed that nonfunctional variants of ABCG2, such as Q126X, essentially block urate excretion and cause gout. Login to comment
126 Different from the rare Mendelian disorders described above, the disease haplotype carrying the ABCG2 Q126X mutation (OR, 5.97; 95% CI, 3.39-10.51; p = 4.10 × 10-12 ) is present in up to 13.5% of primary gout patients in our population, suggesting that Q126X is a major mutation causing gout. Login to comment
135 A meta-analysis of GWAS of European descent also showed that the nine loci, including GLUT9 and ABCG2, influence SUA,[11] which confirms the findings of Dehghan et al.[10] In this study, we identified several nonfunctional ABCG2 mutations, including Q126X, which shows stronger effects on gout development than Q141K did in a previous study (OR < 2.0). Login to comment

[hide] Identification of ABCG2 dysfunction as a major fac... Nucleosides Nucleotides Nucleic Acids. 2011 Dec;30(12):1098-104. Matsuo H, Takada T, Ichida K, Nakamura T, Nakayama A, Takada Y, Okada C, Sakurai Y, Hosoya T, Kanai Y, Suzuki H, Shinomiya N
Identification of ABCG2 dysfunction as a major factor contributing to gout.
Nucleosides Nucleotides Nucleic Acids. 2011 Dec;30(12):1098-104., [PMID:22132963]

Abstract [show]
The ATP-binding cassette, subfamily G, member 2 gene ABCG2/BCRP locates in a gout-susceptibility locus (MIM 138900) on chromosome 4q. Recent genome-wide association studies also showed that the ABCG2 gene relates to serum uric acid levels and gout. Since ABCG2 is also known as a transporter of nucleotide analogs that are structurally similar to urate, and is an exporter that has common polymorphic reduced functionality variants, ABCG2 could be a urate secretion transporter and a gene causing gout. To find candidate mutations in ABCG2, we performed a mutation analysis of the ABCG2 gene in 90 Japanese patients with hyperuricemia and found six non-synonymous mutations. Among the variants, ATP-dependent urate transport was reduced or eliminated in five variants, and two out of the five variants (Q126X and Q141K) were frequently detected in patients. Haplotype frequency analysis revealed that there is no simultaneous presence of Q126X and Q141K in one haplotype. As Q126X and Q141K are a nonfunctional and half-functional haplotype, respectively, their genotype combinations are divided into four estimated functional groups. The association study with 161 male gout patients and 865 male controls showed that all of those who had dysfunctional ABCG2 had an increased risk of gout, and that a remarkable risk was observed in those with </=1/4 function (OR, 25.8; 95% CI, 10.3-64.6; p = 3.39 x 10(-21)). In 2,150 Japanese individuals, the frequency of those with dysfunctional ABCG2 was more than 50%. Our function-based clinicogenetic analysis identified the combinations of dysfunctional variants of ABCG2 as a major contributing factor in Japanese patients with gout.

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16 Among the variants, ATP-dependent urate transport was reduced or eliminated in five variants, and two out of the five variants (Q126X and Q141K) were frequently detected in patients. Login to comment
17 Haplotype frequency analysis revealed that there is no simultaneous presence of Q126X and Q141K in one haplotype. Login to comment
18 As Q126X and Q141K are a nonfunctional and half-functional haplotype, respectively, their genotype combinations are divided into four estimated functional groups. Login to comment
36 Using the site-directed mutagenesis technique, we constructed mutants of ABCG2 (V12M, Q126X, Q141K, G268R, S441N, and F506SfsX4), which were used for urate transport analysis, on the expression vector for ABCG2. Login to comment
45 The following six non-synonymous mutations, V12M, Q126X, Q141K, G268R, S441N, and F506SfsX4, were found (Figure 1A), and the first three mutations were SNPs. Login to comment
49 Results are expressed as means ± SD. V12M, and 2.8% for Q126X. Login to comment
50 With the Hardy-Weinberg equilibrium and the data reported by Maekawa et al. of the Japanese population,[5] we calculated estimates of the minor allele frequencies of Japanese individuals to be 53.6% for Q141K, 34.7% for V12M, and 5.5% for Q126X. Login to comment
52 The ATP-dependent transport of urate was reduced by approximately half (46.7%) in Q141K and was nearly eliminated in Q126X, G268R, S441N, and F506SfsX4 mutants (Figure 1B). Login to comment
54 Additional genotyping of ABCG2 SNPs was performed for 228 Japanese men with hyperuricemia (including 161 men with gout) and identified Q126X homozygous (N = 2) and heterozygous (N = 24) mutations. Login to comment
55 Two patients with Q126X homozygous mutations showed very high SUA (>10 mg/dl) before they were treated for hyperuricemia. Login to comment
56 A total of 871 TABLE 1 Association analysis of ABCG2 genotype combination in gout patients Genotype Number Estimated transport Q126X Q141K Gout Control p value OR* 95% CI* ≤1/4 function T/T C/C 16 8 3.39 × 10-21 25.8 10.3-64.6 T/C A/C - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - 1/2 function T/C C/C 37 110 2.23 × 10-9 4.34 2.61-7.24 C/C A/A - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - 3/4 function C/C A/C 72 308 2.29 × 10-7 3.02 1.96-4.65 - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - Full function C/C C/C 34 439 1.00 *OR = odds ratio; 95% CI = 95% confidence interval. Login to comment
57 OR is obtained by comparing the non-risk genotype combination C/C (Q126X) and C/C (Q141K). Login to comment
58 Risk alleles for Q126X and Q141K are underlined. Login to comment
60 The association study showed that the risk of hyperuricemia was increased by Q126X (odds ratio [OR], 3.61; 95% confidence interval [CI], 2.14-6.08; p = 2.91 × 10-7 ). Login to comment
61 There were Q126X homozygous (N = 1) and heterozygous (N = 21) mutations among the 161 patients with gout, which revealed that Q126X dramatically increased gout risk (OR, 4.25; 95% CI, 2.44-7.38; p = 3.04 × 10-8 ). Login to comment
63 The haplotype frequency analysis revealed no simultaneous presence of the minor alleles of Q126X and Q141K in one haplotype. Login to comment
64 The haplotype with Q126X was present in up to 13.5% of gout patients, and markedly increased gout risk (OR, 5.97; 95% CI, 3.39-10.51; p = 4.10 × 10-12 ) compared with non-risk haplotypes. Login to comment
65 Our data also revealed enrichment of the Q126X minor allele in gout or hyperuricemia patients relative to normouricemic subjects (SUA ≤ 7.0 mg/dl). Login to comment
66 Thus, the Q126X mutation of the ABCG2 gene is identified as a major contributing factor in Japanese gout patients. Login to comment
67 Together, these findings suggest that nonfunctional variants of ABCG2, such as Q126X, essentially block urate excretion and cause gout. Login to comment
70 Because the nonfunctional variant Q126X and half-functional variant Q141K are assigned to different risk haplotypes, their genotype combinations are divided into four functional groups on the basis of the estimated ABCG2 transport functions, i.e., full function, 3/4 function, 1/2 function, and ≤1/4 function (Table 1). Login to comment
79 We also demonstrated that the nonfunctional ABCG2 variant Q126X is assigned to the identical haplotype, which increases gout risk, conferring an OR of 5.97. Login to comment
83 Our approach reported here revealed that nonfunctional variants of ABCG2, such as Q126X, essentially block urate excretion and cause gout. Login to comment
84 The disease haplotype with the ABCG2 Q126X mutation (OR, 5.97; 95% CI, 3.39-10.51; p = 4.10 × 10-12 ) is present in up to 13.5% of primary gout patients in our population, suggesting that Q126X may well be a major causative mutation for gout. Login to comment
93 In our study, we also identified several nonfunctional ABCG2 mutations including Q126X which shows stronger effects on gout development than Q141K did in a previous study (OR < 2.0). Login to comment
94 [3] There is a possibility that these dysfunctional mutations, including Q126X, are specific to the Japanese or Asian population, or alternatively, there may be nonfunctional mutations in the ABCG2 gene that increase the incidence of gout in Caucasians and other groups. Login to comment

[hide] ABCG2 is a high-capacity urate transporter and its... Nucleosides Nucleotides Nucleic Acids. 2011 Dec;30(12):1091-7. Nakayama A, Matsuo H, Takada T, Ichida K, Nakamura T, Ikebuchi Y, Ito K, Hosoya T, Kanai Y, Suzuki H, Shinomiya N
ABCG2 is a high-capacity urate transporter and its genetic impairment increases serum uric acid levels in humans.
Nucleosides Nucleotides Nucleic Acids. 2011 Dec;30(12):1091-7., [PMID:22132962]

Abstract [show]
The ATP-binding cassette, subfamily G, member 2 (ABCG2/BCRP) gene encodes a well-known transporter, which exports various substrates including nucleotide analogs such as 3'-azido-3'-deoxythymidine (AZT). ABCG2 is also located in a gout-susceptibility locus (MIM 138900) on chromosome 4q, and has recently been identified by genome-wide association studies to relate to serum uric acid (SUA) and gout. Becuase urate is structurally similar to nucleotide analogs, we hypothesized that ABCG2 might be a urate exporter. To demonstrate our hypothesis, transport assays were performed with membrane vesicles prepared from ABCG2-overexpressing cells. Transport of estrone-3-sulfate (ES), a typical substrate of ABCG2, is inhibited by urate as well as AZT and ES. ATP-dependent transport of urate was then detected in ABCG2-expressing vesicles but not in control vesicles. Kinetic analysis revealed that ABCG2 is a high-capacity urate transporter that maintained its function even under high-urate concentration. The calculated parameters of ABCG2-mediated transport of urate were a Km of 8.24 +/- 1.44 mM and a Vmax of 6.96 +/- 0.89 nmol/min per mg of protein. Moreover, the quantitative trait locus (QTL) analysis performed in 739 Japanese individuals revealed that a dysfunctional variant of ABCG2 increased SUA as the number of minor alleles of the variant increased (p = 6.60 x 10(-5)). Because ABCG2 is expressed on the apical membrane in several tissues, including kidney, intestine, and liver, these findings indicate that ABCG2, a high-capacity urate exporter, has a physiological role of urate homeostasis in the human body through both renal and extrarenal urate excretion.

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34 With the site-directed mutagenesis technique, we constructed mutants of ABCG2 (V12M, Q126X, and Q141K), which were used for urate transport analysis, on the expression vector for ABCG2. Login to comment
47 We found the following six nonsynonymous mutations: V12M, Q126X, Q141K, G268R, S441N, and F506SfsX4, and the first three mutations are SNPs. Login to comment
48 Maekawa et al.[7] reported that these SNPs are quite common in the Japanese population, and allele frequencies for them are 31.9% for Q141K, 19.2% for V12M, and 2.8% for Q126X, respectively. Login to comment
49 Using Hardy-Weinberg equilibrium and these data on a Japanese population reported by Maekawa et al.,[7] the frequencies of Japanese individuals with these minor alleles were estimated to be 53.6% for Q141K, 34.7% for V12M, and 5.5% for Q126X, respectively. Login to comment
50 [8] To clarify how ABCG2 SNPs affect function, the urate transport capacity of these variants was examined in comparison with that of wild-type ABCG2. ATP-dependent transport of urate was reduced by approximately half (46.7%) in Q141K and was nearly eliminated in Q126X (Figure 2A). Login to comment

[hide] PDZK1 regulates breast cancer resistance protein i... Drug Metab Dispos. 2011 Nov;39(11):2148-54. Epub 2011 Aug 4. Shimizu T, Sugiura T, Wakayama T, Kijima A, Nakamichi N, Iseki S, Silver DL, Kato Y
PDZK1 regulates breast cancer resistance protein in small intestine.
Drug Metab Dispos. 2011 Nov;39(11):2148-54. Epub 2011 Aug 4., [PMID:21816982]

Abstract [show]
Transporter adaptor protein PDZK1 regulates several influx transporters for xenobiotics and nutrients in small intestine, and their expression on the apical membrane is diminished in pdzk1 gene knockout [pdzk1(-/-)] mice. In the present study, we initially attempted to use pdzk1(-/-) mice to functionally identify influx transporters responsible for intestinal absorption of cimetidine. Contrary to our expectation, the plasma concentration of cimetidine after oral administration to pdzk1(-/-) mice was higher than that in wild-type mice, and the double peaks of plasma concentration found in wild-type mice were not observed in pdzk1(-/-) mice. Western blot analysis of intestinal brush-border membranes revealed that expression of breast cancer resistance protein (BCRP) but not of P-glycoprotein is reduced in pdzk1(-/-) mice. This result was compatible with the reduction of apical localization of BCRP in pdzk1(-/-) mice assessed by immunohistochemical analysis. Transcellular transport of cimetidine in the basal-to-apical direction in Madin-Darby canine kidney II (MDCKII) cells stably expressing both BCRP and PDZK1 (MDCKII/BCRP/PDZK1) was higher than that in MDCKII cells stably expressing BCRP (MDCKII/BCRP) cells. Moreover, MDCKII/BCRP/PDZK1 cells are more resistant than MDCKII/BCRP cells to the cytotoxicity of the anticancer agent 7-ethyl-10-hydroxycamptothecin (SN-38), which is a substrate of BCRP. These results were consistent with the higher expression of BCRP on apical membranes in MDCKII/BCRP/PDZK1 cells. Pull-down and immunoprecipitation studies revealed a physical interaction between BCRP and PDZK1. Taken together, these findings demonstrate that PDZK1 plays a pivotal role in the apical localization of BCRP. This is the first identification of a regulatory protein that physically interacts with and regulates BCRP in small intestine in vivo.

