ABCMdb

ABCC1 p.Gly671Val

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Publications

PMID: 16766035 [PubMed] Cascorbi I et al: "Role of pharmacogenetics of ATP-binding cassette transporters in the pharmacokinetics of drugs."

No. Sentence Comment

840 In a recent study on genetic determinants of anthracycline-induced cardiomyopathy in non-hodgkin lymphoma patients, the ABCC1 Gly671Val variant as well as a haplotype of ABCC2 were shown to be significantly associated with acute doxorubicine toxicity. Login to comment
852 Table 5 Frequency of ABCC1 genetic variants in different populations, position on DNA, putative effect, and frequencies (according to Le Saux et al., 2000; Ito et al., 2001; Moriya et al., 2002; Conrad et al., 2002; Oselin et al., 2003b; Wang et al., 2004) Position/ Nucleotide Aminoacid or effect Orientals Caucasians Function 128G>C C43S 0.01 - elevateda 218C>T T73I 0.00-0.04 - 257C>T S92F 0.00 0.00 decreaseda 350C>T T117M - 0.02 (decreased)a 689G>A R230N 0.00 0.00 (decreased)a 816G>A synonymous - 0.04 825T>C synonymous - 0.30 1057G>A V353M 0.00 0.005 elevateda 1299G>T R433S - 0.01 elevated Vmax of doxorubicin, decreased transport of LTC4 a,b 1684T>C synonymous - 0.80 1898G>A R633Q - 0.01 (decreased)a 2012G>T G671V - 0.03 doxorubicine-induced cardiomyopathyc 2168G>A R723Q 0.01-0.07 - decreaseda 2965G>A A989T 0.00 0.005 (decreased)a 3140G>C C1047S 0.00 0.00 3173G>A R1058Q 0.01 - 4002G>A synonymous - 0.28 4535C>T S1512L - 0.03 decreaseda a Letourneau et al. (2005). Login to comment

PMID: 17323126 [PubMed] Huang Y et al: "Pharmacogenetics/genomics of membrane transporters in cancer chemotherapy."

No. Sentence Comment

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
121 The 2012G>T mutation in exon 16 which leads to the substitution of a highly conserved Gly residue at position 671 with Val did not show functional differences with the wild type ABCC1 gene [58]. Login to comment

PMID: 18464048 [PubMed] Gradhand U et al: "Pharmacogenomics of MRP transporters (ABCC1-5) and BCRP (ABCG2)."

No. Sentence Comment

80 There is, however, one interesting publication that associated the aforementioned Gly671Val polymorphism in MRP1 with anthracyclin-induced cardiotoxicity (ACT) among Figure 1 Predicted membrance topology of MRP1 (ABCC1) based on hydrophobicity analysis. Locations of the non-synonymous polymorphisms are indicated with arrows. See Table 1 for allele frequencies and description of funtional consequences. Login to comment
81 MRP1 (ABCC1) NH2 NBD NBD in out Membrane Cys43Ser Ser92Phe Thr117Met Arg230Gln Val353Met Arg633Gln Gly671Val Arg723Gln Arg433Ser Ala989Thr Cys1047Ser Val1146Ile Arg1058Gln Thr1401Met Ser1512Leu Thr73Ile COOH NBD NBD COOH NBD COOH NBD NBD Table1MRP1(ABCC1)singlenucleotidepolymorphisms.Location,allelefrequencyandfunctionaleffects. Positionin codingsequence Aminoacid exchangeLocation Allelefrequency EffectNCBIIDReferenceAfCaJpothers 128G>CCys43SerExon2--1[1]-Decreaseinvincristineresistance[2]rs41395947 Disruptedplasmamembranetraffickingin transfectedcells[2] 218C>TThr73IleExon2--1[1]3.7Chinese[3]Noinfluenceonexpressionandtransportin membranevesicles[4] rs41494447 257C>TSer92PheExon30a 0a 0a 0Chinese[3]Noinfluenceonexpressionandtransportin membranevesicles[4] 350C>TThr117MetExon3-100[5]--Noinfluenceonexpressionandtransportin membranevesicles[4] 689G>AArg230GlnExon70a 0a 0a 0Chinese[3]Noinfluenceonexpressionandtransportin membranevesicles[4] 1057G>AVal353MetExon90a 0.5a 0a -- 1299G>TArg433SerExon10-1.4[6]--Changesintransportandresistance[7] 1898G>AArg633GlnExon13-[8]--Noinfluenceonexpressionandtransportin membranevesicles[4] 2012G>TGly671ValExon16-2.8[6]--Noinfluenceonexpressionandtransportin membranevesicles[6] Associatedwithanthracycline-induced cardiotoxicity[9] 2168G>AArg723GlnExon17--7.3[1]5.6Chinese[3]Noinfluenceonexpressionandtransportin membranevesicles[4]noinfluenceonmRNA expressioninenterocytes(n=1)[10] rs4148356 2965G>AAla989ThrExon220a 0.5a 0a -Noinfluenceonexpressionandtransportin membranevesicles(non-significantreduction inE17βGtransport)[4] 323 3140G>CCys1047SerExon234.5a 0a 0a -Noinfluenceonexpressionandtransportin membranevesicles[4] rs13337489 3173G>AArg1058GlnExon23--1[1]-Noinfluenceonexpressionandtransportin membranevesicles[4] rs41410450 3436G>AVal1146IleExon24-----rs28706727 4102C>TThr1401MetExon29-----rs8057331 4535C>TSer1512LeuExon31-[5]--Noinfluenceonexpressionandtransportin membranevesicles[4] ReferencewithoutfrequencymeansthatSNPwasdetectedbutnofrequencydetermined. Login to comment

PMID: 19949922 [PubMed] Cascorbi I et al: "Pharmacogenetics of ATP-binding cassette transporters and clinical implications."

No. Sentence Comment

146 In a study on genetic determinants of anthracycline-induced cardiomyopathy in non-Hodgkin lymphoma patients, the ABCC1 Gly671Val variant as well as a haplotype of ABCC2 turned out to be significant risk factors. Login to comment
155 ABCC2 (Multidrug Resistance-Associated Protein 2) Table 6.5 Frequency of ABCC1 genetic variants in different populations, position on DNA, putative effect, and frequencies (according to (33, 77-80, 136)) Position Amino acid or effect Orientals Caucasians Function c.128G>C C43S 0.01 - Elevateda c. 218C>T T73I 0.00-0.04 - c. 257C>T S92F 0.00 0.00 Decreaseda c. 350C>T T117M - 0.02 (Decreased)a c. 689G>A R230N 0.00 0.00 (Decreased)a c. 816G>A Synonymous - 0.04 c. 825T>C Synonymous - 0.30 c. 1057G>A V353M 0.00 0.005 Elevateda c. 1299G>T R433S - 0.01 Elevated vmax of doxorubicin, decreased transport of LTC4 a,b c. 1684T>C Synonymous - 0.80 c. 1898G>A R633Q - 0.01 (Decreased)a c. 2012G>T G671V - 0.03 Doxorubicine-induced cardiomyopathyc c. 2168G>A R723Q 0.01-0.07 - Decreaseda c. 2965G>A A989T 0.00 0.005 (Decreased)a c. 3140G>C C1047S 0.00 0.00 c. 3173G>A R1058Q 0.01 - c. 4002G>A Synonymous - 0.28 c. 4535C>T S1512L - 0.03 Decreaseda References: a [81], b [77], c [84] an inducible expression of ABCC2, which contributes also to the phenomenon of drug resistance. Login to comment

PMID: 19950006 [PubMed] Sissung TM et al: "Pharmacogenetics of membrane transporters: an update on current approaches."

No. Sentence Comment

67 Those studied include C43S, T73I, S92F, T117M, R230Q, V353M, R433S, R633Q, G671V, R723Q, A989T, C1047S, R1058Q, A1337T, and S1512L. Login to comment

PMID: 11721885 [PubMed] Conrad S et al: "Identification of human multidrug resistance protein 1 (MRP1) mutations and characterization of a G671V substitution."

No. Sentence Comment

0 J Hum Genet (2001) 46:656-663 (c) Jpn Soc Hum Genet and Springer-Verlag 2001 ORIGINAL ARTICLE Identification of human multidrug resistance protein 1 (MRP1) mutations and characterization of a G671V substitution Silke Conrad · Hans-Martin Kauffmann · Ken-ichi Ito Roger G. Deeley · Susan P.C. Cole · Dieter Schrenk S. Conrad · H.-M. Kauffmann · D. Login to comment
6 One of these mutations (G671V) was of special interest because it is located near the first nucleotide binding domain. Login to comment
45 Site-directed mutagenesis The mutation of Gly671 to Val was generated using the sense primer 5ЈP-CTCCATCCCCGAAGTGGCTTTGGTGGC CG-3Ј (substituted nucleotides are bold and underlined) with the U.S.E. mutagenesis kit (Amersham Pharmacia Biotech, Quebec, Canada), according to the manufacturer`s instructions. Login to comment
78 Mutations in the MRP1 gene and median mRNA expression levels of samples with different MRP1 genotypes Position Location SNPs Change FRE EXPa Intron 7 809ϩ54 C/A Intronic 2.8 101 Exon 8b 825 T/C Silent 2.8 51 Intron 8 1040ϩ13 T/C Intronic 16.7 95 Exon 10 1299 G/T Arg433Ser 1.4 156 Intron 11b 1474-48 C/T Intronic 2.8 146 Intron 11 1474-8 T/C Intronic 9.7 72 Intron 12 1678-9 DEL T Intronic 11.1 106 Exon 13b 1684 T/C Silent 8.3 106 Exon 13 1704 C/T Silent 2.8 59 Exon 16 2012 G/T Gly671Val 2.8 43 Intron 20 2736-36 T/C Intronic 2.8 132 Intron 20 2736-18 CC/TT Intronic 2.8 132 Intron 20 2736-6 T/C Intronic 2.8 132 Intron 21 2871ϩ17 G/A Intronic 1.4 132 Intron 26 3819ϩ7 G/A Intronic 1.4 124 Exon 28b 4002 G/A Silent 2.8 95 Intron 30 4487ϩ5 A/T Intronic 2.8 137 Intron 30 4487ϩ18 A/G Intronic 1.4 142 Intron 30 4487ϩ28 C/G Intronic 2.8 137 Densitometrical analysis was performed with TINA software (Raytest, Straubenhardt, Germany), average relative MRP1 expression was set as 100% FRE, allelic frequency in %; EXP, expression level; SNP, single-nucleotide polymorphism a The average expression level of all samples was 100 Ϯ 55 b Recently described by Ito et al. 2001b Fig. 2. Login to comment
88 These mutations include heterozygous silent mutations in exon 8 and 13 and one heterozygous mutation in exon 16 that could alter the amino acid sequence (G671V). Login to comment
91 These results, together with the localization of G671V close to the first ATP-binding site and the highly conserved nature of Gly671 among ABC proteins (Figure 2) prompted us to analyze the functional importance of this amino acid. Login to comment
92 This was accomplished by introducing the G671V substitution into the pcDNA3.1(-)wt-MRP1K expression vector by site-directed mutagenesis, followed by a transient transfection of the construct into HEKSV293T cells. Login to comment
96 Transport activity of wild-type and mutant G671V-MRP1 in transiently transfected human embryonic kidney (HEKSV293T) cells. Login to comment
97 A Vesicles protein expression levels of pcDNA3.1(-) as control, pcDNA3.1(-)wt-MRP1k (wt-MRPk-1), and pcDNA3.1(-)-MRPk-1- G671V (G671V) were determined by immunoblotting with the MRP1-specific murine Mab QCRL-1. Login to comment
99 B Time course of E217 G uptake in membrane vesicles prepared from HEKSV293T cells transiently transfected with wild-type MRP1 (wt-MRPk-1, solid square), mutant (G671V-MRPk-1, triangle), and empty control (pcDNA3.1(-), open square) cDNA expression vectors. Results shown are means (Ϯ SD) of triplicate determinations in a single experiment. Login to comment
101 C Time course of LTC4 uptake in membrane vesicles prepared from HEKSV293T cells transiently transfected with wild-type MRP1 (wt-MRPk-1, solid square), mutant (G671V-MRPk-1, triangle), and empty control (pcDNA3.1(-), open square) cDNA expression vectors. Results shown are means (Ϯ SD) of triplicate determinations in a single experiment. Login to comment
103 D Determination of Km and Vmax for ATP-dependent uptake of [3 H]LTC4 in membrane vesicles from transiently transfected HEKSV293T cells (wt-MRPk-1, solid square; G671V-MRPk-1, triangle). Login to comment
107 For the [3 H]LTC4 and [3 H]E217 G transport experiments shown in Figures 3B and C, the levels of uptake by G671V-MRP1 were comparable to wild-type MRP1. Login to comment
109 Our findings were supported by Eadie-Hofstee transformation (Figure 3D) of the data obtained from a ATP-dependent [3 H]LTC4 uptake experiment with various substrate concentrations, which yielded similar Km (175.8 and 151.0nM, respectively) and Vmax (107.9 and 111.3pmol/mg/min, respectively) values for G671V-MRP1 and wild-type MRP1, respectively. Login to comment
111 In accordance with previous findings, both wild-type MRP1 and G671V exhibited a markedly enhanced uptake of [3 H]estrone sulfate in the presence of GSH (Qian et al. 2001). Login to comment
113 Thus, the G671V mutant showed a phenotype similar to wild-type MRP1 (Figures 3 and 4) in all transport assays performed. Login to comment
118 They are located in the second transmembrane spanning domain (R433S) and in the vicinity of the first ATP-binding site (G671V). Login to comment
119 G671V is located only six amino acids upstream from the conserved Walker A motif in the nucleotide binding domain, and previous studies have shown that mutations in and near the Walker A motifs can cause a decrease in transport activity (Gao et al. 2000; Szakacs et al. 2000; Ramjeesingh et al. 1999). Login to comment
133 Of all the mutations detected in the present study, we specifically examined the functional consequences of the G671V substitution for three reasons: (1) the reduced mRNA expression of the affected individuals; (2) the high conservation of Gly671 in several subfamily C ABC-transporters; and (3) the location of the exchange position near the essential Walker A motif of NBD1. Login to comment
136 Although organic anion transport appears unaffected, it is possible the G671V substitution could affect drug resistance, since the two properties are not always linked. Login to comment

