ABCMdb

ABCC3 p.Arg1297His

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Publications

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

No. Sentence Comment

164 Only the amino acid exchanges Arg1297His and Gly1423Arg were found with a frequency greater than 5% in Caucasians but not in Japanese subjects (Table 3). Login to comment
172 Figure 3 Predicted membrance topology of MRP3 (ABCC3) based on hydrophobicity analysis. Locations of the non-synonymous polymorphisms are indicated with arrows. See Table 3 for allele frequencies and description of funtional consequences. NH2 COOH NBD NBD in out Membrane Gly11Asp His68Tyr Ser346Phe Lys13Asn Gln513Lys Thr527Arg Ala528Gly Leu548Gln Gln741* Val799Met Gln933Arg_fs Ser1219Arg Arg1297His Pro1300Leu Leu1362Val Ala1398Val Thr1406Met Gly1423Arg Ala1513Asp MRP3 (ABCC3) NBD NBD Lys13Asn NBD NBD Lys13Asn In accordance with the latter finding, Gradhand et al. (2007b) found no impact of the -211C>T polymorphism on the ABCC3 promoter activity in transfected cell lines. Login to comment
174 For example, changing the tryptophan at position 1242 of MRP3 markedly altered the substrate specificity of MRP3 (Oleschuk et al., 2003), as is the case when a similar Table 3 MRP3 (ABCC3) single nucleotide polymorphisms. Location, allele frequency and functional effects. Position in coding sequence Amino acid exchange Location Allele frequency Effect NCBI ID ReferenceAf Ca Jp others 32G>A Gly11Asp Exon 1 - 0 [1] 0.6 [2] - - rs11568609 39G>C Lys13Asn Exon1 - 0.5 [1] 0 [3] - no effect on mRNA or protein in liver [1] 0 [2] 202C>T His68Tyr Exon2 - 1.6 [1] 0[3] 0 [2] - no effect on mRNA or protein in liver [1] 1037C>T Ser346Phe Exon9 - 0.5 [1] 0[3] 0 [2] - no effect on mRNA or protein in liver [1] 1537C>A Gln513Lys Exon12 - 0.5 [1] 0[3] 0 [2] - no effect on mRNA or protein in liver [1] 1580C>G Thr527Arg Exon 12 - - - - - rs1003354 1583C>G Ala528Gly Exon 12 - - - - - rs1003355 1643T>A Leu548Gln Exon 13 - 0.3 [4] 0 [3] 0 [2] - - 2221C>T Gln741* Exon 17 - 0 [1] 0.6 [2] - - 2395G>A Val799Met Exon 18 - 0 [1] 0.6 [2] - - 2798A-2799G del Gln933Arg_fs Exon 21 - 0 [1] 0.6 [2] - frame shift and early stop codon [2] 3657C>A Ser1219Arg Exon 25 - 0 [1] 1.1 [2] - no effect on expression, localization or transport in vesicles from transfected cells [4] 3890G>A Arg1297His Exon27 - 5.2 [1] 8 [4] 0 [3] 0 [2] - no effect on mRNA or protein in liver [1] 3899C>T Pro1300Leu Exon 27 - - - - - rs41280128 4084C>G Leu1362Val Exon 28 - - - - - rs1051625 4193C>T Ala1398Val Exon29 - - - - - rs11549764 4217C>T Thr1406Met Exon29 - 0 [1] 0.6 [2] - - 4267G>A Gly1423Arg Exon29 - 12.5 [1] 0 [3] - no effect on mRNA or protein in liver [1] 0 [2] 4538A>C Ala1513Asp Exon 31 - - - - - rs11656685 1. Login to comment
182 Lee, Y.M., et al., Identification and functional characterization of the natural variant MRP3-Arg1297His of human multidrug resistance protein 3 (MRP3/ABCC3). Login to comment

PMID: 19107936 [PubMed] Muller PJ et al: "Polymorphisms in ABCG2, ABCC3 and CNT1 genes and their possible impact on chemotherapy outcome of lung cancer patients."

No. Sentence Comment

18 The promoter polymorphism C-211T is associated with reduced hepatic expression of ABCC3 mRNA.14 Lee et al.9 described 2 SNPs of the ABCC3 gene: the synonymous mutation C3942T and G3890A resulting in Arg1297His, this latter variant showed no different transport compared to the wildtype. Login to comment

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

No. Sentence Comment

179 However, this was not the case because the MRP3-Arg1297His variant exhibited transport properties similar to those of wild-type MRP3 and also localized correctly to the basolateral membranes of polarized epithelial cells. Login to comment
267 J Hum Genet 2001; 46:656-663. 37 Lee YM, Cui Y, Konig J, Risch A, Jager B, Drings P, et al. Identification and functional characterization of the natural variant MRP3-Arg1297His of human multidrug resistance protein 3 (MRP3/ABCC3). 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