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214 The genotype combination of two dysfunctional variants Q126X and Q141K results in increased serum uric acid concentration and increased risk of gout (Matsuo et al., 2009). Login to comment

[hide] ABCG transporters and disease. FEBS J. 2011 Sep;278(18):3215-25. doi: 10.1111/j.1742-4658.2011.08171.x. Epub 2011 Jun 13. Woodward OM, Kottgen A, Kottgen M
ABCG transporters and disease.
FEBS J. 2011 Sep;278(18):3215-25. doi: 10.1111/j.1742-4658.2011.08171.x. Epub 2011 Jun 13., [PMID:21554546]

Abstract [show]
ATP-binding cassette (ABC) transporters form a large family of transmembrane proteins that facilitate the transport of specific substrates across membranes in an ATP-dependent manner. Transported substrates include lipids, lipopolysaccharides, amino acids, peptides, proteins, inorganic ions, sugars and xenobiotics. Despite this broad array of substrates, the physiological substrate of many ABC transporters has remained elusive. ABC transporters are divided into seven subfamilies, A-G, based on sequence similarity and domain organization. Here we review the role of members of the ABCG subfamily in human disease and how the identification of disease genes helped to determine physiological substrates for specific ABC transporters. We focus on the recent discovery of mutations in ABCG2 causing hyperuricemia and gout, which has led to the identification of urate as a physiological substrate for ABCG2.

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59 R L L A A M AT T T R V S G G G F I T Q R R V K K S G E A D RR V V K K L L G E E E I IN NN D H Q Q R V V V V V L L S G F E N M TT QD D S K R V K L L G F P C Y R K S G F P P C N N A V L L S G G G I N A D R K P P S GG G R V VK K KK L L L LL L S S S GG G PPE E IIII N NN M A A A T D D Y N E A I P E S I D L L F T LS G EI MT D I I P FC L R IH A N T T T T T G L D S S K K K L L L S G G G F F F F Q P P I M M A A A A D H G G LS S S V L L L L L R R RQ Q I I Y Y YS S HE E A T V V V V L Q I S F I I II A A L G G Y K F R S S E E I I L G Y YY Y V V K H S P C M M D R T I II L L L F F YV S S P F N T I A Q Q L L L G F Y Y H S S PR W C N M I I A A A L L G F V V K H W T L I F F C C C D D D A A A QQ Q Q Q G G G G G G G G G G FF FF F F FF Y Y Y Y Y V V V V V VVV K KKK KK K K E E E E P P P P R W W TT TT T TT T T NNNN N N N N N M MM M L L L L L L L L LL LL I I I I I I AA A A A A A S S S S S S S S SS L L L L LL L L LL V V F G GCC T Q Q Q Q Y Y Y KK K K K H H EE E E E E EEE E P P P P R R RW N N N II I I I I I I A AAA A A A S SS S S S S L L LL L L L V V V V F F F F F F F G GG G C TT T T T T K K K K KKKK N NN LL D DDD DS S 395 469 565 644 414 450 495 505 584 625 Signature Walker A WalkerBQ EP MI A V V VF FG GTN N NS S S S P F HE V FG CTT K NN LLD SS AAA I V12M N-terminus C-terminus M MM MM T A A A A L F F Y V V S S S F 524476 Y Q126X G268R S441N F506fs Q141K 44 288 PP AA DD Fig. 2. Login to comment
108 In addition to Q141K, Q126X was identified as a novel loss-of-function variant. Login to comment
109 Q126X was assigned to a different haplotype than Q141K and shown to increase gout risk (odds ratio 5.97) to an even greater extent than the Q141K variant. Login to comment
110 In addition, 10% of the gout patients studied had genotype combinations of the Q141K and Q126X variants that resulted in more than a 75% reduction of ABCG2 function compared with patients that were homozygous for the non-risk allele at both variants (odds ratio 25.8, 95% confidence interval 10.3-64.6). Login to comment

[hide] Drug transport by breast cancer resistance protein... Expert Opin Drug Metab Toxicol. 2010 Nov;6(11):1363-84. Epub 2010 Sep 27. Poguntke M, Hazai E, Fromm MF, Zolk O
Drug transport by breast cancer resistance protein.
Expert Opin Drug Metab Toxicol. 2010 Nov;6(11):1363-84. Epub 2010 Sep 27., [PMID:20873966]

Abstract [show]
IMPORTANCE OF THE FIELD: The ATP-binding cassette transporter ABCG2 is a well-known major mediator of multi-drug resistance in cancers. Beyond multi-drug resistance, experimental and recent clinical studies demonstrate a role for ABCG2 as a determinant of drug pharmacokinetic, safety and efficacy profiles. AREAS COVERED IN THIS REVIEW: The clinical evidence of the role of ABCG2 in pharmacokinetics and pharmacodynamics is reviewed. Key questions that arise from the perspective of preclinical drug evaluation are addressed, including the structure of ABCG2 and mechanisms of drug-transporter interactions, mechanisms responsible for the polyspecificity of ABCG2, methods suitable for studying drug-ABCG2 interactions in vitro and in silico prediction of ABCG2 substrates and inhibitors. WHAT THE READER WILL GAIN: An update on current knowledge of the importance of ABCG2 in drug disposition with special emphasis on drug development. TAKE HOME MESSAGE: The field of drug-ABCG2 interaction is rapidly advancing and beginning to expand into clinical practice. However, the structural understanding of drug binding and transport by ABCG2 is still incomplete. Incorporation of novel concepts of drug-transporter interactions such as electrostatic funneling might help explain the multispecificity of ABCG2 and enable in silico predictions.

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530 (2010) 6(11) 1383 Q126X, known functional variants in vitro, on the disposition of lamivudine. Login to comment

[hide] Common defects of ABCG2, a high-capacity urate exp... Sci Transl Med. 2009 Nov 4;1(5):5ra11. Matsuo H, Takada T, Ichida K, Nakamura T, Nakayama A, Ikebuchi Y, Ito K, Kusanagi Y, Chiba T, Tadokoro S, Takada Y, Oikawa Y, Inoue H, Suzuki K, Okada R, Nishiyama J, Domoto H, Watanabe S, Fujita M, Morimoto Y, Naito M, Nishio K, Hishida A, Wakai K, Asai Y, Niwa K, Kamakura K, Nonoyama S, Sakurai Y, Hosoya T, Kanai Y, Suzuki H, Hamajima N, Shinomiya N
Common defects of ABCG2, a high-capacity urate exporter, cause gout: a function-based genetic analysis in a Japanese population.
Sci Transl Med. 2009 Nov 4;1(5):5ra11., [PMID:20368174]

Abstract [show]
Gout based on hyperuricemia is a common disease with a genetic predisposition, which causes acute arthritis. The ABCG2/BCRP gene, located in a gout-susceptibility locus on chromosome 4q, has been identified by recent genome-wide association studies of serum uric acid concentrations and gout. Urate transport assays demonstrated that ABCG2 is a high-capacity urate secretion transporter. Sequencing of the ABCG2 gene in 90 hyperuricemia patients revealed several nonfunctional ABCG2 mutations, including Q126X. Quantitative trait locus analysis of 739 individuals showed that a common dysfunctional variant of ABCG2, Q141K, increases serum uric acid. Q126X is assigned to the different disease haplotype from Q141K and increases gout risk, conferring an odds ratio of 5.97. Furthermore, 10% of gout patients (16 out of 159 cases) had genotype combinations resulting in more than 75% reduction of ABCG2 function (odds ratio, 25.8). Our findings indicate that nonfunctional variants of ABCG2 essentially block gut and renal urate excretion and cause gout.