PMID: 12042670 [PubMed] Conrad S et al: "A naturally occurring mutation in MRP1 results in a selective decrease in organic anion transport and in increased doxorubicin resistance."

No. Sentence Comment

118 Of all the mutations detected, two are predicted to cause amino acid substitutions in the protein, Gly671 Val and Arg433 Ser. Login to comment
119 The Gly671 Val polymorphism is located near the Walker A motif of the first nucleotide binding domain of MRP1. Login to comment
122 In the present study, we found that this mutation, in contrast to Gly671 Val, results in significant substrate-specific alterations of MRP1 function. Login to comment

PMID: 16006996 [PubMed] Conseil G et al: "Polymorphisms of MRP1 (ABCC1) and related ATP-dependent drug transporters."

No. Sentence Comment

143 For example, although the polymorphic exon 16 variant G2012 Tcauses a highly conserved Gly residue at position 671 close to the WA motif of NBD1 to be replaced with Val, no detectable functional differences between the Gly671Val mutant and wild-type MRP1 proteins were observed [36]. Login to comment
148 Fig. 3 Exon 1 2 3 MSDMSD NBD1 MSD NBD2 C4535T(S1512L) G3173A (R1058Q) G3140C (C1047S) G2965A (A989T) G2168A (R723Q) G2012T(G671V) G1898A (R633Q) G1299T(R433S) G1057A (V353M) G689A (R230Q) C350T(T117M) C257T(S92F) C218T(T73I) C128C (C43S) (TM1-5) (TM6-11) (TM12-17) 4 5 6 7 8 9101112 1314 151617 1819 20 21 22 23 242526272829 30 31 Location of non-synonymous SNPs in the coding regions of the genes in the MRP1/ABCC1 gene. Login to comment
266 Hum Mut 2002; 17:74-75. 36 Conrad S, Kauffmann H-M, Ito K, Deeley R, Cole SPC, Schrenk D. Identification of human MRP1 mutations and characterization of a G671V substitution. Login to comment

PMID: 16041243 [PubMed] Letourneau IJ et al: "Functional characterization of non-synonymous single nucleotide polymorphisms in the gene encoding human multidrug resistance protein 1 (MRP1/ABCC1)."

No. Sentence Comment

7 When the MRP1/ABCC1 non-synonymous SNPs were evaluated by the SIFT algorithm using subsets of homologs and orthologs of MRP1/ABCC1, Arg230Gln, Val353Met, Arg433Ser, Gly671Val and Arg1058 mutations were predicted to be deleterious, whereas the PolyPhen algorithm predicted Ser92Phe and Gly671Val to be potentially damaging. Login to comment
28 Of these mutations, the Fig. 1 128G >C (C43S) 128G >T(T73I) 689G >A (R230Q)1057G >A (V353M) 1299G >T(R433S) 1898G >A (R633Q) 2012G >T(G671V) 2168G >A (R723Q) 3173G >A (R1058Q) 4535C >T(S1512L) 3140G >C (C1047S) 2965G >A (A989T) 350C >T(T117M) 257C >T(S92F) 313029282726252423222120181716151413121110987654321 19 MSD1 MSD1 MSD2 MSD3 MSD2 NBD1 MSD3 NBD2 TM 1 2 3 4 5 6 7 8 Val353Met Ala989Thr Cys1047Ser Arg1058Gln NBD2NBD1 Ser1512Leu Arg633Gln Arg433Ser Arg723Gln Thr73lle Thr117Met Arg230Gln Cys43Ser Ser92Phe Gly671Val 9 10 11 12 13 14 15 16 17 (a) (b) Location of reported non-synonymous single nucleotide polymorphisms (SNPs) in MRP1/ABCC1. Login to comment
36 Finally, the Gly671Val (2012G > T) mutation located in NBD1 caused no discernible changes in MRP1 function, even though this Gly residue is highly conserved among members of the human ABCC family and also in other species [20]. Login to comment
46 The template for generating Table 1 Frequencies of non-synonymous single nucleotide polymorphisms in MRP1/ABCC1 Variant Amino acid substitution Allelic frequency Population References 128G > C Cys43Ser 0% (0/26) Japanese [16] 1% (1/96) Japanese [17] 218C > T Thr73Ile 0% (0/26) Japanese [16] 1% (1/96) Japanese [17] 3.7% (2/54) Chinese [37] 257C > T Ser92Phe 0% (0/220) Caucasian www.pharmGKB.org 0.5% (1/200) African-American 0% (0/60) Japanese 0% (0/14) Pacific-Islander 350C > T Thr117Met 1.6% (1/64) Caucasian [28] 689G > A Arg230Gln 0% (0/220) Caucasian www.pharmGKB.org 0.5% (1/200) African-American 0% (0/60) Japanese 0% (0/14) Pacific-Islander 1057G > A Val353Met 0.5% (1/220) Caucasian www.pharmGKB.org 0% (0/200) African-American 0% (0/60) Japanese 0% (0/14) Pacific-Islander 1299G > T Arg433Ser 1.4% (1/72) Caucasian [20] 0% (0/110) Caucasian [19] 1898G > A Arg633Gln 0.8% (2/234) Caucasian [29] 2012G > T Gly671Val 2.8% (2/72) Caucasian [20] 2.6% (6/234) Caucasian [29] 2168G > A Arg723Gln 3.8% (1/26) Japanese [16] 1% (1/96) Japanese [30] 7.3% (7/96) Japanese [17] 5.6% (3/54) Chinese [37] 2965G > A Ala989Thr 0.5% (1/220) Caucasian www.pharmGKB.org 0% (0/200) African-American 0% (0/60) Japanese 0% (0/14) Pacific-Islander 3140G > C Cys1047Ser 0% (0/220) Caucasian www.pharmGKB.org 4.5% (9/200) African-American 0% (0/60) Japanese 0% (0/14) Pacific-Islander 3173G > A Arg1058Gln 0% (0./26) Japanese [16] 1% (1/96) Japanese [17] 4535C > T Ser1512Leu 3.1% (2/24) Caucasian [28] Characterization of MRP1/ABCC1 variants in vitro Le´tourneau et al. 649 the Arg633Gln and Arg723Gln mutants was created by subcloning a HindIII fragment (1329 bp) encoding amino acids 517-959 into pGEM-3z [20]. Login to comment
94 Results from previously characterized non-synonymous SNPs, Cys43Ser, Arg433Ser and Gly671Val, were included where available for comparison [18-20]. Login to comment
123 Previous mutagenesis and inhibition studies have Fig. 3 Cys43Ser Thr73lle Ser92Phe Thr117Met Arg230Gln Arg433Ser Arg633Gln Gly671Val Arg723Gln Ala989Thr Cys1047Ser Arg1058Gln Ser1512Leu Cys43Ser Thr73lle Ser92Phe Thr117Met Arg230Gln Arg433Ser Arg633Gln Gly671Val Arg723Gln Ala989Thr Cys1047Ser Arg1058Gln Ser1512Leu Thr73lle Ser92Phe Thr117Met Arg230Gln Arg633Gln Arg723Gln Ala989Thr Cys1047Ser Arg1058Gln Ser1512Leu LTC4 % WT-MRP1 uptake 0 25 50 75 100 125 E217βG % WT-MRP1 uptake 0 25 50 75 100 125 150 MTX % WT-MRP1 uptake 0 25 50 75 100 125 (b) (c) (a) ATP-dependent vesicular transport of organic anions by mutant MRP1 proteins. Login to comment
128 Hatched bars represent previously published data on non-synonymous SNPs, Cys43Ser, Arg433Ser and Gly671Val, using membrane vesicles from stably transfected HeLa cells and are included for comparison [18-20]. Login to comment
134 Thus, when the subset included the human homologs MRP2, MRP3 and MRP6, the SIFT analysis predicted that the Arg433Ser, Gly671Val and Arg1058Gln substitutions would be deleterious for MRP1 function. Login to comment
135 However, when the analysis was expanded to include the six known mammalian orthologs of MRP1, the Arg230Gln, Val353Met, Arg433Ser and Gly671Val mutations were also predicted to be deleterious. Login to comment
140 Thus, PolyPhen predicted that the Ser92Phe and Gly671Val mutations would likely be deleterious to MRP1 function which our present and previous experimental data show it is not the case, at least in vitro [20]. Login to comment
158 This observation may be construed as being Table 2 Conservation of the amino acids substituted by non-synonymous SNP of human MRP1/ABCC1a Protein Speciesb C43S T73I S92F T117Mc R230Q V353M R433S R633Qc G671V R723Q A989T C1047S R1058Q S1512L MRP1 Human C T S T R V R R G R A C R S Monkey C T S M R V R R G Q A C R S Dog C T S M R V R R G R A R R S Cow C A S M Q V R R G R A R R S Rat C A S M Q V R W G R A R R S Mouse C T S M H V R R G R A R R S MRP2 Human L A V T K A K R G K A I R E Monkey L A V T K A K R G K A I R E Dog L A V T K A K R G K A I Q Q Rat L A A T K V K R G K A A R E Mouse L A A T K V K V G K A T R E Rabbit L A V T K V K R G K A I R E MRP3 Human C L S M Y I R K G Q A V R A Rat C L S M L L R K G Q A L R V MRP4 Human - - - - I F K R G R Y T K Y MRP5 Human - - - - V T R S G R T R R S MRP6 Human P A A M R I R S G V A L R A CFTR Human - - - - R Y K A G K L I Q Q SUR1 Human V L L A T V Q R G E L R L E SUR2 Human V L H T Q V Q R G E I N L P Pgp Human - - - - - E K S G A G R R Q YCF1 Saccharomyces cervisiae A I L V T V K L G K S Y R G Mrp1 Caenorhabditis elegans T L D F L I R T G R G L R K Mrp2 Caenorhabditis elegans T F D I L I K T G R G I R K AtMRP2 Arabidopsis thaliana Q L R W L M S P G R R K R E AtMRP1 Arabidopsis thaliana H T A V L M S P G R R K R E a Aligned using Clustal W (http://pbil.univ-lyon1.fr/). Login to comment

PMID: 16330681 [PubMed] Wojnowski L et al: "NAD(P)H oxidase and multidrug resistance protein genetic polymorphisms are associated with doxorubicin-induced cardiotoxicity."

No. Sentence Comment

10 In addition, acute ACT was associated with the Gly671Val variant of the doxorubicin efflux transporter multidrug resistance protein 1 (MRP1) (OR, 3.6; 95% CI, 1.6 to 8.4) and with the Val1188Glu-Cys1515Tyr (rs8187694-rs8187710) haplotype of the functionally similar MRP2 (OR, 2.3; 95% CI, 1.0 to 5.4). Login to comment
117 Distribution of Genotypes and Probability Values for Gene Variants Showing Associations With Cardiotoxicity After Doxorubicin Treatment Cardiotoxicity Gene Variant Genotype Distribution P vs Controls Genotypes* n Freidlin Test Fisher Test Acute CYBA His72Tyr(rs4673) CC/CT/TT 13/28/3 0.048 0.054 RAC2 7508T3A(rs13058338) TT/TA/AA 15/23/5 0.002 0.005 NCF4-212A3G(rs1883112) GG/GA/AA 10/22/9 0.372 0.519 MRP1 Gly671Val GG/GT/TT 33/8/1 0.001 0.005 MRP2 Val1188Glu(rs8187694) TT/TA/AA 36/8/0 0.049 0.06 MRP2Cys1515Tyr(rs8187710) GG/GA/AA 36/8/0 0.049 0.06 Chronic CYBA His72Tyr(rs4673) CC/CT/TT 13/27/3 0.062 0.074 RAC2 7508T3A(rs13058338) TT/TA/AA 24/15/4 0.28 0.747 NCF4-212A3G(rs1883112) GG/GA/AA 14/14/15 0.007 0.013 MRP1 Gly671Val GG/GT/TT 39/4/0 0.586 0.537 MRP2 Val1188Glu(rs8187694) TT/TA/AA 37/6/0 0.274 0.269 MRP2Cys1515Tyr(rs8187710) GG/GA/AA 37/6/0 0.274 0.269 Chronic or acute CYBA His72Tyr(rs4673) CC/CT/TT 26/55/6 0.009 0.01 RAC2 7508T3A(rs13058338) TT/TA/AA 39/38/9 0.013 0.04 NCF4-212A3G(rs1883112) GG/GA/AA 24/36/24 0.022 0.031 MRP1 Gly671Val GG/GT/TT 72/12/1 0.012 0.029 MRP2 Val1188Glu(rs8187694) TT/TA/AA 73/14/0 0.044 0.05 MRP2Cys1515Tyr(rs8187710) GG/GA/AA 73/14/0 0.044 0.05 None (controls) CYBA His72Tyr(rs4673) CC/CT/TT 164/154/45 1 1 RAC2 7508T3A(rs13058338) TT/TA/AA 211/132/19 1 1 NCF4-212A3G(rs1883112) GG/GA/AA 106/186/62 1 1 MRP1 Gly671Val GG/GT/TT 331/24/1 1 1 MRP2 Val1188Glu(rs8187694) TT/TA/AA 331/32/0 1 1 MRP2Cys1515Tyr(rs8187710) GG/GA/AA 331/32/0 1 1 *Genotype(s) predisposing to ACT is underlined. Login to comment
126 The predisposing allele A of the MRP1 variant Gly671Val conferred an OR of 3.6 (95% CI, 1.6 to 8.4). Login to comment
16 In addition, acute ACT was associated with the Gly671Val variant of the doxorubicin efflux transporter multidrug resistance protein 1 (MRP1) (OR, 3.6; 95% CI, 1.6 to 8.4) and with the Val1188Glu-Cys1515Tyr (rs8187694-rs8187710) haplotype of the functionally similar MRP2 (OR, 2.3; 95% CI, 1.0 to 5.4). Login to comment
122 Distribution of Genotypes and Probability Values for Gene Variants Showing Associations With Cardiotoxicity After Doxorubicin Treatment Cardiotoxicity Gene Variant Genotype Distribution P vs Controls Genotypes* n Freidlin Test Fisher Test Acute CYBA His72Tyr(rs4673) CC/CT/TT 13/28/3 0.048 0.054 RAC2 7508T3A(rs13058338) TT/TA/AA 15/23/5 0.002 0.005 NCF4-212A3G(rs1883112) GG/GA/AA 10/22/9 0.372 0.519 MRP1 Gly671Val GG/GT/TT 33/8/1 0.001 0.005 MRP2 Val1188Glu(rs8187694) TT/TA/AA 36/8/0 0.049 0.06 MRP2Cys1515Tyr(rs8187710) GG/GA/AA 36/8/0 0.049 0.06 Chronic CYBA His72Tyr(rs4673) CC/CT/TT 13/27/3 0.062 0.074 RAC2 7508T3A(rs13058338) TT/TA/AA 24/15/4 0.28 0.747 NCF4-212A3G(rs1883112) GG/GA/AA 14/14/15 0.007 0.013 MRP1 Gly671Val GG/GT/TT 39/4/0 0.586 0.537 MRP2 Val1188Glu(rs8187694) TT/TA/AA 37/6/0 0.274 0.269 MRP2Cys1515Tyr(rs8187710) GG/GA/AA 37/6/0 0.274 0.269 Chronic or acute CYBA His72Tyr(rs4673) CC/CT/TT 26/55/6 0.009 0.01 RAC2 7508T3A(rs13058338) TT/TA/AA 39/38/9 0.013 0.04 NCF4-212A3G(rs1883112) GG/GA/AA 24/36/24 0.022 0.031 MRP1 Gly671Val GG/GT/TT 72/12/1 0.012 0.029 MRP2 Val1188Glu(rs8187694) TT/TA/AA 73/14/0 0.044 0.05 MRP2Cys1515Tyr(rs8187710) GG/GA/AA 73/14/0 0.044 0.05 None (controls) CYBA His72Tyr(rs4673) CC/CT/TT 164/154/45 1 1 RAC2 7508T3A(rs13058338) TT/TA/AA 211/132/19 1 1 NCF4-212A3G(rs1883112) GG/GA/AA 106/186/62 1 1 MRP1 Gly671Val GG/GT/TT 331/24/1 1 1 MRP2 Val1188Glu(rs8187694) TT/TA/AA 331/32/0 1 1 MRP2Cys1515Tyr(rs8187710) GG/GA/AA 331/32/0 1 1 *Genotype(s) predisposing to ACT is underlined. Login to comment
131 The predisposing allele A of the MRP1 variant Gly671Val conferred an OR of 3.6 (95% CI, 1.6 to 8.4). Login to comment

PMID: 16684361 [PubMed] Wang Z et al: "Nucleotide sequence analyses of the MRP1 gene in four populations suggest negative selection on its coding region."

No. Sentence Comment

8 SNPs E10/1299 G>T (R433S) and E16/2012 G>T (G671V) which occur at low frequency in only one or two of four populations examined were predicted to be functionally deleterious and hence are likely to be under negative selection. Login to comment
45 We found that SNPs E10/1299G>T, which resulted in arginine-serine substitution at amino acid position 433 (R433S) and E16/2012G>T, which resulted in glycine-valine substitution at amino acid position 671 (G671V), may potentially adversely affect the function of MRP1. Login to comment
127 2000 SNPe11 E16/2007 C>T - - - 1.39 0 0 0 SNPe12* E16/2012 G>T G671V 0.00** probably damaging -3.50442 0 0 1.43 2.78 Conrad et al . Login to comment
147 Significantly, all of the three different algorithms predicted that SNP E16/2012 G>T, which resides close to Walker A and results in G671V substitution, was likely to have a potentially deleterious effect on protein function (Fig. 2C). Login to comment
150 The lower expression of the MRP1 G671V transcript is suggestive of greater accumulation of MRP1 drugs in the cells which may lead to adverse drug reactions. Login to comment
151 Curiously, that report also found that the G671V polymorphism did not affect the transport of MRP1 substrates including leukotriene C4, 17β-estradiol 17β-(D)-glucuronide and estrone sulfate by membrane vesicles prepared from transiently transfected HEKSV293T cells [12]. Login to comment
153 The observation that the G671V polymorphism did not affect MRP1 protein expression or transport ability of some MRP1 substrates in vitro [12,51] does not rule out the possibility of functional significance of this polymorphism in vivo especially since the same group reported decreased transcript expression in individuals carrying this polymorphism. Login to comment

PMID: 17329911 [PubMed] Fukushima-Uesaka H et al: "Genetic variations and haplotype structures of the ABC transporter gene ABCC1 in a Japanese population."

No. Sentence Comment

26 In Caucasian populations, 1299GÀT (Arg433Ser), 1898GÀA (Arg633Gln), 2012GÀT (Gly671Val), and 4535CÀT (Ser1512Leu) have been reported.79) In addition, Arg433Ser decreases the transport activity for LTC4 and estrone sulfate, but not for estradiol 17b-glucuronide, in vitro.10) Ito et al. found 16 genetic polymorphisms, including 4 nonsynonymous and 8 synonymous ones, in 48 Japanese subjects.11) An in vitro functional study showed that one of the non-synonymous variations, 2168GÀA (Arg723Gln), leads to reduced transport activity for LTC4, estradiol 17b-glucuronide and methotrexate.12) However, no haplotype analysis has been reported for the Japanese population. Login to comment
69 We also detected three known nonsynonymous variations, 218CÀT (Thr73Ile), 2168GÀA (Arg723Gln), and 3173GÀA (Arg1058Gln) at frequencies of 0.007, 0.065 and 0.003, respectively. These frequencies were similar to those found in the earlier reports for Japanese11) and Chinese.21) One of the variations, Arg723Gln, leads to reduced transport activities for LTC4, estradiol 17b-glucuronide and methotrexate.12) We did not detect three previously reported variations: 2012GÀT (Gly671Val; found with approximately 0.03 frequency in Caucasians), 3140GÀC (Cys1047Ser; 0.05 in African-Americans), and 4535CÀT (Ser1512Leu; 0.03 in Caucasians).8,9,12) These SNPs might be ethnic- specic. Login to comment

PMID: 18220559 [PubMed] Yu XQ et al: "Multidrug resistance associated proteins as determining factors of pharmacokinetics and pharmacodynamics of drugs."

No. Sentence Comment

405 Important Single Nucleotide Polymorphisms (SNPs) of MRP Genes MRP Chromosomal location Amino acid variation Nucleotide variation Location References Cys43Ser Thr73Ile G128C C218T Exon2 Exon2 [239] Arg433Ser G1299T Exon10 [258] Gly671Val G2012T Exon16 [259] Arg723Gln G2168A Exon17 [239] MRP1 16p13.11-p13.12 Arg1058Gln G3173A Exon23 [239] C-24T Promoter [100, 239] Val417Ile G1249A Exon10 [100, 238, 239] Gly676Arg G2026C Exon16 [237] Try709Arg T2125C Exon17 [236] Arg768Trp Ser789Phe C2302T C2366T Exon18 Exon18 [100, 238, 239] I1173F R1150H A3517T G3449A Exon25 Exon25 [240] Ile1324Ile C3972T Exon28 [100, 239] MRP2 10q23-24 Ala1450Thr G4348A Exon31 [100, 238, 239] (Table 2) contd…. Login to comment

PMID: 18851956 [PubMed] Rebecchi IM et al: "ABCB1 and ABCC1 expression in peripheral mononuclear cells is influenced by gene polymorphisms and atorvastatin treatment."

No. Sentence Comment

31 The ABCC1 G2012T (rs45511401) is a non-synonymous SNP (Gly671Val) located in the exon 16 at the nucleotide binding domain of the protein [13]. Login to comment

PMID: 19214144 [PubMed] Yin JY et al: "Characterization and analyses of multidrug resistance-associated protein 1 (MRP1/ABCC1) polymorphisms in Chinese population."