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1 Because this gene is responsible for giving rise to a protein namely the Q126X nonfunctional mutation, confers an even higher risk associated with an increase in uric acid ,ABCG2Now, a team led by Hirotaka Matsuo report that in a Japanese population, another risk variant in high-risk variant in nearly 10% of gout cases in Caucasians. Login to comment
12 Sequencing of the ABCG2 gene in 90 hyperuricemia patients revealed several nonfunctional ABCG2 mutations, including Q126X. Login to comment
14 Q126X is assigned to the different disease haplotype from Q141K and increases gout risk, conferring an odds ratio of 5.97. Login to comment
46 The following six nonsynonymous mutations were found: V12M, Q126X, Q141K, G268R, S441N, and F506SfsX4 (Table 1). Login to comment
48 Maekawa et al. reported that allele frequencies for these SNPs, which are quite common in the Japanese population, were 31.9% for Q141K, 19.2% for V12M, and 2.8% for Q126X, respectively (Table 1) (34). Login to comment
49 Using Hardy-Weinberg equilibrium and these data of a Japanese population reported by Maekawa et al. (34), we calculated estimates of the frequencies of Japanese individuals with these minor alleles to be 53.6% for Q141K, 34.7% for V12M, and 5.5% for Q126X. Login to comment
52 ATP-dependent transport of urate was reduced by approximately half (46.7%) in Q141K and was nearly eliminated in Q126X, G268R, S441N, and F506SfsX4 mutants (Fig. 2B). Login to comment
53 Western blot analysis showed that ABCG2 protein expression levels in the Q141K variant decreased by half (47.2%), whereas Q126X resulted in no protein on membrane vesicles (fig. S4). Login to comment
71 Additional genotyping and association analysis of gout Through additional genotyping of ABCG2 SNPs for 228 Japanese men with hyperuricemia (including 161 men with gout), Q126X homozygous (n = 2) and heterozygous (n = 24) mutations were identified (Table 2). Login to comment
72 Two patients with Q126X homozygous mutations showed very high SUA (>10 mg/dl)before they were treated for hyperuricemia. Login to comment
74 The association study showed that Q126X increased the risk of hyperuricemia [odds ratio (OR), 3.61; 95% confidence interval (CI), 2.14-6.08; P = 2.91 × 10-7 ]. Login to comment
75 Among the 161 patients with gout, Q126X homozygous (n = 1) and heterozygous (n = 21) mutations were found, which revealed that Q126X dramatically increased gout risk (OR, 4.25; 95% CI, 2.44-7.38; P = 3.04 × 10-8 ). Login to comment
77 The call rate, or the ability of the SNP to be reliably decoded, for V12M, Q126X, and LS N N SV FLC S P T AN FK G LM ETS S E V F I P Q G N T N G FV P A A AS LD V S N I C Y R V K K RKPVEKEILSNINGIKPGLNAILGPG GGKSSL LDVLA ARKDP S G T L S G D V L I G A P PR A N F K N S G Y Q D D V V M G T L T V R NE LV VC H Q F S A A A RL L T T TNEKNER HINRVIQELGLDKVADSKVGTQFIRGVG GERR KTSIGME L I T D P S I L F L D E P T T G L D S S T A N A V LL L L K R M S K Q G R I I F S T S I H Q P R Y M S I F K LFDSLTLLASGRLMFHGPAQEALGYFESAGYHCEAN YN T V A L N R E E D F K A T E II E P S K Q D K L I E L A EK I Y V N S S F Y K ETKAELHQLSGGEKKKKITVFKEISYTTSFCHQRWVK SRS AFFLDII N G D S A PD P L F K N LL G N P Q A S A I V G I I T L V A FI I Q V V L G Y AVEFLKNDST G I Q N R A G V L F F L T T Q C F S L V S S N G L S L M L I T P M S F I FV D L R P I C Y W L W Y I Y T Q S R F L NQ S L F P G A H E F Y S Y S E F R G Y I K V K S V Y I H L E V A S S V L M A A M F V A F M S Y M T M F K A T I M L H F I A V K G W I L V C A N L W V A T L M T C F VI F M M I F S G L L VNLTTIASAIAAGQS L S V V LKGL L F N Q L F P S L D Y G Q K V L C Y EEGTCTAYNCPNNGTAN G P G L K L L L K K SYF L Y D L G L M A P K Extracellular Intracellular 50 150 200 300 100 350 395 415 469 450 470 500 525 550 565 585 600 625 608 650 250 655 603 475 644 F506SfsX4 (F506fs) V12M Q126X Q141K S441N G268R V Q F S G Q # C signature Walker B motif Walker A motif C D E 4.0 4.5 5.0 5.5 6.0 C/C C/A A/A Male + female P= 2.02 x 10 -6 5.0 5.5 6.0 6.5 7.0 C/C C/A A/A Male P= 0.0144 Serumuric acid(mg/dl) 4.0 4.5 5.0 5.5 6.0 C/C C/A A/A Female P= 0.0137 (pmol/mgprotein) 0 20 40 60 80 100 120 140 160 180 200 + AMP + ATP B Serumuric acid(mg/dl) Serumuric acid(mg/dl) A [C]Uratetransport 14 G F M C-terminal N-terminal Fig. 2. Login to comment
89 Amino acid change SNP ID dbSNP (NCBI) Exon Type of mutation Number of hyperuricemia patients Allele frequency (%) (in hyperuricemia) Allele frequency* (%) (in Japanese population) Wild-type Heterozygote Homozygote Q141K rs2231142 5 Missense 29 47 14 41.67 31.9 V12M rs2231137 2 Missense 64 23 3 16.11 19.2 Q126X 4 Nonsense 80 10 0 5.56 2.8 G268R 7 Missense 89 1 0 0.56 N.D. S441N 11 Missense 89 1 0 0.56 0.3 F506SfsX4 13 Frameshift 89 1 0 0.56 0.3 * Data from Maekawa et al. (34). Login to comment
90 Q141K was 98.8%, 100%, and 99.2%, respectively. P values for Hardy-Weinberg equilibrium of V12M, Q126X, and Q141K were 0.08, 0.72, and 0.01, respectively. P values that suggested mistyping were not obtained. Login to comment
91 Haplotype frequency analysis revealed that there is no simultaneous presence of the minor alleles of Q126X and Q141K in one haplotype (Table 3). Login to comment
92 The haplotype with Q126X is present in up to 13.5% of gout patients, and it markedly increases gout risk (OR, 5.97; 95% CI, 3.39-10.51; P = 4.10 × 10-12 ) compared with nonrisk haplotypes. Login to comment
94 Our data also show enrichment of the Q126X minor allele in gout or hyperuricemia patients relative to normouricemic subjects (SUA ≤ 7.0 mg/dl). Login to comment
95 Thus, the Q126X mutation of the ABCG2 gene is identified as a major cause of primary gout. Login to comment
96 Together, these findings suggest that nonfunctional variants of ABCG2, such as Q126X, essentially block urate excretion and cause gout. Login to comment
99 Because Q126X and Q141K are assigned to different risk haplotypes, nonfunctional and half-functional haplotype, respectively, their genotype combinations are divided into four groups on the basis of the estimated ABCG2 transport functions, that is, full function, ¾ function, ½ function, and ≤¼ function (Table 4). Login to comment
106 We also demonstrated that nonfunctional ABCG2 mutation Q126X is assigned to the identical haplotype, which increases gout risk, conferring an OR of 5.97. Login to comment
115 Phenotype SNP Genotype* Allele frequency mode Case Control P value P value OR 95% CI 1/1 1/2 2/2 MAF 1/1 1/2 2/2 MAF Q126X 1 21 139 0.071 0 31 840 0.018 1.74 × 10-7 3.04 × 10-8 4.25 2.44-7.38 Gout Q141K 31 87 41 0.469 87 316 462 0.281 5.80 × 10-10 5.54 × 10-11 2.23 1.75-2.87 V12M 3 43 112 0.155 30 306 526 0.212 0.055 0.020 0.68 0.49-0.94 Q126X 2 24 202 0.061 0 31 840 0.018 1.91 × 10-6 2.91 × 10-7 3.61 2.14-6.08 Hyperuricemia Q141K 45 113 68 0.449 87 316 462 0.281 5.32 × 10-10 1.53 × 10-11 2.06 1.67-2.55 V12M 7 55 163 0.153 30 306 526 0.212 0.006 0.005 0.67 0.51-0.89 * Minor allele was referred to as allele 1 and major allele as 2. Login to comment
116 Allele 1 is T and allele 2 is C in Q126X. Login to comment
120 Haplotype frequency analysis of V12M, Q126X, and Q141K. Login to comment
122 Risk alleles for Q126X and Q141K are underlined. Login to comment
123 Allele Frequency P value OR 95% CI V12M Q126X Q141K Gout Control G C A 0.465 0.284 2.26 × 10-13 2.50 1.94-3.20 G T C 0.071 0.018 4.10 × 10-12 5.97 3.39-10.51 G C C 0.306 0.486 - - - A C C 0.155 0.212 - - - of ABCG2, such as rosuvastatin (42) and gefitinib (43), have been reported. Login to comment
137 The approach reported here (fig. S1) revealed that nonfunctional variants of ABCG2, such as Q126X, essentially block urate excretion and cause gout. Login to comment
138 In contrast to the rare Mendelian disorders described above, the disease haplotype carrying the ABCG2 Q126X mutation (OR, 5.97; 95% CI, 3.39-10.51; P = 4.10 × 10-12 ) is present in as many as 13.5% of primary gout patients in our population, suggesting that Q126X is a major causative mutation for gout. Login to comment
144 OR is obtained by comparing with nonrisk genotype combination C/C(Q126X) and C/C(Q141K). Login to comment
145 Risk alleles for Q126X and Q141K are underlined. Login to comment
146 Estimated transport Genotype Number P value OR 95% CI Q126X Q141K Gout Control ≤¼ function T/T C/C 16 8 3.39 × 10-21 25.8 10.3-64.6 T/C A/C ½ function T/C C/C 37 110 2.23 × 10-9 4.34 2.61-7.24 C/C A/A ¾ function C/C A/C 72 308 2.29 × 10-7 3.02 1.96-4.65 Full function C/C C/C 34 439 Normal control UA ABCG2 transport Gout <UA 7.0 mg/dl 23.3% 10.1% 35.6% 12.7% 0.9% patients Gout no function Q126X T/T Q141K C/C 25% function 50% function =< T/C A/C 45.3% 50.8% 100% function 75% function 50% function C/C C/C T/C A/C A/A C/C 21.4%s 100% function C/C C/C Other gout risk G G G G G N G Fig. 3. Login to comment
148 The genotype combinations of Q126X and Q141K are divided into several groups based on estimated ABCG2 transport functions. Login to comment
149 The Q126X homozygous and heterozygous mutations were identified in up to 13.5% of total gout patients (n = 161). Login to comment
156 In this study, we identified several nonfunctional ABCG2 mutations, including Q126X, in Japanese gout patients, which shows stronger effects on gout development than Q141K did in a previous study (OR < 2.0) (22). Login to comment
157 There is a possibility that these nonfunctional mutations, including Q126X, are specific to a Japanese or Asian population, or alternatively, there may be nonfunctional mutations in the ABCG2 gene that cause gout in Caucasians and other groups. Login to comment
181 Using the site-directed mutagenesis technique, we constructed mutants of ABCG2 (V12M, Q126X, Q141K, G268R, S441N, and F506SfsX4), which were used for urate transport analysis, on the expression vector for ABCG2. Login to comment

[hide] Genetics of hyperuricemia and gout: implications f... Curr Rheumatol Rep. 2013 Feb;15(2):309. doi: 10.1007/s11926-012-0309-8. George RL, Keenan RT
Genetics of hyperuricemia and gout: implications for the present and future.
Curr Rheumatol Rep. 2013 Feb;15(2):309. doi: 10.1007/s11926-012-0309-8., [PMID:23307580]

Abstract [show]
Gout is the most common inflammatory arthropathy and occurs in the setting of elevated serum urate levels. Gout is also known to be associated with multiple comorbidities including cardiovascular disease and the metabolic syndrome. Recent advances in research have increased our understanding and improved our knowledge of the pathophysiology of gout. Genome-wide association studies have permitted the identification of several new and common genetic factors that contribute to hyperuricemia and gout. Most of these are involved with the renal urate transport system (the uric acid transportasome), generally considered the most influential regulator of serum urate homeostasis. Thus far, SCL22A12, SCL2A9, and GLUT9 have been found to have the greatest variation and most influence on serum urate levels. However, genetics are only a part of the explanation in the development of hyperuricemia and gout. As results have been mixed, the role of known urate influential genes in gout's associated comorbidities remains unclear. Regardless, GWAS findings have expanded our understanding of the pathophysiology of hyperuricemia and gout, and will likely play a role in the development of future therapies and treatment of this ancient disease.

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129 The investigators found that common dysfunctional genotype combinations of ABCG2 gene (variants, Q126X and Q141K) are a major cause of gout [48]. Login to comment
135 The relationship between overproduction, hyperuricemia, and ABCG2 dysfunction led the authors to propose a new, testable model of hyperuricemia that takes into account population genotypes such as Q126X and Q141K affecting ABCG2 function. Login to comment

[hide] No association between MTHFR C677T and serum uric ... Nagoya J Med Sci. 2013 Feb;75(1-2):93-100. Hinohara Y, Naito M, Okada R, Yin G, Higashibata T, Tamura T, Kawai S, Morita E, Wakai K, Matsuo H, Mori A, Hamajima N
No association between MTHFR C677T and serum uric acid levels among Japanese with ABCG2 126QQ and SLC22A12 258WW.
Nagoya J Med Sci. 2013 Feb;75(1-2):93-100., [PMID:23544272]

Abstract [show]
Several genome-wide association studies (GWAS) have revealed that single nucleotide polymorphisms (SNPs) of ABCG2 and SLC22A12 were strongly associated with serum uric acid (SUA), but those of methylene tetrahydrofolate reductase (MTHFR) were not. However, there were several studies indicating the association with MTHFR C677T polymorphism. This study examined the association with the polymorphism, taking into account the genotypes of ABCG2 Q126X and SLC22A12 W258X. Subjects were 5,028 health checkup examinees of Seirei Preventive Health Care Center (3,416 males and 1,612 females) aged 35 to 69 years, who participated in the Japan Multi-Institutional Collaborative Cohort Study (J-MICC Study). Hyperuricemia was defined as SUA equal to 7 mg/dL or over. The genotype frequency was 35.9% for CC, 48.1% for CT, and 16.0% for TT, being in Hardy-Weinberg equilibrium (p=0.90). Among 4,425 participants with ABCG2 126QQ and SLC22A12 258WW who were not under medication for hyperuricemia, the mean SUA was 5.6 mg/dL, 5.6 mg/dL, and 5.7 mg/dL, respectively. When 114 participants with ABCG2 126QQ and SLC22A12 258WW under medication for hyperuricemia were included in hyperuricemia cases, the sex-age adjusted odds ratio (OR) of hyperuricemia was not significant; OR=1.00 (95% confidence interval, 0.89-1.24) for CT genotype and OR=0.98 (0.84-1.32) for TT genotype, relative to CC genotype. The present study indicated no association between SUA and MTHFR C677T genotype, after the influences of ABCG2 Q126X and SLC22A12 W258X were removed.