No. Sentence Comment

25 To date, only three naturally occurring mutations of MRP1/ABCC1 (Gly671Val, Arg433Ser, and Cys43Ser) have been fully investigated for their effects on MRP1/ ABCC1-mediated MDR [18-20]. Login to comment
157 It has also been reported that Gly671Val and Arg433Ser mutations were found in Caucasian, but not in Asian populations [15,18,19]. Login to comment

PMID: 19687781 [PubMed] Siedlinski M et al: "ABCC1 polymorphisms contribute to level and decline of lung function in two population-based cohorts."

No. Sentence Comment

72 Table 2 Additive effects of 53 ABCC1 SNPs on the level and change of FEV1 in the Doetinchem cohort (n = 1152) Additive effect on the level of FEV1 (ml)a Additive effect on the change of FEV1 (ml/year)b SNP Position MAF (%) HWE P value B SE P B SE P rs4148330 50 region 34.2 0.96 - 63.2 20.4 0.002 - 1.8 1.4 0.20 rs504348 [28] 50 region 19.3 0.61 - 54.9 24.7 0.03 - 2.4 1.7 0.15 rs152022 Intron 1 20.3 0.12 9.0 24.0 0.71 0.4 1.6 0.83 rs215049 Intron 1 31.9 0.72 - 32.5 21.1 0.12 - 1.5 1.5 0.31 rs215068 Intron 1 30.9 0.21 22.7 21.5 0.29 - 0.7 1.5 0.64 rs215079 Intron 1 21.0 0.24 3.2 23.9 0.89 - 1.5 1.7 0.37 rs215100 Intron 1 32.1 0.77 - 48.8 20.9 0.02 - 1.0 1.4 0.50 rs246220 Intron 1 12.6 0.34 - 19.0 30.1 0.53 1.2 2.1 0.55 rs4781699 Intron 1 31.4 0.63 - 56.6 20.9 0.01 - 2.2 1.4 0.13 rs8060750 Intron 1 12.7 0.52 24.4 29.2 0.40 - 1.1 2.0 0.59 rs8045000 Intron 1 32.8 - - 51.2 20.8 0.01 - 1.8 1.4 0.20 rs7190484 Intron 1 38.1 - - 48.8 20.1 0.02 - 1.8 1.4 0.19 rs7196970 Intron 1 40.6 - - 28.6 20.1 0.15 - 1.0 1.4 0.49 rs215101 Intron 1 10.5 - 36.2 33.1 0.27 - 0.9 2.2 0.70 rs4781711 Intron 1 6.9 - - 22.0 41.5 0.60 0.3 2.9 0.91 rs215059 Intron 1 14.2 - 15.6 28.8 0.59 0.8 2.0 0.69 rs4148337 Intron 3 31.9 0.72 - 25.4 21.0 0.23 - 1.0 1.4 0.51 rs4781718 Intron 3 14.3 0.39 - 0.1 27.8 0.99 - 2.1 1.9 0.28 rs246213 Intron 5 8.8 0.97 - 46.9 34.9 0.18 - 2.9 2.4 0.24 rs246240 Intron 5 18.0 0.28 3.1 25.3 0.90 - 0.7 1.7 0.71 rs7188937 Intron 5 46.4 - - 22.0 19.2 0.25 - 1.9 1.3 0.14 rs246233 Intron 6 9.0 - - 8.8 37.7 0.82 1.8 2.6 0.49 rs246230 Intron 7 14.6 0.42 - 5.2 27.5 0.85 - 0.1 1.9 0.97 rs193537 Intron 7 29.5 - - 14.0 22.3 0.53 - 0.2 1.5 0.89 rs60782127 (Arg433Ser) [29,30] Exon 10 2.2 1.00 - 25.2 68.0 0.71 3.3 4.7 0.48 rs12445600 Intron 10 27.8 0.57 - 22.8 22.0 0.30 - 0.5 1.5 0.74 rs4148344 Intron 10 15.7 - 12.5 28.4 0.66 0.5 1.9 0.80 rs35596 Intron 12 23.1 0.44 - 11.0 23.7 0.64 0.9 1.6 0.57 rs35597 Intron 12 46.7 0.33 32.9 20.1 0.10 3.1 1.4 0.02 rs35610 Intron 13 15.8 0.30 - 38.0 27.5 0.17 - 1.6 1.9 0.41 rs35621 Intron 14 10.7 0.61 -7.8 31.4 0.80 - 3.0 2.1 0.17 rs4148353 Intron 15 14.8 0.46 - 4.5 28.3 0.87 0.4 2.0 0.84 rs45511401 (Gly671Val) [30,31] Exon 16 4.9 1.00 22.5 45.4 0.62 - 0.7 3.1 0.81 rs2074086 Intron 18 31.9 0.43 11.7 21.0 0.58 - 1.0 1.4 0.49 rs2074087 Intron 18 14.2 - 42.1 30.6 0.17 - 3.6 2.1 0.08 rs4148358 Intron 19 23.5 0.94 11.1 23.2 0.63 - 0.1 1.6 0.93 rs2283515 Intron 19 46.6 - - 17.5 19.8 0.38 - 2.8 1.3 0.04 rs12449239 Intron 19 14.9 - - 20.4 29.8 0.49 - 0.7 2.0 0.74 rs11864374 Intron 21 22.6 0.62 - 27.4 24.2 0.26 - 2.9 1.6 0.08 rs9933511 Intron 21 27.1 0.09 9.5 22.7 0.68 - 0.5 1.5 0.75 rs3819552 Intron 21 49.0 0.57 6.6 19.9 0.74 2.7 1.4 0.04 rs2238475 Intron 23 4.6 0.16 - 10.8 46.0 0.82 1.2 3.2 0.71 rs2238476 Intron 23 5.9 0.74 28.0 41.5 0.50 - 1.5 2.8 0.59 rs12599429 Intron 26 31.8 0.85 17.7 21.5 0.41 2.0 1.5 0.17 rs212079 Intron 26 4.1 0.85 - 20.3 50.0 0.69 - 5.9 3.4 0.09 rs212083 Intron 27 19.5 0.46 - 10.6 24.6 0.67 - 3.9 1.7 0.02 rs2230671 (Ser1334Ser) Exon 28 29.8 0.98 5.7 21.6 0.79 1.9 1.5 0.19 rs3743527 30 UTR 22.5 0.09 - 58.6 23.5 0.01 - 1.3 1.6 0.44 rs212090 30 UTR 45.5 - - 11.2 19.4 0.56 4.3 1.3 0.001 rs212093 30 region 45.3 0.10 - 42.5 19.3 0.03 - 2.9 1.3 0.03 rs4148382 30 region 9.7 1.00 94.2 33.4 0.005 - 3.6 2.3 0.11 rs212094 30 region 18.0 - 15.9 25.8 0.54 - 5.3 1.8 0.003 rs12448760 30 region 29.1 - -7.5 21.6 0.73 2.7 1.5 0.07 The lack of HWE P values indicates haplotype-tagged SNPs. Login to comment

PMID: 21143116 [PubMed] He SM et al: "Structural and functional properties of human multidrug resistance protein 1 (MRP1/ABCC1)."

No. Sentence Comment

816 There are at least 15 naturally occurring mutations identified in MRP1/ABCC1, including Cys43Ser in TM1, Thr73Ile in CL1, Ser92Phe in TM2, Arg230Asn in L0, Val353Met at TM6/TM7 interface, Arg433Ser in TM8, Gly671Val in TM11, Arg723Gln located between the Walker A and Walker B motifs of NBD1, Ala861Thr at NBD1/TM12 interface, Ala989Thr in TM12, Cys1047Ser in TM13, Arg1058Gln in CL7, Val1146Ile in CL7, Thr1337Ala between the Walker A and Walker B motifs of NBD2, and Thr1401Met, and many of them have been found to affect its transport activity [171, 362, 363, 366, 367, 377-384]. Login to comment

PMID: 21736601 [PubMed] Yin JY et al: "ABCC1 polymorphism Arg723Gln (2168G > A) is associated with lung cancer susceptibility in a Chinese population."

No. Sentence Comment

25 For instance, 1684T>C affected the pharmacokinetics of the drug irinotecan in cancer patients.9 In another study, is was found that individuals with the Gly671Val (2012C>T) mutation have just half of the MRP1/ABCC1 mRNA expression level in peripheral blood compared with wild-type subjects.10 In a large sample size case control study, it was shown that non-Hodgkin lymphoma patients carrying the Gly671Val allele had increased propensity to anthracycline-induced cardiotoxicity.11 Although it has been shown that MRP1/ABCC1 polymorphisms cause significant alterations in protein function, the association between MRP1/ABCC1 polymorphisms and disease susceptibility, as well as the response to chemotherapy, remains unclear. Login to comment

PMID: 10811882 [PubMed] Ringpfeil F et al: "Pseudoxanthoma elasticum: mutations in the MRP6 gene encoding a transmembrane ATP-binding cassette (ABC) transporter."

No. Sentence Comment

59 NM004996) revealed a neutral polymorphism (2031G3C; V677V) in one PXE family (family 4 in Fig. 1), and a heterozygous glycine-to-valine polymorphism (2012G3T; G671V) in another (family 2 in Fig. 1). Login to comment

PMID: 20103563 [PubMed] Klaassen CD et al: "Xenobiotic, bile acid, and cholesterol transporters: function and regulation."

No. Sentence Comment

7118 Nucleotide Change Amino Acid Change In Vitro Function Protein Expression/Localization ABCC1 MRP1 G128C C43S 1↔ Intracellular C218T T73I 1↔ Normal C257T S92F 2↔ Normal C350T T117M 2↔ Normal G689A R230Q ↔ Normal G1057A V353M N.D. N.D. G1299T R433S 2↔ Normal G1898A R633Q 2↔ Normal G2012T G671V ↔ Normal G2168A R723Q 2 Normal G2965A A989T 2↔ Normal G3140C C1047S 1↔ Normal G3173A R1058Q ↔ Normal C4535T S1512L ↔ Normal ABCC2 MRP2 C-24T N.D. N.D. G1058A R353H N.D. N.D. G1249A V417I ↔ Normal C2366T S789F 12 Intracellular T2780G L927R N.D. N.D. C3298T R1100C N.D. N.D. G3299A R1100H N.D. N.D. T3563A V1188E N.D. N.D. G4348A A1450T ↔ Normal/Intracellular G4544A C1515Y N.D. N.D. ABCC3 MRP3 G32A G11D ↔ Normal C202T H68Y N.D. N.D. G296A R99Q N.D. Normal C1037T S346F 2 Normal C1537A Q513K N.D. N.D. T1643A L548Q N.D. N.D. G1820A S607N 2 Normal C2221T Gln741STOP N.D. N.D. G2293C V765L ↔ Normal G2395A V799M N.D. N.D. C2758T P920S 1 Normal G2768A R923Q 1 Normal C3657A S1219R N.D. N.D. C3856G R1286G ↔ Normal G3890A R1297H N.D. N.D. C4042T R1348C 1 Normal A4094G Q1365R ↔ Normal C4141A R1381S ↔ Intracellular C4217T T1406M N.D. N.D. G4267A G1423R N.D. N.D. ABCC4 MRP4 C52A L18I N.D. N.D. C232G P78A 2↔ Normal T551C M184T N.D. N.D. G559T G187W 2 Reduced A877G K293E ↔ Normal G912T K304N ↔ Normal C1067T T356M N.D. N.D. C1208T P403L 2↔ Normal G1460A G487E 2 Normal A1492G K498E ↔ Normal A1875G I625M N.D. N.D. C2000T P667L N.D. N.D. A2230G M744V ↔ Normal G2269A E757K N.D. Intracellular G2459T R820I N.D. N.D. G2560T V854F N.D. N.D. G2698T V900L N.D. N.D. G2867C C956S 1↔ Normal G3211A V1071I ↔ Normal C3425T T1142M N.D. N.D. G3659A R1220Q N.D. N.D. A3941G Q1314R N.D. N.D. 2, reduced function; 1, increased function; ↔, no change in function; N.D. not determined. Login to comment
7115 Nucleotide Change Amino Acid Change In Vitro Function Protein Expression/Localization ABCC1 MRP1 G128C C43S 1࢒ Intracellular C218T T73I 1࢒ Normal C257T S92F 2࢒ Normal C350T T117M 2࢒ Normal G689A R230Q ࢒ Normal G1057A V353M N.D. N.D. G1299T R433S 2࢒ Normal G1898A R633Q 2࢒ Normal G2012T G671V ࢒ Normal G2168A R723Q 2 Normal G2965A A989T 2࢒ Normal G3140C C1047S 1࢒ Normal G3173A R1058Q ࢒ Normal C4535T S1512L ࢒ Normal ABCC2 MRP2 C-24T N.D. N.D. G1058A R353H N.D. N.D. G1249A V417I ࢒ Normal C2366T S789F 12 Intracellular T2780G L927R N.D. N.D. C3298T R1100C N.D. N.D. G3299A R1100H N.D. N.D. T3563A V1188E N.D. N.D. G4348A A1450T ࢒ Normal/Intracellular G4544A C1515Y N.D. N.D. ABCC3 MRP3 G32A G11D ࢒ Normal C202T H68Y N.D. N.D. G296A R99Q N.D. Normal C1037T S346F 2 Normal C1537A Q513K N.D. N.D. T1643A L548Q N.D. N.D. G1820A S607N 2 Normal C2221T Gln741STOP N.D. N.D. G2293C V765L ࢒ Normal G2395A V799M N.D. N.D. C2758T P920S 1 Normal G2768A R923Q 1 Normal C3657A S1219R N.D. N.D. C3856G R1286G ࢒ Normal G3890A R1297H N.D. N.D. C4042T R1348C 1 Normal A4094G Q1365R ࢒ Normal C4141A R1381S ࢒ Intracellular C4217T T1406M N.D. N.D. G4267A G1423R N.D. N.D. ABCC4 MRP4 C52A L18I N.D. N.D. C232G P78A 2࢒ Normal T551C M184T N.D. N.D. G559T G187W 2 Reduced A877G K293E ࢒ Normal G912T K304N ࢒ Normal C1067T T356M N.D. N.D. C1208T P403L 2࢒ Normal G1460A G487E 2 Normal A1492G K498E ࢒ Normal A1875G I625M N.D. N.D. C2000T P667L N.D. N.D. A2230G M744V ࢒ Normal G2269A E757K N.D. Intracellular G2459T R820I N.D. N.D. G2560T V854F N.D. N.D. G2698T V900L N.D. N.D. G2867C C956S 1࢒ Normal G3211A V1071I ࢒ Normal C3425T T1142M N.D. N.D. G3659A R1220Q N.D. N.D. A3941G Q1314R N.D. N.D. 2, reduced function; 1, increased function; ࢒, no change in function; N.D. not determined. Login to comment