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5 This study examined the association with the polymorphism, taking into account the genotypes of ABCG2 Q126X and SLC22A12 W258X. Login to comment
11 The present study indicated no association between SUA and MTHFR C677T genotype, after the influences of ABCG2 Q126X and SLC22A12 W258X were removed. Login to comment
12 Key Words: Serum uric acid, Urate transporter polymorphisms, MTHFR C677T INTRODUCTION It is well known that serum uric acid (SUA) levels are associated with various factors such as sex, age, body mass index (BMI), dietary habit and drinking habit.1-3) In addition, there is evidence that genetic traits influence SUA concentrations; the heritability was estimated to be up to 73%.4) A recent genome-wide association study performed in Japan showed strong associations of SUA with genetic polymorphisms of SLC22A12 coding uric acid transporter 1 (URAT1), Received: January 13, 2013; accepted: January 24, 2013 Corresponding author: Yukako Hinohara MD, MPH Department of Preventive Medicine, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan Phone: +81 52 744 2132, Fax: +81 52 744 2971, E-mail address: y.hinohara@soumu.go.jp SLC2A9 coding glucose transporter 9 (GLUT9), and ABCG2 coding ATP-binding cassette subfamily G member 2 (ABCG2),5) which were also reported to have associations in European ancestry.6) Among the polymorphisms, SLC22A12 W258X,7,8) SLC2A9 R380W and R198C,9) and ABCG2 Q126X and Q141K10,11) were confirmed to have associations with SUA, although the association of ABCG2 Q141K was relatively weak. Login to comment
14 Although not detected in the genome-wide association study, methylenetetrahydrofolate reductase (MTHFR) C677T was reported to have associations with SUA.12-14) A recent meta-analysis on the association with six studies (two from Iran, two from China, one from Korea, and one from Japan) demonstrated that the summary odds ratio (OR) was 1.879 (95% confidence interval (CI), 1.596-2.213).15) The present study investigated the association of MTHFR C677T with SUA levels among Japanese health checkup examinees, after taking into account the genotypes of SLC22A12 W258X and ABCG2 Q126X. Login to comment
62 A systematic review showed that the ethnicity may affect the relationship between the MTHFR mutation and SUA levels.33) In conclusion, though some limitations remain, the present study indicated no association between SUA and MTHFR C677T genotype among Japanese, after the influences of ABCG2 Q126X and SLC22A12 W258X were removed. Login to comment

[hide] [Transporter-mediated regulation of pharmacokineti... Yakugaku Zasshi. 2013;133(4):451-61. Takada T
[Transporter-mediated regulation of pharmacokinetics of lifestyle-related substances].
Yakugaku Zasshi. 2013;133(4):451-61., [PMID:23546589]

Abstract [show]
Recent studies revealed the importance of transporters in the behaviors of small molecules in the body. In mammals, the presence of a lot of transporters has been suggested, such as ATP-binding cassette (ABC) transporters and solute ligand carrier (SLC) transporters, some of which are clarified to be causative genes for various kinds of genetic disorders. In addition, a lot of transporters are known to mediate cellular import or export of drugs, to contribute to the pharmacokinetics of substrate drugs and to be involved in the interindividual differences of drug responses. In this review, I introduce our recent work on the transporter-mediated regulation of pharmacokinetics of lifestyle-related substances, such as cholesterol and urate.

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24 c3f; ⏚ ᣸ 3fa; c8; e9; f3; b9; dd; fc; bf; fc; ABCG2 Ĳe; SNPs ௼ ad8;c3f;⏚⊈Kc7;fb;Kdb;ba8;ea;b9;af; ˯f;d3b;fd2;᠓Kc5;௼ ௱௺Me5;఑Ĵc;Ĵb; ad8;c3f;⏚⊈Kc7;ఌKdb;ba8;Ĳf;,d05;ca2;Kc5;௼௤௦a00; ℁İc;௢Ĵb;ఐ௦Ĳb;,Pa5;e80;ఌ ad8;d7;ea;f3;bdf;Ĳe;ᤪbdf;Έe;ɏa;Ĳa;௽ Ĳe;Jb0;᛻⌕8e0;Ĳb;d77;8e0;௳Ĵb;௼ὃ௨఑Ĵc;௺௤ıf;İc;,fd1;e74;Ĳe; Ẇa76;Ĳb;ఐĴa;΋a;f1d;ḄĲa;⌕8e0;Ĳe;b58;ᙠఊ̙a;ᖂ௯Ĵc;௺௤ıf;&#ff0e; 2004 e74;,5f0;e7e;Ĳe;Ẇa76;b0;eb;fc;d7;ఐĴa;,d2;c8;b2c; 4 Cd3; ⁐f53;╩ΊĲb;ʠa;Me5;Ĳe;Kdb;ba8;Kc5;8e0;΋a;f1d;b50;İc;b58;ᙠ௳Ĵb;5ef;Pfd;ឋ İc;ᛇȠa;௯Ĵc;ıf;İc;, 26) ᎛Xdc;♚9df;Ĳb;Ĳf;ɏa;İf;Ĳe;΋a;f1d;b50;İc;Ȟb; ĳe;Ĵc;௺İa;Ĵa;,ᐹf53;ḄĲa;Kc5;8e0;΋a;f1d;b50;Ĳf;Ȝc;b9a;௯Ĵc;௺௤Ĳa; İb;௷ıf;&#ff0e;ıd;௭௻,d30;Pde;̳c;e0a;Ĳb;İa;௤௺f38;〈9fa;cea;Ĳe;᣸3fa; Ĳb;fc2;Ĵf;Ĵb; ABCG2/breast cancer resistance protein (BCRP) ΋a;f1d;b50;İc;௭Ĳe;♚9df;Ĳb;b58;ᙠ௳Ĵb;௭௼, ABCG2 Ĳb;Ĳf;a5f;Pfd;᜕4d5;ఔf34;௦ϗb;ea6;Ĳe; ad8;௤΋a;f1d;b50;ɏa;ɂb;İc;b58;ᙠ௳ Ĵb;௭௼,Ae2;Me5;Ĳe;f38;〈9fa;cea;௼Ĳe;bd4;f03;İb;఑c3f;⏚Ĳf; ABCG2 Ĳe;9fa;cea;Ĳb;Ĳa;Ĵa;f97;Ĵb;௼ὃ௨఑Ĵc;ıf;௭௼Ĳa;௽Ĳe;ᳮᵫĲb;ఐ Ĵa;,b46;ὅ఑Ĳf; ABCG2 Ĳb;_a2;௳Ĵb;ʳc;a0e;ఔ⍈ఉıf;(௵Ĳa; ĳf;Ĳb;,ıd;Ĳe;f8c;Ĳe; GWAS Ĳb;İa;௤௺ఊ⊈e05;c3f;⏚ᎠĲe;᜕ 4d5;Ĳb;_a2;⌿௳Ĵb;΋a;f1d;b50;௼௱௺ ABCG2 Ĳf;ᛇȠa;௯Ĵc;௺௤ Ĵb;) &#ff0e; 27&#e30f; 29) ABCG2/BCRP Ĳf;ıd;Ĳe;Ȝd;Ĳe;΅a;Ĵa;,ɏa;ᒐὊឋĲb;_a2;e0e; ௳Ĵb;8e0;b50;௼௱௺˿a;΂b;௯Ĵc;ıf;c8;e9;f3;b9;dd;fc;bf;fc;௻௢Ĵb; İc;,e83;bc4;Ĳa;d44;e54;ᑖe03;௼e83;௤9fa;cea;a8d;b58;ឋఔᨵ௳Ĵb;௭௼ İc;b21;b2c;Ĳb;ʔe;఑İb;௼Ĳa;Ĵa;,Ife;ᙠ௻Ĳf;ɏa;Ed8;Ĳa;⌤Fb9;İb;఑Ẇ a76;İc;⍈ఉ఑Ĵc;௺௤Ĵb;&#ff0e;Ae5;ʠc;eba;Ĳb;İa;௫Ĵb; ABCG2 ΋a;f1d; b50;ɏa;ɂb;Ĳe;a2;ec;eb;ϗb;ea6;Ĳf; ad8;İf;,˿a;Ife;[cf;5ca;ఁa5f;Pfd;᜕ᓄఔ f34;Ĵf;Ĳa;௤ 34G&#ff1e;A(V12M)Ĳf; 19.2%,bf;f3;d1;af;cea; ˿a;Ife;[cf;İc;d04;Ȗa;ᑖĲb;f4e;e0b;௳Ĵb; 421C&#ff1e;A(Q141K)Ĳf; 31.9%,d42;b62;b3;c9;f3;İc;˯f;௲a5f;Pfd;b20;ʀd;௼Ĳa;Ĵb; 376C&#ff1e;T (Q126X)Ĳf; 2.8%௻௢Ĵb;௼ᛇȠa;௯Ĵc;௺௤Ĵb;&#ff0e; 30) ௭Ĵc; ఑Ĳe;௦௵,ϗb;ea6;İc; ad8;İf;a5f;Pfd;f4e;e0b;ఔf34;௦ 421C&#ff1e;A (Q141K)Ĳb;௸௤௺Ĳf;Qe8;e8a;ḄĲb;ఊఐİf;Ẇa76;௯Ĵc;௺İa; Ĵa;,Uac;ᱥ4d5;ɦb;Ĳe;᜕4d5;௼௱௺Ĳf;,b9;eb;d5;a1;b5;e9;b8;f3;Ĳe; d88;ᓄba1;ᔾ5ce;Ĳe;e0a;᧏,ed;b9;d0;b9;bf;c1;f3;ఌd5;eb;d0;b9;bf;c1; f3;Ĳe;d4c;5e3;ᢗe0e;᧲Ĳe; AUC(Uac;ᱥ⊈e2d;fc3;ea6;ߟ᧲╹Bf2;dda; e0b;☢a4d;)ఌ Cmax(ᨬ ad8;⊈e2d;fc3;ea6;)Ĳe;e0a;᧏İc;Yb3;bdf;௯ Ĵc;௺௤Ĵb;&#ff0e;௭Ĳe;ఐ௦Ĳb;,Uac;ᱥc8;e9;f3;b9;dd;fc;bf;fc; ABCG2 Ĳe;Uac;ᱥ4d5;ɦb;ᑴfa1;8e0;b50;௼௱௺Ĳe;[cd;⌕ឋĲf;a8d;b58; ௯Ĵc;௺௤ıf;ఊĲe;Ĳe;,d2;c8;Ĳb;İa;௫Ĵb;˯f;ᳮḄ9fa;cea;ఌ˯f;ᳮ a5f;Pfd;Ĳb;௸௤௺Ĳf;e0d;ʔe;௻௢௷ıf;&#ff0e; ABCG2 Ĳb;ఐĴb;c3f;⏚f38;〈Ĳb;௸௤௺ʳc;a0e;௳Ĵb;ıf;ఉ, ABCG2 ˿a;Ife;d30;Pde;İb;఑abf;Xfd;௱ıf;d30;Pde;̳c;c0f;Pde;ఔᵨ௤ıf; f38;〈b9f; a13;ఔʹc;௷ıf;d50;ʧc;,ABCG2 Ĳf;˯f;ᳮḄfc3;ea6;௻Ĳf; bfd;Ȥc;௱Ĳa;௤ ad8;bb9;[cf;ឋfb;f4e;Yaa;Ȥc;ឋĲe;c3f;⏚f38;〈ఔ>c5;௦௭ ௼İc;ʔe;఑İb;௼Ĳa;௷ıf;(c3f;⏚Ĳe;eb6;Ye3;ea6;Ĳe;bd4;f03;Ḅ ad8;௤ ad8; pH e0b;௻c42;ఉ఑Ĵc;ıf; Km ᎠĲf; 8.24&#b1;1.44 mM ௻௢ Ĵa;,⊈e05;c3f;⏚Ꭰ(f8b;௨௾ 7.0 mg/dL&#ff1d;d04; 420 mM) ௼bd4;ఇ௺Ĳf;Ĵb;İb;Ĳb; ad8;௤) &#ff0e; 31) ĳe;ıf;,᜕ᶒf53;Ye3;᪆Ĳe;d50; ʧc;,ed6;Ĳe;f38;〈9fa;cea;௼Ȝc;Ed8;,c3f;⏚f38;〈Ĳb;İa;௤௺ఊ Q141K ௻Ĳf;a5f;Pfd;İc;Ȗa;e1b;,Q126X ௻Ĳf;a5f;Pfd;İc;d88;ᜫ௳ Ĵb;௭௼İc;̙a;௯Ĵc;ıf;&#ff0e; ௸௹௤௺,Ae5;ʠc;eba;Ĳe;Ꮙeb7;a3a;Aad;5d7;a3a;ὅĲe;b5;f3;d7;eb;ఔ ᵨ௤௺,⊈e05;c3f;⏚Ꭰ௼ ABCG2 ΋a;f1d;b50;ɏa;ɂb;Ĳe;_a2;fc2;Ĳb; ௸௤௺ʳc;a0e;௱ıf;d50;ʧc;,Q141K ᜕ᶒĲe;fdd;ᢝᦪİc;ɏa;௤ ĳb;௽,⊈e05;c3f;⏚Ꭰİc;e0a;᧏௱௺௤ıf;&#ff0e; 31) ĳe;ıf;,cf;d7;ed; bf;a4;d7;ϗb;ea6;Ye3;᪆Ĳb;ఐĴa;,Q126X ௼ Q141K Ĳe;e21;᜕ᶒ 4. Proposed Model of ABCG2-mediated Urate Secretion31) 458 Vol. 133 (2013) Ĳf;Ȝc;௲Cd3;⁐f53;e0a;Ĳb;Ĳf;b58;ᙠ௱Ĳa;௤௭௼İc;̙a;௯Ĵc;ıf;&#ff0e;ıd; ௭௻,e21;᜕ᶒĲe;ϗb;ea6;Ĳb;௸௤௺Ae5;ʠc;eba;ᵱឋĲe;Kdb;ba8;Kc7;f8b; ௼Ꮙe38;ὅ௻bd4;f03;௱ıf;d50;ʧc;,Q126X ௼ Q141K Ĳe;d44;ĳf; ᔠĴf;ıb;İb;఑?a8;b9a;௯Ĵc;Ĵb;c3f;⏚f38;〈d3b;ឋĲe;f4e;e0b;Ĳb;f34;௤, aa;c3;ba;bd4;௻̙a;௯Ĵc;Ĵb;Kdb;ba8;˿a;Kc7;ea;b9;af;İc;♿℉Ĳb; ad8;ĳe;Ĵb; ௭ ௼ İc; ʔe; ఑ İb; ௼ Ĳa; ௷ ıf; &#ff0e; 31) ௭ Ĵc; ఑ Ĳe; d50; ʧc; Ĳf; , ABCG2 İc;˯f;f53;ᑁĲb;İa;௫Ĵb;c3f;⏚Ĳe;f53;᜜ఆĲe;᣸cc4;Ĳb;_a2; e0e;௱௺İa;Ĵa;,ıd;Ĳe;a5f;Pfd;f4e;e0b;Ĳf;⊈e05;c3f;⏚Ꭰ31,32)5ca;ఁKdb; ba8;˿a;Kc7;ea;b9;af;31)Ĳe;e0a;᧏ఔఊıf;఑௳௭௼ఔ̙a;௳ఊĲe;௻ ௢௷ıf;&#ff0e;ABCG2 Ĳf;̩d;Qd3;,̮e;Qd3;,c0f;ῲĲa;௽Ĳe;♊aef;̳c; Ĳb;˿a;Ife;௱,f38;〈9fa;cea;Ĳe;f53;᜜ఆĲe;᣸3fa;Ĳb;fc2;Ĵf;Ĵb;௭௼İc; Me5;఑Ĵc;௺௤Ĵb;௭௼,c3f;⏚Ĳf;c3f;e2d;Ĳe;ĳf;Ĳa;఑ıa;cde;e2d;Ĳb;ఊ ᣸ cc4; ௯ Ĵc; Ĵb; ௭ ௼ İc; ᛇ Ƞa; ௯ Ĵc; ௺ ௤ ıf; ௭ ௼ İb; ఑ , ABCG2 Ĳf;௭Ĵc;఑Ĳe;d44;e54;İb;఑Ĳe;c3f;⏚ᑖccc;Ĳb;_a2;e0e;௱௺ ௤Ĵb;5ef;Pfd;ឋİc;ὃ௨఑Ĵc;ıf;(Fig. 4) &#ff0e; 31) 5-2. Login to comment

[hide] Common dysfunctional variants in ABCG2 are a major... Sci Rep. 2013;3:2014. doi: 10.1038/srep02014. Matsuo H, Ichida K, Takada T, Nakayama A, Nakashima H, Nakamura T, Kawamura Y, Takada Y, Yamamoto K, Inoue H, Oikawa Y, Naito M, Hishida A, Wakai K, Okada C, Shimizu S, Sakiyama M, Chiba T, Ogata H, Niwa K, Hosoyamada M, Mori A, Hamajima N, Suzuki H, Kanai Y, Sakurai Y, Hosoya T, Shimizu T, Shinomiya N
Common dysfunctional variants in ABCG2 are a major cause of early-onset gout.
Sci Rep. 2013;3:2014. doi: 10.1038/srep02014., [PMID:23774753]

Abstract [show]
Gout is a common disease which mostly occurs after middle age, but more people nowadays develop it before the age of thirty. We investigated whether common dysfunction of ABCG2, a high-capacity urate transporter which regulates serum uric acid levels, causes early-onset gout. 705 Japanese male gout cases with onset age data and 1,887 male controls were genotyped, and the ABCG2 functions which are estimated by its genotype combination were determined. The onset age was 6.5 years earlier with severe ABCG2 dysfunction than with normal ABCG2 function (P = 6.14 x 10(-3)). Patients with mild to severe ABCG2 dysfunction accounted for 88.2% of early-onset cases (twenties or younger). Severe ABCG2 dysfunction particularly increased the risk of early-onset gout (odds ratio 22.2, P = 4.66 x 10(-6)). Our finding that common dysfunction of ABCG2 is a major cause of early-onset gout will serve to improve earlier prevention and therapy for high-risk individuals.

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17 We also showed that genotyping of only two dysfunctional variants, Q126X (rs72552713) and Q141K (rs2231142), is sufficient to estimate the severity of ABCG2 dysfunction; i.e. full function, 3/4 function (mild dysfunction), 1/2 function (moderate dysfunction), and # 1/4 function (severe dysfunction). Login to comment
39 Table 1 | ABCG2 functions of participants Estimated Function Genotype Combination Number (%) Q126X* (rs72552713) Q141K* (rs2231142) Gout Control #1/4 function T/T C/C 37 (5.2) 22 (1.2) T/C C/A 1/2 function T/C C/C 169 (24.0) 219 (11.6) C/C A/A 3/4 function C/C C/A 331 (47.0) 699 (37.0) Full function C/C C/C 168 (23.8) 947 (50.2) Total 705 (100.0) 1,887 (100.0) * Risk alleles (T for Q126X, A for Q141K) are indicated in bold type at four locations, respectively. Login to comment
73 Genotyping of Q126X (rs72552713) and Q141K (rs2231142) in ABCG2 gene by high-resolution melting (HRM) analysis was performed with a LightCycler 480 (Roche Diagnostics)41 . Login to comment

[hide] ABCG2 dysfunction causes hyperuricemia due to both... Sci Rep. 2014 Jan 20;4:3755. doi: 10.1038/srep03755. Matsuo H, Nakayama A, Sakiyama M, Chiba T, Shimizu S, Kawamura Y, Nakashima H, Nakamura T, Takada Y, Oikawa Y, Takada T, Nakaoka H, Abe J, Inoue H, Wakai K, Kawai S, Guang Y, Nakagawa H, Ito T, Niwa K, Yamamoto K, Sakurai Y, Suzuki H, Hosoya T, Ichida K, Shimizu T, Shinomiya N
ABCG2 dysfunction causes hyperuricemia due to both renal urate underexcretion and renal urate overload.
Sci Rep. 2014 Jan 20;4:3755. doi: 10.1038/srep03755., [PMID:24441388]

Abstract [show]
Gout is a common disease which results from hyperuricemia. We have reported that the dysfunction of urate exporter ABCG2 is the major cause of renal overload (ROL) hyperuricemia, but its involvement in renal underexcretion (RUE) hyperuricemia, the most prevalent subtype, is not clearly explained so far. In this study, the association analysis with 644 hyperuricemia patients and 1,623 controls in male Japanese revealed that ABCG2 dysfunction significantly increased the risk of RUE hyperuricemia as well as overall and ROL hyperuricemia, according to the severity of impairment. ABCG2 dysfunction caused renal urate underexcretion and induced hyperuricemia even if the renal urate overload was not remarkable. These results show that ABCG2 plays physiologically important roles in both renal and extra-renal urate excretion mechanisms. Our findings indicate the importance of ABCG2 as a promising therapeutic and screening target of hyperuricemia and gout.

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17 Their functional ABCG2 activities were estimated from their genotype combinations of its two dysfunctional missense variants, Q126X (rs72552713) and Q141K (rs2231142). Login to comment
18 Because there is no simultaneous presence of the minor alleles of non-functional variant Q126X and half-functional variant Q141K in one hap- lotype5,7 , we defined three haplotype IDs as *1, *2, and *3, as shown in Figure 1a. Login to comment
24 Furthermore, Q126X homozygote signifying complete deficiency of ABCG2 was identified in one case with gout in the ROL hyperuricemia group. Login to comment
26 When hyperuricemia was divided into three distinct types (i.e., RUE type, combined type, and ROL type as shown in Supplementary Fig. S1), severe ABCG2 dysfunction (#1/4 function) significantly raised the risk of combined and ROL types but not that of RUE type Figure 1 | Estimation of ABCG2 function from diplotype of Q126X and Q141K alleles. Login to comment
27 (a) ABCG2*2 or *3 represents a haplotype with Q141K or Q126X variant, respectively. Login to comment
28 ABCG2*1 indicates a haplotype with neither Q141K nor Q126X variant. Login to comment
29 Since Q141K is a half-functional variant and Q126X is a nonfunctional variant, relative function of ABCG2*1, *2, and *3 is 1, 1/2, and 0, respectively, which is visualized by black-indicated areas. Login to comment
32 Table 1 | ABCG2 functions of participants Estimated transport activity Diplotype of Q126X (rs72552713) and Q141K (rs2231142) alleles** Case{ Control N % N % #1/4 function *3/*3 or *2/*3 29 (26) 4.5 (4.7) 22 1.3 1/2 function *1/*3 or *2/*2 151 (135) 23.4 (23.5) 190 11.7 3/4 function *1/*2 307 (277) 47.7 (48.2) 600 37.0 Full function *1/*1 157 (136) 24.4 (23.7) 811 50.0 Total 644 (575) 100.0 (100.0) 1,887 100.0 **Haplotypes ''Q-Q``, ''Q-K``, and ''X-Q`` of two SNPs (Q126X and Q141K) are referred to as *1, *2, and *3, respectively. Login to comment
33 Risk alleles are X for Q126X, and K for Q141K. Login to comment
67 Genotyping of ABCG2 Q126X (rs72552713) and Q141K (rs2231142) was performed by high-resolution melting analysis with a LightCycler 480 (Roche Diagnostics)19 . Login to comment
68 From the haplotype analyses reported in the previous studies5,7 , there is no simultaneous presence of the minor alleles (risk alleles) of non-functional variant Q126X and half-functional variant Q141K in one haplotype. Login to comment
69 In this study, their haplotype IDs, *1, *2, and *3, were defined as Figure 1a; the combination of wild-type Q126X and Q141K alleles (''Q-Q``) was designated as ABCG2*1, which corresponds to the cDNA sequence of GenBank (accession number NM_004827). Login to comment
71 Based on the diplotype of Q126X and Q141K alleles (Fig. 1b)5,7 , ABCG2 function was estimated and divided into four groups5-7 ; i.e., full function, 3/4 function, 1/2 function, and #1/4 function (Table 1). Login to comment

[hide] Influence of the ABCG2 gout risk 141 K allele on u... Arthritis Res Ther. 2014 Jan 30;16(1):R34. doi: 10.1186/ar4463. Dalbeth N, House ME, Gamble GD, Pool B, Horne A, Purvis L, Stewart A, Merriman M, Cadzow M, Phipps-Green A, Merriman TR
Influence of the ABCG2 gout risk 141 K allele on urate metabolism during a fructose challenge.
Arthritis Res Ther. 2014 Jan 30;16(1):R34. doi: 10.1186/ar4463., [PMID:24476385]

Abstract [show]
INTRODUCTION: Both genetic variation in ATP-binding cassette sub-family G member 2 (ABCG2) and intake of fructose-containing beverages are major risk factors for hyperuricemia and gout. This study aimed to test the hypothesis that the ABCG2 gout risk allele 141 K promotes the hyperuricaemic response to fructose loading. METHODS: Healthy volunteers (n = 74) provided serum and urine samples immediately before and 30, 60, 120 and 180 minutes after ingesting a 64 g fructose solution. Data were analyzed based on the presence or absence of the ABCG2 141 K gout risk allele. RESULTS: The 141 K risk allele was present in 23 participants (31%). Overall, serum urate (SU) concentrations during the fructose load were similar in those with and without the 141 K allele (PSNP = 0.15). However, the 141 K allele was associated with a smaller increase in SU following fructose intake (PSNP <0.0001). Those with the 141 K allele also had a smaller increase in serum glucose following the fructose load (PSNP = 0.002). Higher fractional excretion of uric acid (FEUA) at baseline and throughout the fructose load was observed in those with the 141 K risk allele (PSNP <0.0001). However, the change in FEUA in response to fructose was not different in those with and without the 141 K risk allele (PSNP = 0.39). The 141 K allele effects on serum urate and glucose were more pronounced in Polynesian participants and in those with a body mass index >/=25 kg/m(2). CONCLUSIONS: In contrast to the predicted responses for a hyperuricemia/gout risk allele, the 141 K allele is associated with smaller increases in SU and higher FEUA following a fructose load. The results suggest that ABCG2 interacts with extra-renal metabolic pathways in a complex manner to regulate SU and gout risk. CLINICAL TRIALS REGISTRATION: The study was registered by the Australian Clinical Trials Registry (ACTRN12610001036000).