PMID: 21900104 [PubMed] Visscher H et al: "Pharmacogenomic prediction of anthracycline-induced cardiotoxicity in children."

No. Sentence Comment

98 We found one variant in ABCC1 (rs4148350) to be associated with ACT. This variant is located in close proximity (Ͻ 3 Kb) and within the same haplotype block as the previously associated nonsynonymous variant G671V,10 suggesting these variants are likely in linkage disequilibrium. Login to comment

PMID: 22565165 [PubMed] Grover S et al: "Genetic association analysis of transporters identifies ABCC2 loci for seizure control in women with epilepsy on first-line antiepileptic drugs."

No. Sentence Comment

87 - 330-21247T > C Intron 1 0.005 6 rs4148731 chr7:87239329 c.-330 - 8935C > T Intron 1 0.000 7 rs9282564 chr7:87229440 c.61A > G Exon 3 (Asn21Asp) 0.000 8 rs9282565 chr7:87214875 c.239C > A Exon 5 (Ala80Glu) 0.000 9 rs28381826 chr7:87214531 c.286 + 297G > A Intron 5 0.000 10 rs1989830 chr7:87205663 c.287 - 6124C > T Intron 5 0.135 11 rs2520464 chr7:87201086 c.287 - 1547A > G Intron 5 0.409 12 rs2235023 chr7:87190452 c.827+ 127G > A Intron 9 0.000 13 rs10276036 chr7:87180198 c.1000 - 44C > T Intron 10 0.401 14 rs2229109 chr7:87179809 c.1199G > A Exon 12 (Ser400Asn) 0.000 15 rs1128503 chr7:87179601 c.1236T > C Exon 13 (Gly412Gly) 0.390 16 rs2235036 chr7:87175271 c.1795G > A Exon 16 (Ala599Thr) 0.000 17 rs2235039 chr7:87165854 c.2401G > A Exon 21 (Val801Met) 0.000 18 rs2235040 chr7:87165750 c.2481 + 24G > A Intron 21 0.155 19 rs2032581 chr7:87160810 c.2485A > G Exon 22 (Ile829Val) 0.000 20 rs2032582 chr7:87160618 c.2677T/A > G Exon 22 (Ser/Thr893Ala) 0.318 21 rs7779562 chr7:87144816 c.3085 -72G > C Intron 25 0.043 22 rs2707944 chr7:87144641 c.3188C > G Exon 26 (Ala1063Gly) 0.000 23 rs2229107 chr7:87138659 c.3421A > T Exon 27 (Thr1141Ser) 0.000 24 rs1045642 chr7:87138645 c.3435T > C Exon 27 (Ile1145Ile) m Expression and activity [28] m mRNA expression [29] Altered substrate specificity [30] 0.375 25 rs2235048 chr7:87138511 c.3489 + 80C > T Intron 27 0.381 26 rs17064 chr7:87133470 c.3932A > T 30 UTR 0.000 ABCC1 1 rs504348 chr16:16043174 rs50438C > G Near gene region k Promoter activity [31] 0.135 2 rs215106 chr16:16047542 c.48 + 3886A > G Intron 1 0.210 3 rs215049 chr16:16070768 c.48 + 27112G > C Intron 1 0.245 4 rs246220 chr16:16082128 c.49 - 19545C > G Intron 1 0.118 5 rs119774 chr16:16086833 c.49 - 14840G > A Intron 1 0.089 6 rs246217 chr16:16090354 c.49 - 11319C > A Intron 1 0.118 7 rs2014800 chr16:16099966 c.49 - 1707C > T Intron 1 0.398 8 rs41494447 chr16:16101842 c.218C > T Exon 2 (Thr73Ile) 0.000 9 rs4781712 chr16:16103232 c.226 - 401A > G Intron 2 0.355 10 rs246240 chr16:16119024 c.616 -7942A > G Intron 5 0.114 11 rs924135 chr16:16123459 c.616 - 3507A > T Intron 5 0.412 12 rs903880 chr16:16130514 c.809 + 54C > A Intron 7 0.147 13 rs8187852 chr16:16139709 c.1057G > A Exon 9 (Met353Val) 0.000 14 rs35587 chr16:16139714 c.1062T > C Exon 9 (Asn354Asn) 0.182 15 rs35592 chr16:16141823 c.1219 - 176T > C Intron 9 0.172 16 rs60782127 chr16:16142079 c.1299G > T Exon 10 (Arg433Ser) k Transport of leukotriene C4 and estrone sulfate [32] 0.008 17 rs3765129 chr16:16149901 c.1474 - 48C > T Intron 11 0.032 18 rs35597 chr16:16158034 c.1678 - 3979G > A Intron 12 0.320 19 rs35621 chr16:16168608 c.1913 - 1575C > T Intron 14 0.103 20 rs45511401 chr16:16173232 c.2012G > T Exon 16 (Gly671Val) 0.024 21 rs4148356 chr16:16177275 c.2168G > A Exon 17 (Arg723Gln) 0.000 22 rs3851713 chr16:16184873 c.2644 + 428A > T Intron 19 0.340 23 rs2239995 chr16:16192565 c.2645 - 3919G > A Intron 19 0.324 24 rs11864374 chr16:16201885 c.2871 + 1155G > A Intron 21 0.338 25 rs35529209 chr16:16205325 c.2965G > A Exon 22 (Thr989Ala) k Transport of estradiol 17b-glucuronide [32] 0.000 26 rs3887893 chr16:16205501 c.3079 + 62G > A Intron 22 0.448 27 rs13337489 chr16:16208683 c.3140G > C Exon 23 (Ser1047Cys) 0.000 28 rs2299670 chr16:16220858 c.3819 + 1090A > G Intron 26 0.399 29 rs8057331 chr16:16230411 c.4202C > T Exon 29 (Thr1401Met) 0.000 30 rs212090 chr16:16236004 c.5462T > A 30 UTR 0.357 31 rs212093 chr16:16237754 rs212093G > A Near gene region 0.429 32 rs4148382 chr16:16238494 rs4148382G > A Near gene region 0.034 ABCC2 1 g.-1774G > delG chr10:101535688 g.-1774G > delG Near gene region k Promoter activity [33] 0.000 2 rs1885301 chr10:101541053 c.-1549G > A Near gene region k Promoter activity [haplotype containing (- 1549A)-(- 24T)] [33] k Clearance of irinotecan (ABCC2*2 containing the G allele) [34] 0.379 450 Pharmacogenetics and Genomics 2012, Vol 22 No 6 Table 2 (continued) N dbSNP ida Positionb Allelesc Gene location (effect) Function MAF 3 rs2804402 chr10:101541583 c. Login to comment

PMID: 15083066 [PubMed] Lee YM et al: "Identification and functional characterization of the natural variant MRP3-Arg1297His of human multidrug resistance protein 3 (MRP3/ABCC3)."

No. Sentence Comment

210 By contrast, another natural polymorphic variant, MRP1-Gly671 Val, which is located near the first NBD of MRP1, had similar transport characteristics as MRP1 [46]. Login to comment

PMID: 12406648 [PubMed] Adachi M et al: "Therapeutic and biological importance of getting nucleotides out of cells: a case for the ABC transporters, MRP4 and 5."

No. Sentence Comment

226 G671V substitution, J. Hum. Genet. 46 (2001) 656-663. Login to comment
221 G671V substitution, J. Hum. Genet. 46 (2001) 656-663. Login to comment

PMID: 16815813 [PubMed] Choudhuri S et al: "Structure, function, expression, genomic organization, and single nucleotide polymorphisms of human ABCB1 (MDR1), ABCC (MRP), and ABCG2 (BCRP) efflux transporters."

No. Sentence Comment

311 Another SNP G2012T in exon 16 (Gly671Val) was found to have no functional consequences, whereas exon 10 SNP G1299T (Arg433Ser; in the cytosolic interface of transmembrane segment 8) resulted in significant decrease in the transport ability of many organic anions but increased doxorubicin resistance (Conseil, Deeley, and Cole 2005). Login to comment

PMID: 21590773 [PubMed] Budde T et al: "Acute exposure to doxorubicin results in increased cardiac P-glycoprotein expression."

No. Sentence Comment

125 OCTN1 for doxorubicin transport, but data on their role for cardiac uptake are missing.29,30 In contrast, efflux transporters of the ABC transporter family have already been shown to affect pharmacokinetics of their substrates and are present and functionally active in the heart.31,32 Among them MRP1 and P-gp are capable to transport doxorubicin, thereby possibly affecting cardiac drug concentrations.9,10 Therefore, it was not surprising that cardiac MRP1 expression and function have been associated with doxorubicin-induced cardiomyopathy.18,33 These findings were underlined by a human study indicating an association between a MRP1 polymorphism (Gly671Val) and acute anthracycline-induced cardiotoxicity.34 In contrast to MRP1, the effect of doxorubicin on cardiac P-gp expression has not been investigated so far. Login to comment

PMID: 22293538 [PubMed] Jungsuwadee P et al: "The G671V variant of MRP1/ABCC1 links doxorubicin-induced acute cardiac toxicity to disposition of the glutathione conjugate of 4-hydroxy-2-trans-nonenal."