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54 The Q126X SNP rs72552713 was also genotyped using the Taqman assay as described above (the context sequence for rs72552713 (assay ID C__98388180_20) is [VIC/ FAM] AATGCAAACCCACTAATACTTACTT[G/A]TAC CACGTAACCTGAATTACATTTG). Login to comment

[hide] Structure and function of BCRP, a broad specificit... Arch Toxicol. 2014 Jun;88(6):1205-48. doi: 10.1007/s00204-014-1224-8. Epub 2014 Apr 29. Jani M, Ambrus C, Magnan R, Jakab KT, Beery E, Zolnerciks JK, Krajcsi P
Structure and function of BCRP, a broad specificity transporter of xenobiotics and endobiotics.
Arch Toxicol. 2014 Jun;88(6):1205-48. doi: 10.1007/s00204-014-1224-8. Epub 2014 Apr 29., [PMID:24777822]

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The discovery and characterization of breast cancer resistance protein (BCRP) as an efflux transporter conferring multidrug resistance has set off a remarkable trajectory in the understanding of its role in physiology and disease. While the relevance in drug resistance and general pharmacokinetic properties quickly became apparent, the lack of a characteristic phenotype in genetically impaired animals and humans cast doubt on the physiological importance of this ATP-binding cassette family member, similarly to fellow multidrug transporters, despite well-known endogenous substrates. Later, high-performance genetic analyses and fine resolution tissue expression data forayed into unexpected territories concerning BCRP relevance, and ultimately, the rise of quantitative proteomics allows putting observed interactions into absolute frameworks for modeling and insight into interindividual and species differences. This overview summarizes existing knowledge on the BCRP transporter on molecular, tissue and system level, both in physiology and disease, and describes a selection of experimental procedures that are the most widely applied for the identification and characterization of substrate and inhibitor-type interactions.

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95 Histone deacetylase inhibitors rescue newly synthesized transporter proteins and prevent aggresome targeting by disturbing TableÊf;1ߒߙMajor non-synonymous single-nucleotide polymorphisms found in the ABCG2 coding region Allele frequencies presented in this table do not reflect interethnic differences Mutation Position in BCRP Cellular effects of SNP Allele frequency % References 34G>A, V12M (rs2231137) N-terminus Lower expression, no impact on function 0-29.8 Tamura et al. (2006), Bosch et al. (2005), Mizuarai et al. (2004), Imai et al. (2002), Kobayashi et al. (2005), Backstrom et al. (2003), Honjo et al. (2002), Kondo et al. (2004) 151G>T, G51C N-terminus Slightly overexpressed, decreased transport activity 0.1 Tamura et al. (2006), Yoshioka et al. (2007) 376C>T, Q126X (rs7255271) NBD No expression, no activity 0-1.7 Tamura et al. (2006), Mizuarai et al. (2004), Itoda et al. (2003), Imai et al. (2002), Kobayashi et al. (2005), Kondo et al. (2004) 421C>A, Q141K (rs2231142) NBD Lower expression, decreased transport activity, substrate specificity altered 0-35.7 Tamura et al. (2006), Bosch et al. (2005), Mizuarai et al. (2004), Imai et al. (2002), Kobayashi et al. (2005), Backstrom et al. (2003), Honjo et al. (2002), Kondo et al. (2004) 458C>T, T153 M NBD Slightly lower expression, no impact on function 3.3 Tamura et al. (2006), Mizuarai et al. (2004) 479G>A, R160Q NBD Not determined 0.5 Bosch et al. (2005), Tamura et al. (2006) 496C>G, Q166E (rs1061017) NBD Slightly lower expression, no impact on function 0-1.1 Tamura et al. (2006), Kondo et al. (2004), Yoshioka et al. (2007) 616A>C, I206L (rs12721643) NBD Well expressed, decreased transport activity 0-10.0 Tamura et al. (2006), Zamber et al. (2003), Vethanayagam et al. (2005), Ieiri (2012a) 623T>C, F208 (rs1061018) NBD No expression, no transport activity 0.9-3.9 Tamura et al. (2006) 742T>C, S248P (rs3116448) NBD Well expressed, no transport activity 0.5 Tamura et al. (2006), Yoshioka et al. (2007) 1000G>T, E334X (rs3201997) NBD No expression, no transport activity Not determined Tamura et al. (2006), Ishikawa et al. (2005) 1291T>C F431L ECL1 Lower expression, substrate specificity altered 0.6-0.8 Tamura et al. (2006), Itoda et al. (2003), Yoshioka et al. (2007) 1322G>A, S441 N ECL1 Slightly lower expression, no transport activity 0.5 Tamura et al. (2006), Kobayashi et al. (2005), Kondo et al. (2004) 1465T>C, F489L TM3 Slightly lower expression, no transport activity 0.5-0.8 Tamura et al. (2006), Itoda et al. (2003), Kobayashi et al. (2005) 1515delC, F506S TM4 Not determined 0.5 Itoda et al. (2003), Kobayashi et al. (2005) 1515delC, F507L 1515delC, V508L 1515delC, M509X 1711T>A, F571I (rs9282571) TM5 Well expressed, substrate specificity altered 0.5 Tamura et al. (2006) 1723C>T, R575X TM5 Not determined 0.5 Tamura et al. (2006) 1768A>T, N590Y (rs34264773) ECL3 Slightly overexpressed, substrate specificity altered 0-9.7 Tamura et al. (2006), Mizuarai et al. (2004), Zamber et al. (2003), Vethanayagam et al. (2005) 1858G>A, D620 N (rs34783571) ECL3 Slightly overexpressed, substrate specificity altered 0-11.1 Tamura et al. (2006), Bosch et al. (2005), Honjo et al. (2002), Vethanayagam et al. (2005) the trafficking along microtubules (Basseville et al. 2012). Login to comment

[hide] Functional polymorphisms of the ABCG2 gene are ass... Int J Mol Sci. 2014 May 22;15(5):9149-59. doi: 10.3390/ijms15059149. Zhou D, Liu Y, Zhang X, Gu X, Wang H, Luo X, Zhang J, Zou H, Guan M
Functional polymorphisms of the ABCG2 gene are associated with gout disease in the Chinese Han male population.
Int J Mol Sci. 2014 May 22;15(5):9149-59. doi: 10.3390/ijms15059149., [PMID:24857923]

Abstract [show]
BACKGROUND: Gout is a common type of arthritis that is characterized by hyperuricemia, tophi and joint inflammation. Genetic variations in the ABCG2 gene have been reported to influence serum uric acid levels and to participate in the pathogenesis of gout, but no further data have been reported in the Han Chinese population. METHODS: Peripheral blood DNA was isolated from 352 male patients with gout and 350 gout-free normal male controls. High-resolution melting analysis and Sanger sequencing were performed to identify the genetic polymorphisms V12M, Q141K and Q126X in the ABCG2 gene. Genotype and haplotype analyses were utilized to determine the disease odds ratios (ORs). A prediction model for gout risk using ABCG2 protein function was established based on the genotype combination of Q126X and Q141K. RESULTS: For Q141K, the A allele frequency was 49.6% in the gout patients and 30.9% in the controls (OR 2.20, 95% confidence interval (CI): 1.77-2.74, p=8.99x10(-)(1)(3)). Regarding Q126X, the T allele frequency was 4.7% in the gout patients and 1.7% in the controls (OR 2.91, 95% CI: 1.49-5.68, p=1.57x10(-)(3)). The A allele frequency for V12M was lower (18.3%) in the gout patients than in the controls (29%) (OR 0.55, 95% CI 0.43-0.71, p=2.55x10(-)(6)). In the order of V12M, Q126X and Q141K, the GCA and GTC haplotypes indicated increased disease risk (OR=2.30 and 2.71, respectively). Patients with mild to severe ABCG2 dysfunction accounted for 78.4% of gout cases. CONCLUSION: The ABCG2 126X and 141K alleles are associated with an increased risk of gout, whereas 12M has a protective effect on gout susceptibility in the Han Chinese population. ABCG2 dysfunction can be used to evaluate gout risk.

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5 High-resolution melting analysis and Sanger sequencing were performed to identify the genetic polymorphisms V12M, Q141K and Q126X in the ABCG2 gene. Login to comment
7 A prediction model for gout risk using ABCG2 protein function was established based on the genotype combination of Q126X and Q141K. Login to comment
9 Regarding Q126X, the T allele frequency was 4.7% in the gout patients and 1.7% in the controls (OR 2.91, 95% CI: 1.49-5.68, p = 1.57 &#d7; 10-3 ). Login to comment
11 In the order of V12M, Q126X and Q141K, the GCA and GTC haplotypes indicated increased disease risk (OR = 2.30 and 2.71, respectively). Login to comment
33 Furthermore, the SNPs Q141K and Q126X in the human ABCG2 gene have recently been recognized as clinical biomarkers to assess hyperuricemia and gout. Login to comment
37 In the present study, we developed an HRM assay to detect three functional SNPs (Q141K, V12M and Q126X) and then assessed the genetic association of those SNPs in the ABCG2 gene with gout to investigate the association between ABCG2 dysfunction and gout risk in a Han Chinese male population. Login to comment
42 The results obtained from the DNA sequencing analysis confirmed the reliability of the HRM assay. The genotype and allelic frequencies of the three SNPs (Q141K, V12M and Q126X) among the cases and controls were in Hardy-Weinberg equilibrium for all of the polymorphisms analyzed. Login to comment
44 Regarding Q126X, the T allele was found on 4.7% of the chromosomes from the gout patients compared with 1.7% of the chromosomes from the controls (OR 2.91, 95% CI: 1.49-5.68, p = 1.57 &#d7; 10-3 ). Login to comment
48 The three groups are well distinguished: (A) V12M; (B) Q126X; and (C) Q141K. Login to comment
54 SNP Genotype * Allele Frequency Mode Case Control p-Value p-Value OR 95% CI 1/1 1/2 2/2 MAF 1/1 1/2 2/2 MAF Q141K 84 181 87 0.496 33 150 167 0.309 1.18 &#d7; 10-11 8.99 &#d7; 10-13 2.20 1.77-2.74 Q126X 0 33 319 0.047 0 12 338 0.017 1.31 &#d7; 10-3 1.57 &#d7; 10-3 2.91 1.49-5.68 V12M 16 97 239 0.183 35 133 182 0.290 3.67 &#d7; 10-5 2.55 &#d7; 10-6 0.55 0.43-0.71 * The minor allele was referred to as allele 1, and the major allele was referred to as allele 2. Login to comment
55 Allele 1 is A and allele 2 is C in Q141K. Allele 1 is T and allele 2 is C in Q126X. Login to comment
58 Haplotype Analysis We performed a 3-SNP haplotype analysis (in the order V12M, Q126X and Q141K). Login to comment
63 Haplotype frequency analysis of V12M, Q126X and Q141K. Allele Frequency p-Value OR 95% CI V12M Q126X Q141K Gout Control G C A 0.481 0.289 1.26 &#d7; 10-13 2.30 1.84-2.87 G T C 0.044 0.017 2.97 &#d7; 10-3 2.71 1.37-5.36 G C C 0.292 0.404 8.27 &#d7; 10-6 0.60 0.48-0.75 A C C 0.165 0.271 1.53 &#d7; 10-6 0.53 0.41-0.69 2.3. Login to comment
74 Estimated Function Genotype Combination Number (%) p-Value OR 95% CI Q141K Q126X Gout Control ࣘ1/4 function C/A T/C 22 (6.2) 8 (2.3) 8.47 &#d7; 10-6 5.90 2.56-13.58 1/2 function C/C T/C 95 (27.0) 37 (10.5) 1.12 &#d7; 10-13 5.51 3.46-8.77 A/A C/C 3/4 function C/A C/C 159 (45.2) 142 (40.6) 1.00 &#d7; 10-6 2.40 1.69-3.42 Full function C/C C/C 76 (21.6) 163 (46.6) ߟ ߟ p-Value, OR and 95% CI for each ABCG2 dysfunction were obtained via comparisons with full function. Login to comment
76 Discussion This study is the first to examine the possible role of ABCG2 variants, which have previously been found to be associated with gout, in terms of their genetic susceptibility to gout in the Han Chinese population. We found that the Q141K, Q126X and V12M alleles were strongly associated with gout in Chinese males. Login to comment
91 The other nonfunctional variant, Q126X, is consistently observed in certain Japanese and Korean cohorts [18,32]. Login to comment
93 These findings reflect the diversity of the Q126X and Q141K distributions in different ethnic populations, which may explain the different prevalence of gout in Chinese and Caucasian populations. Login to comment
94 Among the 352 patients with gout, Q126X heterozygous (n = 33) mutations were found that revealed that non-functional 126X dramatically increased gout risk (OR 2.91). Login to comment
96 Matsuo et al. [16,18] reported that the genotype combination of Q126X and Q141K is a clinically important biomarker for predicting gout risk in the Japanese population. We analyzed the relationship between ABCG2 transport dysfunction and gout and found that dysfunctional ABCG2 is responsible for approximately 78.4% of gout cases. Login to comment
115 We selected three functional ABCG2 SNPs: V12M, Q126X and Q141K. Login to comment
124 SNP ID SNP Allele Sequence (5'-3') Size V12M A/G ATGGTATGGGCCATTCATTG 250 bp ATGCCTTCAGGTCATTGGAA Q141K A/C ATGTTGTGATGGGCACTCTG 158 bp CCACATTACCTTGGAGTCTG Q126X C/T GCTGCAAGGAAAGATCCAAG 163 bp CAGCCAAAGCACTTACCCAT 4.3. Login to comment
137 The recent findings on the roles of the ABCG2 Q141K and Q126X polymorphism in gout may pave the way for pharmacological chaperones targeting ABCG2 as a potential new therapeutic target for gout. Login to comment

[hide] Common dysfunctional variants of ABCG2 have strong... Sci Rep. 2014 Jun 9;4:5227. doi: 10.1038/srep05227. Nakayama A, Matsuo H, Nakaoka H, Nakamura T, Nakashima H, Takada Y, Oikawa Y, Takada T, Sakiyama M, Shimizu S, Kawamura Y, Chiba T, Abe J, Wakai K, Kawai S, Okada R, Tamura T, Shichijo Y, Akashi A, Suzuki H, Hosoya T, Sakurai Y, Ichida K, Shinomiya N
Common dysfunctional variants of ABCG2 have stronger impact on hyperuricemia progression than typical environmental risk factors.
Sci Rep. 2014 Jun 9;4:5227. doi: 10.1038/srep05227., [PMID:24909660]

Abstract [show]
Gout/hyperuricemia is a common multifactorial disease having typical environmental risks. Recently, common dysfunctional variants of ABCG2, a urate exporter gene also known as BCRP, are revealed to be a major cause of gout/hyperuricemia. Here, we compared the influence of ABCG2 dysfunction on serum uric acid (SUA) levels with other typical risk factors in a cohort of 5,005 Japanese participants. ABCG2 dysfunction was observed in 53.3% of the population investigated, and its population-attributable risk percent (PAR%) for hyperuricemia was 29.2%, much higher than those of the other typical environmental risks, i.e. overweight/obesity (BMI >/= 25.0; PAR% = 18.7%), heavy drinking (>196 g/week (male) or >98 g/week (female) of pure alcohol; PAR% = 15.4%), and aging (>/=60 years old; PAR% = 5.74%). SUA significantly increased as the ABCG2 function decreased (P = 5.99 x 10(-19)). A regression analysis revealed that ABCG2 dysfunction had a stronger effect than other factors; a 25% decrease in ABCG2 function was equivalent to "an increase of BMI by 1.97-point" or "552.1 g/week alcohol intake as pure ethanol" in terms of ability to increase SUA. Therefore, ABCG2 dysfunction originating from common genetic variants has a much stronger impact on the progression of hyperuricemia than other familiar risks. Our study provides a better understanding of common genetic factors for common diseases.

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18 Based on the previous studies8,11 , all of the participants were divided into four groups by the combination of common dysfunctional variants of ABCG2, non-functional Q126X (rs72552713) and half-functional Q141K (rs2231142), as follows: full function (normal function), 3/ 4 function (mild dysfunction), 1/2 function (moderate dysfunction) and #1/4 function (severe dysfunction) (see Supplementary Figure S1 and Table S2). Login to comment
36 We also found that ABCG2 has two common dysfunctional variants: a nonsense variant Q126X and a missense variant Q141K8 . Login to comment
37 Functional analyses revealed that Q126X is a nonfunctional variant and Q141K is a half-functional variant due to the halved ABCG2 expression on the membrane8 . Login to comment
38 Since haplotype frequency analyses demonstrated no simultaneous presence of the minor alleles of Q126X and Q141K in one haplotype, the combination of nonfunctional variant Q126X and half-functional variant Q141K makes it possible to estimate dysfunctional levels of ABCG28,10 (Supplementary Figure S1 and Table S2). Login to comment
46 Ours is the first report to show the PAR% of ABCG2 dysfunction using the combination of Q126X and Q141K for functional evaluation. Login to comment
49 In the present study, we defined hyperuricemia as SUA .7.0 mg/dl17 and obtained the PAR% of Q141K and Q126X as 23.5% and 2.6%, respectively. Login to comment
52 Subsequent regression analysis revealed that ABCG2 dysfunction defined by the combination of Q126X and Q141K significantly increased SUA, while previous studies showed the association of SUA and only Q141K7,8 . Login to comment
76 Genotyping of the two variants in ABCG2 gene, Q126X and Q141K, was performed with a LightCycler 480 (Roche Diagnostics) by high resolution melting (HRM) analysis22 . Login to comment
79 The MAFs of Q126X and Q141K were 0.025 and 0.294, respectively, and both variants were in Hardy-Weinberg equilibrium (P . Login to comment

[hide] Sunitinib-induced severe toxicities in a Japanese ... BMC Cancer. 2014 Dec 16;14:964. doi: 10.1186/1471-2407-14-964. Miura Y, Imamura CK, Fukunaga K, Katsuyama Y, Suyama K, Okaneya T, Mushiroda T, Ando Y, Takano T, Tanigawara Y
Sunitinib-induced severe toxicities in a Japanese patient with the ABCG2 421 AA genotype.
BMC Cancer. 2014 Dec 16;14:964. doi: 10.1186/1471-2407-14-964., [PMID:25515134]

Abstract [show]
BACKGROUND: Sunitinib is a multi-targeted receptor tyrosine kinase inhibitor that acts against receptors for vascular endothelial growth factor and platelet-derived growth factor. Common toxicities of sunitinib treatment include hypertension, hand-foot syndrome, vomiting, and diarrhea, and the proportion of grade 3 or 4 adverse events relating to sunitinib treatment range from 1 to 13% for all categories. It is reported that increased exposure to sunitinib is associated with improved clinical outcomes but also carries an increased risk of adverse effects. CASE PRESENTATION: A 73-year-old Japanese woman with metastatic renal cell carcinoma who received sunitinib at a dose of 50 mg once daily suffered a high-grade fever on day 11 of treatment. Sunitinib treatment was discontinued on day 12; however, severe thrombocytopenia and transaminase elevation occurred and persisted more than a week. Additionally, severe hypoxia due to pleural effusion and pulmonary edema developed despite immediate discontinuation of sunitinib. On day 14, three days after the discontinuation of sunitinib, the plasma concentrations of sunitinib and its major active metabolite N-desethyl sunitinib (SU12662) were extremely high (131.9 ng/mL and 28.4 ng/mL, respectively). By day 25, all toxicities had resolved, and a CT scan revealed marked tumor shrinkage. Genotyping of seven single-nucleotide polymorphisms that are potentially relevant to the pharmacokinetics of sunitinib was performed. The patient's genotype of ABCG2 (ATP-binding cassette, sub-family G (WHITE), member 2) 421C > A was homozygous for the variant allele (AA), which was reported to be associated with high exposure to sunitinib. Therefore, we speculated that the extremely high plasma concentrations of sunitinib and SU12662 caused by the ABCG2 421 AA genotype might have resulted in severe toxicities to the patient. CONCLUSION: The minor allele frequencies of ABCG2 421C > A are approximately three-fold higher in Asians than in Caucasians. Our report suggests that pharmacogenetic factors should be considered when severe and rapid-onset adverse drug reactions occur in Asian patients, including Japanese treated with sunitinib.

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85 Another population pharmacokinetics study also identified ethnic background as a significant covariate for the Table 1 Genotypes of seven SNPs in CYP3A5, ABCB1 and ABCG2 Gene SNP Allele Amino acid Genotype CYP3A5 rs776746 6986A > G Splice Site AG ABCB1 rs1128503 1236C > T G412G CT ABCB1 rs2032582 2677G > T/A A893S/T GT ABCB1 rs1045642 3435C > T I1145I CT ABCG2 rs2231137 34G > A V12M GG ABCG2 rs72552713 376G > A Q126X GG ABCG2 rs2231142 421C > A Q141K AA prediction of oral clearance [16]. Login to comment

[hide] ASSOCIATIONS BETWEEN BODY MASS INDEX AND SERUM URI... Nagoya J Med Sci. 2014 Aug;76(3-4):333-9. Suma S, Naito M, Okada R, Kawai S, Yin G, Morita E, Wakai K, Matsuo H, Hamajima N
ASSOCIATIONS BETWEEN BODY MASS INDEX AND SERUM URIC ACID LEVELS IN A JAPANESE POPULATION WERE SIGNIFICANTLY MODIFIED BY LRP2 rs2544390.
Nagoya J Med Sci. 2014 Aug;76(3-4):333-9., [PMID:25741042]

Abstract [show]
The genome-wide association study identified associations between the LRP2 polymorphism rs2544390 and serum uric acid (SUA) levels in a Japanese population. Our previous study on the LRP2 rs2544390 polymorphism identified an interaction between SUA and alcohol consumption. Here, we investigated an interaction with body mass index (BMI) using the same dataset. Subjects were 3,742 health checkup examinees (2,544 males and 1,198 females) aged 35-69 years. Those with the SLC22A12 258WW genotype, SLC2A9 rs11722228 C allele, and ABCG2 126QQ genotype and 141Q allele were selected for analysis to remove the strong influences of these genetic traits. In males, the odds ratio of BMI >/=25.0 relative to BMI <18.5 for hyperuricemia (SUA >/=7 mg/dL and/or under medication for hyperuricemia) was 6.58 (95% confidence interval [CI], 0.84-51.32) for CC, 10.08 (2.38-42.83) for CT, and 2.53 (0.54-11.78) for TT. The interaction was 0.59 (p=0.029) from the model including BMI (<25.0 and >/=25.0), genotype (CC/CT and TT), and the multiplicative interaction term between BMI >/=25.0 and the TT genotype. In females, the odds ratio of BMI >/=25.0 relative to BMI <18.5 for high SUA (>/=5 mg/dL and/or under medication for hyperuricemia) was 6.35 (95%CI, 1.68-24.08) for CC, 4.55 (1.85-11.18) for CT, and 5.93 (1.97-17.90) for TT. The interaction term was significant in the opposite direction for females (OR=2.75, p=0.011). The association between BMI and SUA was therefore modified by the LRP2 polymorphism in this Japanese population.

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17 Polymorphisms ABCG2 Q126X (rs72552713) and Q141K (rs2231142) have been shown to influence the risk of hyperuricemia through reduction of the uric acid transportation activity.16-18) Our previous studies have confirmed the associations with these polymorphisms,16,19,20) and we observed an interaction with alcohol consumption on SUA in our investigation of the LRP2 intron 1 polymorphism rs2544390.21) Because obesity is an important factor that determines SUA,6) the present study aimed to investigate the interaction between LRP2 rs2544390 and BMI on SUA levels using the same dataset as our previous work. Login to comment

[hide] Reactive oxygen species derived from xanthine oxid... Biochem Pharmacol. 2015 Sep 1;97(1):89-98. doi: 10.1016/j.bcp.2015.06.021. Epub 2015 Jun 25. Ogura J, Kuwayama K, Sasaki S, Kaneko C, Koizumi T, Yabe K, Tsujimoto T, Takeno R, Takaya A, Kobayashi M, Yamaguchi H, Iseki K
Reactive oxygen species derived from xanthine oxidase interrupt dimerization of breast cancer resistance protein, resulting in suppression of uric acid excretion to the intestinal lumen.
Biochem Pharmacol. 2015 Sep 1;97(1):89-98. doi: 10.1016/j.bcp.2015.06.021. Epub 2015 Jun 25., [PMID:26119820]

Abstract [show]
The prevalence of hyperuricemia/gout increases with aging. However, the effect of aging on function for excretion of uric acid to out of the body has not been clarified. We found that ileal uric acid clearance in middle-aged rats (11-12 months) was decreased compared with that in young rats (2 months). In middle-aged rats, xanthine oxidase (XO) activity in the ileum was significantly higher than that in young rats. Inosine-induced reactive oxygen species (ROS), which are derived from XO, also decreased ileal uric acid clearance. ROS derived from XO decreased the active homodimer level of breast cancer resistance protein (BCRP), which is a uric acid efflux transporter, in the ileum. Pre-administration of allopurinol recovered the BCRP homodimer level, resulting in the recovering ileal uric acid clearance. Moreover, we investigated the effects of ROS derived from XO on BCRP homodimer level directly in Caco-2 cells using hypoxanthine. Treatment with hypoxanthine decreased BCRP homodimer level. Treatment with hypoxanthine induced mitochondrial dysfunction, suggesting that the decreasing BCRP homodimer level might be caused by mitochondrial dysfunction. In conclusion, ROS derived from XO decrease BCRP homodimer level, resulting in suppression of function for uric acid excretion to the ileal lumen. ROS derived from XO may cause the suppression of function of the ileum for the excretion of uric acid with aging. The results of our study provide a new insight into the causes of increasing hyperuricemia/gout prevalence with aging.