No. Sentence Comment

0 The G671V variant of MRP1/ABCC1 links doxorubicin-induced acute cardiac toxicity to disposition of the glutathione conjugate of 4-hydroxy-2-trans-nonenal Paiboon Jungsuwadeea,c , Tianyong Zhaoa , Elzbieta I. Stolarczyka , Christian M. Paumia , D. Allan Butterfieldb , Daret K. St Claira and Mary Vorea Objective Doxorubicin-induced acute cardiotoxicity is associated with the Gly671Val (G671V; rs45511401) variant of multidrug resistance-associated protein 1 (MRP1). Login to comment
3 Methods We established stable HEK293 cell lines overexpressing wild-type MRP1 (HEKMRP1), G671V (HEKG671V), and R433S (HEKR433S), a variant not associated with doxorubicin-induced cardiotoxicity and investigated the sensitivity of HEKG671V cells to doxorubicin and transport capacity of G671V toward GS-HNE. Login to comment
4 Results In ATP-dependent transport studies using plasma membrane-derived vesicles, the Vmax (pmol/min/mg) for GS-HNE transport was the lowest for G671V (69 ± 4) and the highest for R433S (972 ± 213) compared with wild-type MRP1 (416 ± 22), whereas the Km values were 2.8 ± 0.4, 6.0 or more, and 1.7 ± 0.2 lmol/l, respectively. Login to comment
9 Conclusion These data suggest that decreased MRP1-dependent GS-HNE efflux contributes to increased doxorubicin toxicity in HEKG671V and potentially in individuals carrying the G671V variant. Login to comment
20 Among several variants, they identified Arg433Ser (R433S), Original article 273 1744-6872 c 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins DOI: 10.1097/FPC.b013e328350e270 located in the second transmembrane spanning domain, and Gly671Val (G671V; rs45511401), near the Walker A motif in the first nucleotide-binding domain. Login to comment
22 The G671V variant showed no difference in in-vitro transport assays using LTC4 or estradiol-17b-glucuronide (E217G) as substrates. Login to comment
24 The frequency of the G671V variant (exon 16, 2012G > T) was 2.78% for the T allele in Whites and 1.43% in the Indian population, with none reported in the Asian population [9]. Login to comment
26 Importantly, in a nested case-control cohort clinical study, patients with the G671V variant showed a significantly increased doxorubicin-induced acute cardiac toxicity that accounted for 6.4% of the incidence of acute cardiac toxicity, with an odds ratio of 3.6 (95% confidence interval: 1.6-8.4) [10]. Login to comment
36 In addition, on the basis of the fact that (a) cumulative doses of doxorubicin are a risk for doxorubicin-induced cardiac toxicity, (b) HNE and HNE metabolites (e.g. GS-HNE) have been shown to be associated with oxidative stress in a myocardial ischemic model [21], and (c) MRP1 is highly expressed in the heart [22,23], we postulated that the association of the MRP1 G671V variant with doxorubicin-induced acute cardiac toxicity [10] could be due to a change in its substrate specificity. Login to comment
37 In this study, we examined whether cells expressing the G671V and R433S variants versus WT MRP1 were more sensitive to doxorubicin, and characterized the transport properties of WT MRP1 relative to the G671V and R433S MRP1 variants, specifically with respect to GS-HNE transport activity. Login to comment
46 MRP1 variants of G671Vand R433S were generated using the QuickChange II XL site-directed mutagenesis kit (Stratagene, La Jolla, California, USA) according to the manufacturer`s instructions with the following mutagenic primers (for G671V, forward primer: 50 -TCCATCCCCGAAGTTGCTTTGGTG 274 GCCGTG-30 and reverse primer: 50 -CACGGCCACCAAAG CAACTTCGGGGATGGA-30 ; for R433S, forward primer: 50 -GTGGACGCTCAGAGCTTCATGGACTTGGC-30 and reverse primer: 50 -GCCAAGTCCATGAAGCTCTGAGCGT CCAC-30 ). Login to comment
78 Membranes were incubated with the primary antibodies for MRP1 (1:1000) and Na+ /K+ -ATPasea1 (1:20 000), washed three times, each for 5 min with TBS-T, followed by incubation with the secondary MRP1 G671V decreases GS-HNE transport Jungsuwadee et al. 275 antibody (1 : 5000) 1-2 h at room temperature, and finally washed twice with TBS-T buffer for 5 min. Login to comment
113 Results HEKG671V cells are more sensitive to doxorubicin cytotoxicity than HEKMRP1 and HEKR433S Patients with the G671V variant showed a significantly increased doxorubicin-induced acute cardiac toxicity [10]. Login to comment
114 In an attempt to understand this phenomenon, we developed HEK293 cell lines that stably expressed human MRP1 SNPs G671V, and three different control cells: HEK293 cells transfected with pUSEamp(+) vector (HEKpUSE), WT MRP1 (HEKMRP1), or the R433S variant (HEKR433S), which is not associated with doxorubicin-induced acute cardiac toxicity. Login to comment
117 To determine the impact of the G671V SNP on cell viability and to estimate the doxorubicin IC50 value, we cultured cells in the presence of doxorubicin at various concentrations for 48 h (Fig. 2a); IC50 values were calculated from the percent survival curves (Fig. 2b). Login to comment
121 To determine whether the G671V variant influenced retention of doxorubicin, we incubated cells with doxorubicin (50 mmol/l, 1 h) and then cultured cells for an additional 30 min in the absence of doxorubicin to determine its MRP1-mediated efflux. Login to comment
141 MRP1 G671V decreases GS-HNE transport Jungsuwadee et al. 277 Fig. 1 (b) 3000 MRP1pUSE G671V R433S *** *** *** 2000 Meanfluorescenceintensity 1000 0 pUSE MRP1 G671V R433S (a) (c) 10.0 * * * 7.5 5.0 2.5 MRP1/18S 0.0 pUSE MRP1 G671V R433S Expression in stable cell lines of multidrug resistance-associated protein 1 (MRP1) and its variants. Login to comment
149 Fig. 2 (a) (b) Genotype Doxorubicin IC50 nmol/l (95% CI) pUSE 58.0 (51.4-65.5) MRP1 463.0 (332.7-644.2) G671V 181.4 (137.4-239.5) R433S 645.2 (158.3-2630.0) pUSE125 100 75 50 Percentsurvival 25 0 MRP1 G671V R433S 10 Doxorubicin (μmol/l) -1-2-3 Percent survival of HEKpUSE, HEKMRP1, HEKR433S, and HEKG671V cells in the presence of doxorubicin. Login to comment
154 278 G671V single nucleotide polymorphism maintains LTC4 transport activity but loses glutathione-conjugated 4-hydroxy-2-trans-nonenal transport capacity In view of the cellular GS-HNE retention in HEKG671V cells, we examined further whether the MRP1 polymorphisms would have an impact on their substrate specificity or transport capacity. Login to comment
156 The G671V variant was comparable with WT MRP1 with respect to LTC4 transport, whereas LTC4 transport was decreased by 75% in the R433S variant compared with WT MRP1 (Fig. 6b), consistent with previous reports [7,8]. Login to comment
157 To determine whether the G671V variant might have an altered dependence on glutathione for transport, we examined the effects of glutathione; 0.5 mmol/l of glutathione had no effect on transport, whereas 5 mmol/l of glutathione completely inhibited LTC4 transport by MRP1 and both its variants (Fig. 6b). Login to comment
159 GS-HNE was transported by Michaelis-Menten kinetics (Fig. 6c), and showed a markedly reduced transport by the G671V variant such that the Vmax was decreased to about 15% of that by WT MRP1 (Fig. 6c). Login to comment
161 The Km value of the G671V variants did not differ significantly from that of WT MRP1 (Fig. 6c), and agreed well with the Km of 1.6 mmol/l reported previously for MRP1 [20]. Login to comment
163 The Vmax/Km of the G671V variant was only about 10% (0.025 mg/l/min) of that of WT MRP1 (0.24 mg/l/min), indicating a markedly decreased transport efficiency of the G671V variant. Login to comment
165 To investigate whether the cardiac sarcolemma can transport GS-HNE, and the Fig. 3 (a) (b) (c) (d) 1.5 ** ** **** ** ** ** *** ** 1.0 Fractionofcontrol doxorubicinaccumulation Fractionofcontrol doxorubicinaccumulation 0.5 0.0 8 250 200 150 100 GS-HNE(%control) 50 0 pUSE MRP1 G671V R433S 6 4 GS-HNE(nmol/mg) 2 0 Doxorubicin (1.5 μmol/l) - + - + - + - + pUSE MRP1 G671V R433S 1.5 1.0 0.5 0.0 pUSE 1 h M RP1 h G 671V 1 h R433S 1 h pUSE 24 h M RP1 24 h G 671V 24 h R433S 24 h Doxorubicin and glutathione-conjugated 4-hydroxy-2-trans-nonenal (GS-HNE) retention in HEKpUSE, HEKMRP1, HEKR433S, and HEKG671V cells. Login to comment
171 MRP1 G671V decreases GS-HNE transport Jungsuwadee et al. 279 importance of Mrp1, we isolated sarcolemma membranes from FVB WT and Mrp1- / - mice that were treated with doxorubicin (20mg/kg, intraperitoneally) and killed 24h later. Login to comment
174 Discussion The increased incidence of acute doxorubicin-induced cardiac toxicity in patients who carry the G671V variant of MRP1 suggests that the glycine to valine variant at amino acid 671 of MRP1 affects its transport function for certain substrates. Login to comment
175 Consistent with this hypothesis is the result predicted by PolyPhen-2 (http://genetics.bwh.harvard.edu/ pph2/), in which this G671V variant is predicted to be 'probably damaging`, likely due to the proximity of G671 to the Walker A motif. Login to comment
176 The present studies provided clear evidence that the ability to transport GS-HNE was markedly decreased by 85% in the G671V MRP1 variant relative to WT MRP1. Login to comment
177 In a previous study [7], the G671V variant did not show altered transport of several MRP1 substrates (LTC4, estrone sulfate, and E217G), and in this study, we confirmed that transport of LTC4 was not impacted. Login to comment
197 On the basis of Vmax values, the GS-HNE transport capacity of the G671V variant was decreased 85% relative to WT MRP1 (Fig. 6c), and exhibited a 10-fold decrease in Vmax/Km. Login to comment
204 These are the first data demonstrating that the G671V variant has a decreased capacity to efflux GS-HNE, despite retention of the ability of this MRP1 variant to transport other classic MRP1 substrates, that is, LTC4, estrone sulfate, and E217G [7]. Login to comment
212 MRP1 G671V decreases GS-HNE transport Jungsuwadee et al. 281 MRP3, Grant et al. [30] substituted amino acids 425-516 of MRP1 in the region spanning transmembrane helices 8 and with those of amino acids 411-502 of MRP3, and found complete loss of LTC4 transport, but a modest enhancement in E217bG transport, with minimal effects on transport of methotrexate, a substrate common to both MRP1 and MRP3 [30]. Login to comment
218 In conclusion, cells expressing the G671V MRP1 variant were more sensitive to doxorubicin than cells expressing WT MRP1, most likely due to an increase in the accumulation of intracellular GS-HNE, together with a decrease in the glutathione/GSSG ratio, indicating oxidative stress that can lead to cytotoxicity. Login to comment
219 Although increased retention of doxorubicin could also contribute to the increased oxidative stress in cells expressing the G671V variant, because amino acids in the third membrane spanning domain, especially between amino acids 959 and 1187, are considered most critical for doxorubicin transport [35], it seems less Fig. 6 Genotype Km ± SE (μmol/l) Vmax± SE (pmol/min/mg) Vmax/Km (mg/l/min) pUSE (95% CI) 6.3 ±12.9 (0.0-33.5) 28.4± 36.4 (0.0-104.8) 4.5 MRP1 (95% CI) 1.7 ±0.2 (1.2-2.1) 416.1±21.7 (371.1-461.2) 244.7 G671V (95% CI) 2.8± 0.4 (2.1-3.6) 69.1 ±4.1 (60.5-77.7) 24.7 R433S (95% CI) ≥6 972.1± 212.7 (531.0-1413) Approximately 160 pUSE MRP1 600 500 Protein(pmol/min/mg) 400 300 200 100 0 0 1 2 3 GS-HNE (μmol/l) 4 5 6 7 G671V R433S 125 *** *** 100 75 50 25 0 PercentLTC4efflux relativetoWT M RP1G 671VR433S M RP1+glutathione 5 G 671V+glutathione 5 R433S+glutathione 5 M RP1+glutathione 0.5 G 671V+glutathione 0.5 R433S+glutathione 0.5 2.5 (a) (b) (c) MRP1 pUSE/293 MRP1 G671V R433S Na/K-ATPase MRP1/NaK-ATPase banddensity (arbitraryunit) 2.0 1.5 1.0 0.5 0.0 MRP1 G671V R433S Multidrug resistance-associated protein 1 (MRP1) expression and transport activities of HEKMRP1, HEKR433S, and HEKG671V. Login to comment
228 282 likely that the G671V variant alters MRP1 recognition of doxorubicin. Login to comment
229 The decreased GS-HNE transport capacity of the G671V variant further indicates that MRP1 polymorphisms can play a significant role in MRP1 activity, and that these findings may be clinically important in patients receiving chemotherapy, particularly doxorubicin. Login to comment

PMID: 21929509 [PubMed] Semsei AF et al: "ABCC1 polymorphisms in anthracycline-induced cardiotoxicity in childhood acute lymphoblastic leukaemia."

No. Sentence Comment

121 This study found an association between chronic anthracycline-induced cardiotoxicity and a polymorphism in the NAD(P)H oxidase subunit NFC4 (rs1883112), and between: acute anthracycline-induced cardiotoxicity and the NAD(P)H oxidase subunits CYBA (rs4673) and RAC2 (rs1305 8338); and the ABC transporter ABCC1 Gly671Val variant (which is rs45511401) and the Val1188Glu-Cys1515Tyr (rs8187694- rs8187710) haplotype of the ABCC2 gene. Login to comment

PMID: 20367109 [PubMed] Giraud C et al: "ABC transporters in human lymphocytes: expression, activity and role, modulating factors and consequences for antiretroviral therapies."

No. Sentence Comment

179 3.1.2.1 ABCC1/MRP1 In 2001, Conrad et al. described two non-synonymous polymorphisms, R433S and G671V. Login to comment
544 Conrad S, Kauffmann HM, Ito K, et al. Identification of human multidrug resistance protein 1 (MRP1) mutations and characterization of a G671V substitution. Login to comment

PMID: 23396606 [PubMed] Vulsteke C et al: "Genetic variability in the multidrug resistance associated protein-1 (ABCC1/MRP1) predicts hematological toxicity in breast cancer patients receiving (neo-)adjuvant chemotherapy with 5-fluorouracil, epirubicin and cyclophosphamide (FEC)."

No. Sentence Comment

153 Since rs45511401 encodes a Gly671Val nonsynonymous mutation, whereas rs4148350 represents an intronic ABCC1/MRP1, rs45511401 most likely represents the causal variant underlying the association with toxicity. Login to comment
364 Jungsuwadee P, Zhao T, Stolarczyk El et al. The G671V variant of MRP1/ABCC1 links doxorubicin-induced acute cardiac toxicity to disposition of the glutathione conjugate of 4-hydroxy-2-trans-nonenal. Login to comment

PMID: 24080162 [PubMed] Conseil G et al: "Two polymorphic variants of ABCC1 selectively alter drug resistance and inhibitor sensitivity of the multidrug and organic anion transporter multidrug resistance protein 1."

No. Sentence Comment

5 In contrast, levels and membrane trafficking of R633Q, G671V, R723Q, A989T, and C1047S were similar to wild-type MRP1. Login to comment
9 In conclusion, although six in silico analyses consistently predict deleterious consequences of ABCC1 nsSNPs G671V, changes in drug resistance and inhibitor sensitivity were only observed for A989T and C1047S, which may relate to GSH transport differences. Login to comment
27 Previously, we generated and partially characterized recombinant forms of ABCC1 nsSNPs: rs45511401 (2012G.T; G671V), rs60782127 (1299G.T; R433S), and rs41395947 (128G.C; C43S) (Conrad et al., 2001, 2002; Leslie et al., 2003). Login to comment
28 We found that the G671V mutation had no deleterious effects on the levels or organic anion (i.e., LTC4, E217bG) transport function of MRP1 when expressed in human embryonic kidney (HEK) cells, despite the fact this mutation is located near NBD1 (Conrad et al., 2001). Login to comment
34 In contrast to our experimental data, the predictive algorithms SIFT (Sorting Tolerant From Intolerant) and PolyPhen indicated that G671V would adversely affect MRP1 function but C43S and A989T were less likely to do so, whereas predictions for R433S were mixed (L&#e9;tourneau et al., 2005). Login to comment
40 Four (C43S, S92F, G671V, A989T) were mutants that our earlier studies showed had a phenotype discordant from that predicted by Polyphen and/or SIFT (L&#e9;tourneau et al., 2005). Login to comment
58 Lysates (10 mg protein per lane) prepared from HEK293 cell lines expressing wild-type (WT) and mutant (R633Q, G671V, R723Q, A989T, C1047S) MRP1 proteins and the untransfected control cell line (HEK) were immunoblotted, and MRP1 was detected with mAb QCRL-1. Login to comment
111 All the algorithms and matrices are in agreement that the G671V mutation located close to the Walker A motif in NBD1 is the most likely to affect MRP1 activity. Login to comment
120 According to this method, the mutants ranked (from highest to lowest likelihood of an adverse effect) as follows: G671V . Login to comment
126 nsSNPs R633Q, G671V, R723Q, A989T, and C1047S Have No Effect on Total on Plasma Membrane MRP1 Levels in HEK293 Cells. Login to comment
127 After we had isolated stably transfected HEK293 cell lines by G418 selection, cell lines expressing R633Q, G671V, R723Q, A989T, and C1047S and wild-type MRP1 were cloned to .90% homogeneity for MRP1 expression. Login to comment
128 Immunoblots of cell lysates showed that the levels of the five mutant proteins were comparable to (R633Q, A989T, C1047S) or somewhat (,50%) higher than (G671V, R723Q) wild-type MRP1, indicating that the mutations do not cause any major misfolding of MRP1 that would result in its degradation (Fig. 1B). Login to comment
132 Confocal fluorescence microscopy experiments showed that the R633Q, G671V, R723Q, A989T, and C1047S mutant proteins in the five clonal HEK cell lines were also routed correctly to the plasma membrane in a manner indistinguishable from wild-type MRP1 (Fig. 2). Login to comment
136 The HEK cell lines expressing R633Q, G671V, R723Q, A989T, and C1047S were tested for their levels of resistance to five xenobiotics for which human MRP1 is known to confer resistance, including the antineoplastic agents vincristine, etoposide (VP-16), doxorubicin, and the heavy metal oxyanions arsenite and antimony tartrate (Cole et al., 1994). Login to comment
141 TABLE 1 Predicted effects of MRP1 nsSNPs examined in this study according to various in silico prediction methods nsSNP SIFT/SIFTBLink Probability Scoresa PolyPhen2 Classificationb (Score) I-Mutant Suite "Stability"c (DDG in kcal mol21 ) Grantham Value Difference (D)d Blosum50e PAM250f (Threshold) (,0.05) (.1.000) (,20.5; .0.5) (.50) (,0) (,0) C43S 0.51/0.08 possibly damaging (0.819) decrease (20.74) 112 21 0 S92F 0.11/0.05 possibly damaging (0.303) neutral (20.05) 155 23 23 NBD1-R633Q 0.66/0.57 benign (0.001) decrease (21.16) 43 1 1 NBD1-G671V 0.00/0.02 probably damaging (1.000) decrease (20.57) 109 24 21 NBD1-R723Q 0.49/0.39 benign(0.002) decrease (20.71) 43 1 1 A989T 0.53/0.12 benign (0.000) decrease (20.73) 58 0 1 C1047S 0.07/0.64 benign (0.001) decrease (20.67) 112 21 0 a SIFT (Sorting Intolerant From Tolerant) was used by manually entering a sequence alignment comprising only human homologs of MRP1, and SIFT-BLink probability scores were obtained using 100 aligned computer-selected sequences (threshold for nontolerated substitution set at ,0.05). Login to comment
153 To determine whether the five nsSNPs, R633Q, G671V, R723Q, A989T, and C1047S, affected the ability of MRP1 to mediate efflux of calcein, HEK293 cells stably expressing wild-type and mutant MRP1 as well as untransfected HEK cells were incubated with several concentrations of the cell permeable acetoxymethyl ester of calcein (calcein-AM) at 37&#b0;C; 3 hours later, the intracellular hydrolyzed calcein that had not been effluxed by MRP1 was measured. Login to comment
167 TABLE 2 Effect of nsSNP mutations on MRP1-mediated resistance to chemotherapeutic agents and metalloids in HEK293 cell lines Cell Line/ nsSNP Relative Resistancea Vincristine Doxorubicin Etoposide Na+ Arsenite K+ Antimony Tartrate Wild-type 12.2 6 0.6 3.9 6 1.6 7.1 6 0.6 1.4; 2.2 5.2; 6.4 R633Q 15.3 6 2.9 3.3 6 1.0 5.1 6 0.9 ND ND G671V 9.3 6 2.8 3.4 6 0.6 7.1 6 0.7 ND ND R723Q 21.3 6 7.2 2.5 6 0.1 6.9 6 0.5 ND ND A989T 4.4 6 1.1b ** 2.5 6 0.6 5.0 6 0.9 1.6; 2.3 3.1; 3.5 C1047S 5.1 6 0.5*** 1.8 6 0.2 4.5 6 0.7* 2.0; 1.8 2.2; 1.7 ND, not determined. Login to comment
189 HEK293 cells stably expressing wild-type (WT-MRP1) and mutant (R633Q, G671V, R723Q, A989T, C1047S) MRP1 were incubated in the presence of increasing concentrations of calcein-AM (0-6mM), and the intracellular calcein remaining in the cells after 3 hours was measured by fluorometry as described in Materials and Methods. Login to comment
227 The second category of mutants examined includes the three nsSNPs located in NBD1 (R633Q, G671V, R723Q), which exhibited little, if any, change in transport levels or sensitivity to MRP1 substrates or inhibitors. Login to comment
231 This contrasts with G671V, which all prediction algorithms, physicochemical parameters, and structure analyses concur should be deleterious (Table 2). Login to comment
232 Indeed, the G671V mutation ranked as the most damaging of all seven nsSNPs examined here. Login to comment
235 T (G671V) nsSNP has been associated with an altered response to certain drugs, including adverse reactions, in several studies. Login to comment
240 These findings are consistent with our earlier observation that lymphocytes from normal individuals bearing this G671V nsSNP expressed ABCC1 mRNA at relatively low levels (Conrad et al., 2001), and they suggest a change in mRNA structure is more important than the amino acid change caused by this nSNP. Login to comment
244 The reasons for the discordance between most of the experimental observations with the G671V mutant protein versus the uniformly adverse effects predicted for the Val substitution of Gly671 by the in silico analytical methods and the genetic association studies are unclear but may well be related to the cellular context in which the Fig. 6. Login to comment
250 It is also possible that analyses in a cell culture setting may not be adequate to discern all aspects of G671V function. Login to comment
269 Typically, either a cell-based or membrane-based functional assay is used to measure MRP1 function, but experience with the 2012C.T (G671V) allele suggests that additional nucleic acid-based methods should also be included. Login to comment

PMID: 24670052 [PubMed] Kunicka T et al: "Importance of ABCC1 for cancer therapy and prognosis."