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254 BCRP mutations, such as partially functional mutation Q126K and nonfunctional mutation Q126X, markedly increase gout risk [12,13], indicating that BCRP dysfunction affects serum uric acid level. Login to comment

[hide] ABCG2: the molecular mechanisms of urate secretion... Am J Physiol Renal Physiol. 2015 Sep 15;309(6):F485-8. doi: 10.1152/ajprenal.00242.2015. Epub 2015 Jul 1. Woodward OM
ABCG2: the molecular mechanisms of urate secretion and gout.
Am J Physiol Renal Physiol. 2015 Sep 15;309(6):F485-8. doi: 10.1152/ajprenal.00242.2015. Epub 2015 Jul 1., [PMID:26136557]

Abstract [show]
The human propensity for high levels of serum uric acid (SUA) is a trait that has defied explanation. Is it beneficial? Is it pathogenic? Its role in the human diseases like gout and kidney stones was discovered over a century ago [Richette P, Bardin T. Lancet 375: 318-328, 2010; Rivard C, Thomas J, Lanaspa MA, Johnson RJ. Rheumatology (Oxford) 52: 421-426, 2013], but today emerging new genetic and epidemiological techniques have revived an age-old debate over whether high uric acid levels (hyperuricemia) independently increase risk for diseases like hypertension and chronic kidney disease [Feig DI. J Clin Hypertens (Greenwich) 14: 346-352, 2012; Feig DI, Madero M, Jalal DI, Sanchez-Lozada LG, Johnson RJ. J Pediatr 162: 896-902, 2013; Feig DI, Soletsky B, Johnson RJ. JAMA 300: 924-932, 2008; Wang J, Qin T, Chen J, Li Y, Wang L, Huang H, Li J. PLoS One 9: e114259, 2014; Zhu P, Liu Y, Han L, Xu G, Ran JM. PLoS One 9: e100801, 2014]. Part of the mystery of the role uric acid plays in human health stems from our lack of understanding of how humans regulate uric acid homeostasis, an understanding that could shed light on the historic role of uric acid in human adaptation and its present role in human pathogenesis. This review will highlight the recent work to identify the first important human uric acid secretory transporter, ABCG2, and the identification of a common causal ABCG2 variant, Q141K, for hyperuricemia and gout.

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42 Matsuo et al. compared gouty and normal cohorts of Japanese males and found two ABCG2 mutations, Q141K (50% function) and Q126X (no function), and used these to correlate ABCG2 function with age of gout onset. Login to comment

[hide] Genetic variation in the ABCG2 gene is associated ... Clin Rheumatol. 2015 Oct 27. Jiri M, Zhang L, Lan B, He N, Feng T, Liu K, Jin T, Kang L
Genetic variation in the ABCG2 gene is associated with gout risk in the Chinese Han population.
Clin Rheumatol. 2015 Oct 27., [PMID:26506822]

Abstract [show]
Gout is a common type of arthritis that is characterized by hyperuricemia, tophi, and joint inflammation. Current evidence suggests that heredity contributes to the progression of gout. Previous studies have shown that regulation of the ATP-binding cassette subfamily G member 2 (ABCG2) pathways plays a role in gout occurrence. To investigate and validate potential genetic associations with the risk of gout, we conducted a case-control study. We conducted 143 cases and 310 controls and genotyped seven single-nucleotide polymorphisms (SNPs) in ABCG2 gene. ABCG2 SNP association analyses were performed using SPSS 17.0 Statistical Package, PLINK Software, HaploView software package, and SHEsis software platform. We identified that four susceptibility SNPs were potentially associated with occurrence of gout. Rs2622621 and rs3114018 in ABCG2 can actually increase the risk of gout in log-additive model (rs2622621, odds ratio (OR) = 1.90, 95 % confidence interval (CI) 1.39-2.61, p < 0.001; rs3114018, OR = 1.55, 95 % CI 1.13-2.13, p = 0.006). We found that rs17731799G/T-G/G and rs3114020 T/C-T/T in ABCG2 can actually increase the risk of gout in dominant model (rs17731799, OR = 1.67, 95 % CI 1.05-2.66, p = 0.028; rs3114020, OR = 1.58, 95 % CI 1.00-2.51, p = 0.048). The ABCG2 haplotype "GGCTCTC" (OR = 0.46, 95 % CI 0.28-0.75, p = 0.0019) decreased the gout risk. Our results, combined with those from previous studies, suggest that genetic variation in ABCG2 may influence gout susceptibility in the Han population.

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74 ABCG2 is a high-capacity urate transporter which physiologically excretes urate Fig. 1 Haplotype block map for ABCG2 SNPs Table 3 ABCG2 haplotype frequencies and their association with gout (adjust by age and sex) Gene(s) Haplotype Frequency OR (95 % CI) p value ABCG2 GCCTAGT 0.2868 1 - GGCTCTC 0.2092 0.46 (0.28-0.75) 0.0019 AGACCTC 0.2014 0.71 (0.45-1.12) 0.14 GCCTCTC 0.0735 1.10 (0.57-2.13) 0.78 GGACCTC 0.0669 0.57 (0.27-1.18) 0.13 GCCTATC 0.0582 1.53 (0.75-3.14) 0.24 GGCTAGT 0.0378 0.37 (0.12-1.16) 0.09 GCCTAGC 0.0124 0.80 (0.19-3.46) 0.77 GCCTAGT 0.0538 0.47 (0.19-.13) 0.092 p value<0.05 indicates statistical significance OR odds ratio, CI confidence interval for the regulation of SUA. ABCG2 has the following two common dysfunctional variants: a non-sense variant Q126X and a missense variant Q141K [19, 22]. Login to comment

[hide] A meta-analysis of the associations between the Q1... Int J Clin Exp Pathol. 2015 Sep 1;8(9):9812-23. eCollection 2015. Li R, Miao L, Qin L, Xiang Y, Zhang X, Peng H, Mailamuguli, Sun Y, Yao H
A meta-analysis of the associations between the Q141K and Q126X ABCG2 gene variants and gout risk.
Int J Clin Exp Pathol. 2015 Sep 1;8(9):9812-23. eCollection 2015., [PMID:26617691]

Abstract [show]
BACKGROUND: Gout is an inflammatory disease in which genetic factors play a role. ABCG2 is a urate transporter, and the Q141K and Q126X variants of ABCG2 have been associated with a risk of developing gout, though previous studies of these associations have been inconsistent. Therefore, we conducted a meta-analysis to explore the relationship between these genetic variants and gout. METHODS: We examined 8 electronic literature databases. In total, 9 eligible articles on the associations between the Q141K (rs2231142) and Q126X (rs72552713) variants and gout risk, including 11 case-control studies were selected. We used odds ratios (OR) and 95% confidence intervals (CI) to assess the strength of these relationships in dominant, recessive, and co-dominant models. RESULTS: This study included 6652 participants (2499 gout patients and 4153 controls). The Q141K variant was found to significantly increase the risk of gout in Asians (dominant model: OR=2.64, 95% CI=2.04-3.43, P=0.02 for heterogeneity; recessive model: OR=3.19, 95% CI=2.56-3.97, P=0.28 for heterogeneity; co-dominant model: OR=1.37, 95% CI=1.18-1.59, P=0.09 for heterogeneity) and other populations (dominant model: OR=1.85, 95% CI=1.20-2.85, P<0.0001 for heterogeneity; recessive model: OR=3.78, 95% CI=2.28-6.27, P=0.19 for heterogeneity; co-dominant model: OR=1.48, 95% CI=1.26-1.74, P=0.19 for heterogeneity). The Q126X variant also significantly increased the risk of gout in Asians (dominant model: OR=3.87, 95% CI=2.07-7.24, P=0.06 for heterogeneity). CONCLUSIONS: These results suggest associations between the rs2231142 and rs72552713 ABCG2 gene polymorphisms and gout risk, which led to unfavorable outcomes. However, studies with larger sample sizes and homogeneous populations should be performed to confirm these results.

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3 ABCG2 is a urate transporter, and the Q141K and Q126X variants of ABCG2 have been associated with a risk of developing gout, though previous studies of these associations have been inconsistent. Login to comment
5 In total, 9 eligible articles on the associations between the Q141K (rs2231142) and Q126X (rs72552713) variants and gout risk, including 11 case-control studies were selected. Login to comment
9 The Q126X variant also significantly increased the risk of gout in Asians (dominant model: OR=3.87, 95% CI=2.07-7.24, P=0.06 for heterogeneity). Login to comment
12 Keywords: Gout, Q141K, Q126X, single nucleotide polymorphism, meta-analysis Introduction Gout is a recurrent relapsing inflammatory disease, caused by the precipitation of monosodium urate (MSU) crystals in the joints and soft tissues. Login to comment
26 Among these, Q141K and Q126X are the most commonly studied. Login to comment
29 SNP rs72552713, also referred to as C376T or Q126X in ABCG2, has also been shown to play a role in gout. Login to comment
33 The literature search was performed in English and Chinese using the following primary key words: gout, ABCG2, C421A, Q141K, rs2231142, C376T, Q126X, and rs72552713. Login to comment
38 Characteristics of the included studies (Q126X) First author (Ref.) Year Ethnicity/ country Diagnostic standard Study design Sample size (case/control) HWE p-value Genotype distribution (case/control) Genotype frequency (case/control) CC CT TT CC (%) CT (%) TT (%) Zhang Xin-Lei [28] 2014 Asians China ACR preliminary diagnostic criteria for acute gout (1977) Case-control 136/321 Yes 127/320 9/1 0/0 93.4/99.7 6.6/0.3 0/0 Danqiu Zhou [36] 2014 Asians China ACR preliminary diagnostic criteria for acute gout (1977) Case-control 352/350 Yes 319/338 33/12 0/0 90.6/96.6 9.4/3.4 0/0 The following index terms were used: gout and ABCG2, gout and C421A, gout and Q141K, gout and rs2231142, gout and C376T, gout and Q126X, and gout and rs72552713. Login to comment
53 Each relationship was assessed in a dominant model (Q141K: CC compared to AC+AA; Q126X: CC compared to CT+TT), a recessive model (Q141K: AA compared to CC+AC), and a co-dominant model (Q141K: AC compared to CC+AA). Login to comment
66 All of these 9 studies involved the Q141K variant, and only 2 studies referred to the Q126X variant. Login to comment
72 We extracted the characteristics of these studies, which are summarized in Tables 1, 2 of Article 9 on the Q126X variant. Login to comment
75 Subgroup analysis by ethnicity also revealed significant associations for both Asians (dominant model: OR=2.64, 95% CI=2.043.43, P=0.02 for heterogeneity; recessive model: OR=3.19, 95% CI=2.56-3.97, P=0.28 for heterogeneity; co-dominant model: OR=1.37, 95% CI=1.181.59, P=0.09 for heterogeneity) and other populations (dominant model: OR=1.85, Figure 6. Forest plot for the association between the Q126X variant and gout risk using the dominant model (CT+TT compared to CC). Login to comment
87 Among the ABCG2 polymorphisms, Q141K and Q126X are the most commonly studied. Login to comment
88 Nevertheless, the role of the Q141K variant in gout risk and the potential for the Q126X variant to increase gout risk are controversial. Login to comment
92 Until now, there has been no meta-analysis demonstrating the role of Q126X in gout. Login to comment
95 Our results suggested that the Q141K variant results in increased gout risk in dominant, recessive, and co-dominant models, and in subgroup analyses, Q126X also increased gout risk in a dominant model. Login to comment
118 Our evidence revealed that Q141K and Q126X are risk factors for the development of gout. Login to comment