No. Sentence Comment

144 Gly671Val (G2012T, rs45511401) SNP was especially interesting because it is located near the NBD1, only six amino acids upstream from the conserved Walker A motif. Login to comment
159 NCBI ID Reference Amino acid exchange Nucleotide exchange Location Function MAFa rs41395947 Cys43Ser G128C Exon 2 Non-synonymous Unknown rs41494447 Thr73Ile C218T Exon 2 Non-synonymous T &#bc; 0.003 rs8187844 Ser92Phe C257T Exon 3 Non-synonymous T &#bc; 0.004 rs8187848 Arg230Gln G689A Exon 7 Non-synonymous A &#bc; 0.009 rs2230669 Pro272Pro G816A Exon 8 Synonymous A &#bc; 0.037 rs246221 Val275Val T825C Exon 8 Synonymous C &#bc; 0.301 rs35592 non-coding T-176C Intron 9 Non-coding C &#bc; 0.257 rs60782127 Arg433Ser G1299T Exon 10 Non-synonymous T &#bc; 0.004 rs35605 Leu562Leu T1684C Exon 13 Synonymous T &#bc; 0.173 rs112282109 Arg633Gln G1898A Exon 14 Non-synonymous A &#bc; 0.004 rs45511401 Gly671Val G2012T Exon 16 Non-synonymous T &#bc; 0.050 rs4148356 Arg723Gln G2168A Exon17 Non-synonymous A &#bc; 0.027 rs35529209 Ala989Thr G2965A Exon 22 Non-synonymous Unknown rs13337489 Cys1047Ser G3140C Exon 23 Non-synonymous C &#bc; 0.000 rs41410450 Arg1058Gln G3173A Exon 23 Non-synonymous Unknown rs2238476 non-coding G-1960A Intron 23 Non-coding T &#bc; 0.062 rs2230671 Ser1334Ser G4002A Exon 28 Synonymous T &#bc; 0.208 rs28364006 Thr1337Ala A4009G Exon 28 Non-synonymous Unknown rs369410659 Ser1512Leu C4535T Exon 31 Non-synonymous Unknown a Minor allele frequencies for Caucasinans in dbSNP based on HapMap-CEU population or 1000 genomes. Login to comment
479 Identification of human multidrug resistance protein 1 (MRP1) mutations and characterization of a G671V substitution. Login to comment
706 The G671V variant of MRP1/ABCC1 links doxorubicin-induced acute cardiac toxicity to disposition of the glutathione conjugate of 4-hydroxy-2-trans-nonenal. Login to comment

PMID: 25078270 [PubMed] Kunicka T et al: "Non-coding polymorphisms in nucleotide binding domain 1 in ABCC1 gene associate with transcript level and survival of patients with breast cancer."

No. Sentence Comment

38 For instance, Gly671Val (dbSNP: rs45511401) SNP located near the nucleotide binding domain 1 (NBD1, Figure 1) which is important for the ATPase activity was associated with reduced levels of ABCC1 transcript [14]. Login to comment

PMID: 26354996 [PubMed] Deng J et al: "Elevated glutathione is not sufficient to protect against doxorubicin-induced nuclear damage in heart in multidrug resistance-associated protein 1 (Mrp1/Abcc1) null mice."

No. Sentence Comment

26 Wojnowski et al., (2005) reported that patients with a single nucleotide polymorphism in MRP1, G671V, have an increased risk of DOX-induced cardiotoxicity. Login to comment
27 We expressed this G671V variant in HEK293 cells and demonstrated that its Vmax for efflux of GS-HNE was decreased 85% relative to wild-type (WT) MRP1.We also showed that Mrp1 is the sole mediator of ATP-dependent transport of GS-HNE in mouse cardiac sarcolemmal vesicles (Jungsuwadee et al., 2012). Login to comment

PMID: 26395522 [PubMed] Slomka M et al: "Genetic variation of the ABC transporter gene ABCC1 (Multidrug resistance protein 1-MRP1) in the Polish population."

No. Sentence Comment

121 Among all detected non-synonymous variants, only one, c.2012G > T (p.Gly671Val), occurred as a homozygote with estimated MAF = 0.077. Login to comment
134 We found statistically significant difference in MAF values obtained in the both our studies for only two loci - c.1062 T > C (p.Asn354+) and c.2012G > T (p.Gly671Val). Login to comment
137 Additional four variants located in the loop containing NBD1 alter amino acids sequence: c.1898G > A (p.Arg633Gln) and c.2012G > T (p.Gly671Val) are located 44 and 6 amino acids upstream of the Walker A motif, respectively, while c.2168G > A (p.Arg723Gln) and c.2876A > G (p.Lys959Arg) are located 37 amino acids downstream of this motif, respectively. Login to comment
142 The novel variant c.596C > T (p.Ser199Leu) was estimated as a probably damaging substitution, likewise as four others: c.1299G > T (Arg433 Ser), c.2012G > T (p.Gly671Val), c.3886C > T (p.Arg 1296Trp) and c.3901C > T (p.Arg1301Cys). Login to comment
143 On the other hand, analysis for HumVar-trained model indicated that three polymorphisms: c.1299G > T (Arg433Ser), c.2012G > T (p.Gly671Val), c.3901C > T (p.Arg1301Cys), lead to probably damaging substitutions and two others, c.596C > T (p.Ser199Leu) and c.3886C > T (p.Arg1296Cys), are possibly damaging variants. Login to comment
144 Table 2 Summary of ABCC1 variants detected during scanning by HRM Exon scanned by HRM dbSNP ID Variant position NM_004996.3: Intron/amino acid residue NP_004987.2: Observed genotypesa, b (n) HWE exact test P-valuec MAFd R/R R/V V/V 2 rs8187843 c.225 + 26G > A Intron 164 25 0 1 (A) 0.066 4 rs587783373* c.352-79G > A Intron 185 1 0 1 (A) 0.003 4 rs4148337 c.352-66 T > C Intron 15 80 91 0.727 (T) 0.296 5 rs483352860* c.596C > T p.Ser199Leu 186 1 0 1 (T) 0.003 6 rs8187846 c.677 + 17C > T Intron 188 1 0 1 (T) 0.003 7 rs483352864* c.809 + 16C > T Intron 188 1 0 1 (T) 0.003 7 rs45609533 c.809 + 31G > T Intron 183 5 0 1 (T) 0.013 7 rs903880 c.809 + 54C > A Intron 112 65 11 0.684 (A) 0.231 7 rs246232 c.809 + 64C > G Intron 84 90 14 0.174 (G) 0.314 8 rs546943313 c.810-73C > T Intron 187 1 0 1 (T) 0.003 8 rs200194736 c.814C > T p.Pro272Ser 187 1 0 1 (T) 0.003 8 rs2230669 c.816G > A p.Pro272= 172 16 0 1 (A) 0.043 8 rs246221 c.825 T > C p.Val275= 84 92 12 0.059 (C) 0.309 8 rs587783372* c.855G > A p.Pro285= 187 1 0 1 (A) 0.003 9 rs35587 c.1062 T > C p.Asn354= 78 91 16 0.185 (C) 0.332 9 rs35588 c.1218 + 8A > G Intron 82 91 16 0.245 (G) 0.327 9 rs483352877* c.1218 + 9C > T Intron 188 1 0 1 (T) 0.003 10 rs60782127 c.1299G > T p.Arg433Ser 186 2 0 1 (T) 0.005 12 rs17265551 c.1677 + 56C > T Intron 162 27 0 0.604 (T) 0.072 13 rs35604 c.1678-37G > A Intron 2 45 142 0.745 (G) 0.130 13 rs483352863* c.1678-34G > A Intron 188 1 0 1 (A) 0.003 13 rs35605 c.1684 T > C p.Leu562= 2 45 142 0.745 (T) 0.130 13 rs8187858 c.1704C > T p.Tyr568= 157 31 1 1 (T) 0.088 14 rs112282109 c.1898G > A p.Arg633Gln 187 1 0 1 (A) 0.003 16 rs8187863 c.2001C > T p.Ser667= 187 1 0 1 (T) 0.003 16 rs45511401 c.2012G > T p.Gly671Val 161 25 2 0.296 (T) 0.077 17 rs4148356 c.2168G > A p.Arg723Gln 181 9 0 1 (A) 0.024 19 rs45607032 c.2461-39_2461-38delAT Intron 179 9 0 1 (delAT) 0.024 19 rs2074087 c.2461-30C > G Intron 0 44 144 0.083 (C) 0.117 19 rs45492500 c.2461-27G > A Intron 172 14 2 0.056 (A) 0.048 21 rs11075296 c.2871 + 26C > T Intron 0 0 189 1 - 22 rs768191257 c.2876A > G p.Lys959Arg 187 1 0 1 (G) 0.003 22 rs3851716 c.3079 + 10G > A Intron 0 0 188 1 - 22 rs34794353 c.3079 + 24C > T Intron 187 1 0 1 (T) 0.003 22 rs3887893 c.3079 + 62 T > C Intron 67 96 25 0.358 (C) 0.388 23 rs191017838 c.3171G > A p.Leu1057= 187 2 0 1 (A) 0.005 23 rs199773531 c.3196C > T p.Arg1066Trp 188 1 0 1 (T) 0.003 25 rs41278168 c.3591-5C > T Intron 187 1 0 1 (T) 0.003 27 rs200922662 c.3886C > T p.Arg1296Trp 187 1 0 1 (T) 0.003 27 rs201533167 c.3901C > T p.Arg1301Cys 187 1 0 1 (T) 0.003 Linkage disequilibrium analysis Based on full genotype sets of 44 polymorphic variants confirmed by Hardy-Weinberg equilibrium exact test (Table 2), linkage disequilibrium analysis using r2 and |D`| statistics was performed (Additional file 4). Login to comment
154 Bold variants signifies the ones which were validated by genotyping results Table 3 Summary of ABCC1 selected SNPs genotyping by HRM and comparing them with scanning results dbSNP ID Variant residue NM_004996.3: Intron/amino acid residue NP_004987.2: Observed genotypesa (n) HWE exact test P-valueb MAFc (genotyping) MAFc (scanning) Chi-square test P-valued R/R R/V V/V rs41395947 c.128G > C p.Cys43Se 380 0 0 1 - - - rs2230669 c.816G > A p.Pro272= 362 18 0 1 (A) 0.024 (A) 0.043 0.079 rs246221 c.825 T > C p.Val275 197 160 23 0.243 (C) 0.271 (C) 0.309 0.187 rs8187852 c.1057G > A p.Val353Met 379 0 0 1 - - - rs35587 c.1062 T > C p.Asn354= 204 142 33 0.247 (C) 0.274 (C) 0.332 0.044 rs35588 c.1218 + 8A > G Intron 190 160 30 0.709 (G) 0.289 (G) 0.325 0.214 rs60782127 c.1299G > T p.Arg433Ser 373 6 0 1 (T) 0.008 (T) 0.005 0.623 rs35605 c.1684 T > C p.Leu562= 13 105 262 0.588 (T) 0.172 (T) 0.130 0.063 rs8187858 c.1704C > T p.Tyr568= 325 55 0 0.242 (T) 0.072 (T) 0.087 0.374 rs45511401 c.2012G > T p.Gly671Val 346 28 3 0.007 (T) 0.045 (T) 0.077 0.038 rs4148356 c.2168G > A p.Arg723Gln 360 19 0 1 (A) 0.025 (A) 0.024 0.888 rs45517537 c.2581G > A p.Ala861Thr 380 0 0 1 - - - rs35529209 c.2965G > A p.Ala989Thr 378 0 0 1 - - - rs13337489 c.3140G > C p.Cys1047Ser 380 0 0 1 - - - rs28706727 c.3436G > A p.Val1146Ile 380 0 0 1 - - - rs2230671 c.4002G > A p.Ser1334= 204 140 32 0.296 (A) 0.271 (A) 0.277 0.850 rs28364006 c.4009A > G p.Thr1337Ala 380 0 0 1 - - - a Number of genotypes detected during this study, R - reference allele, V - variant allele. b P-value is consistent with Hardy-Weinberg equilibrium if P > 0.001. c Minor allele shown in brackets with its frequency. Login to comment
169 Marginal statistical significance (0.05 > P > 0.01) of difference between MAF values for scanning and targeted genotyping methods for two SNPs c.1062 T > C (p.Asn354=) and c.2012G > T (p.Gly671Val) is probably caused by sample size effect (there was no overlap between groups of individuals selected for both stages of the study). Login to comment
205 A similar observation was also reported previously for the SNP c.2012G > T (p.Gly671Val), detected also by us. Login to comment
207 Recently, other data confirmed these observations and none of the amino acid substitutions: p.Arg633Gln, p.Gly671Val, p.Arg723Gln, detected also in our study, was found to change functionality of MRP1 transporter. Login to comment
212 Two other polymorphic variants detected in this study c.825 T > C (p.Val275=) and c.2012G > T (p.Gly671Val), were correlated with febrile neutropenia as an effect of FEC-induced hematological toxicity in breast cancer patients [38]. Login to comment
215 The discrepancy observed in different studies on clinical significance of c.2012G > T (p.Gly671Val) and c.2168G > A (p.Arg723Gln) is of unclear origin. Login to comment
379 Identification of human multidrug resistance protein 1 (MRP1) mutations and characterization of a G671V substitution. Login to comment