406 MRP Chromosomal location Amino acid variation Nucleotide variation Location References Lys13Asn G39GC Exon1 His68Tyr C202T Exon2 Ser346Phe C1037T Exon9 Gln513Lys C1537A Exon12 Arg1297His G3890A Exon27 MRP3 17q21.3 Gly1423Arg G4267A Exon29 [241] MRP4 13q32.1 Unknown MRP5 3q27 Unknown L63L W64R 189G>C 190T>C Exon2 Exon2 [250] T364R Q378X 1091C>G 1132C>T Exon9 Exon9 [260, 261] R518X R518Q 1552 C>T 1553G>A Exon12 Exon12 [247, 262] R1141X R1138Q T1130M R1114C M1127T 3421C>T 3413G>A 3389C>T 3340C>T 3380C>T Exon24 Exon24 Exon24 Exon24 Exon24 [246, 247] R1275X 3823C>T Exon27 [246] P1346S 4036C>T Exon28 [246] MRP6 16p13.1 E1400K 4198G>A Exon29 [247] MRP7 6p12-21 Unknown MRP8 16q12.1 Unknown MRP9 16q12.1 Unknown CONCLUSIONS AND FUTURE DIRECTIONS MRPs which belong to the ABC transporter family are able to transport a remarkable array of diverse endo- and xenobiotics and their metabolites. Login to comment
360 The SNPs G39GC (allele frequency = 0.5%, in exon 1), C202T (1.6%, exon 2), C1037T (0.5%, exon 9), C1537A (0.5%, exon 12), G3890A (5.2%, exon 27) and G4267A (0.6%, exon 29) led to Lys13Asn, His68Tyr, Ser346Phe, Gln513Lys, Arg1297His and Gly1423Arg amino acid substitutions, respectively (Tablke 2). Login to comment

PMID: 21619426 [PubMed] Stieger B et al: "Pharmacogenetics of drug transporters in the enterohepatic circulation."

No. Sentence Comment

97 Gene name Transporter SNP Protein Population size (n) In vitro function Ref. Intestinal efflux transporters (cont.) ABCC2 MRP2 c.1249G>A p.V417I N/A Unchanged [221] c.1249G>A p.S789F N/A Reduced transport protein expression, no change in transport activity [221] c.1249G>A p.A1450T N/A Reduced transport protein expression, no change in transport activity [221] ABCC3 MRP3 c.32G>A p.G11D N/A Unchanged [222] c.1037C>T p.S346F N/A Reduced transport activity [222] c.1820G>A p.S607N N/A Reduced transport activity [222] c.2293G>C p.V765L N/A Unchanged [222] c.2758C>T p.P920S N/A Unchanged [222] c.2768G>A p.R923Q N/A Increased transport activity [222] c.3856G>C p.R1286G N/A Unchanged [222] c.3890G>A p.R1297H 52 Unchanged [131] c.4042C>T p.R1348C N/A Increased transport activity [222] c.4094A>G p.Q1365R N/A Unchanged [222] c.4141C>A p.R1381S N/A Unchanged [222] Liver uptake transporters SLCO1B1 OATP1B1 c.218T>C p.F73L N/A Increased Km , reduced protein synthesis and membrane expression [143] c.245T>C p.V82A N/A [143] c.388A>G p.N130D N/A Increased Km [143] c.455G>A p.R152K N/A [143] c.463C>A p.P155T N/A Unchanged [143] c.467A>G p.E156G N/A [143] c.521T>C p.V174A N/A Decreased Vmax , reduced transport protein expression [143] c.721G>A p.D241N N/A [143] c.1058T>C p.I353T N/A Increased Km , reduced transport protein expression [143] c.1294A>G p.N432D N/A Decreased Vmax [143] c.1385A>G p.D462G N/A Decreased Vmax [143] c.1463G>C p.G488A N/A Reduced intrinsic clearance, reduced transport protein expression [143] c.1964A>G p.D655G N/A Increased Km [143] c.2000A>G p.E667G N/A Unchanged [143] SLCO1B3 OATP1B3 c.334T>G p.S112A N/A Unchanged [223,224] c.439A>G p.T147A N/A Unchanged [223] c.699G>A p.M233I N/A Reduced transport activity, substrate-dependent alteration of Km [223,224] c.767G>C p.G256A N/A Unchanged [223] c.1559A>G p.H520P N/A Reduced transport activity [223] c.1564G>T p.G522C N/A Reduced transport activity [224] c.1679T>C p.V560A N/A Reduced transport activity [223] SLCO2B1 OATP2B1 c.43C>T p.P15S N/A Reduced transport activity [149] c.601G>A p.V201M N/A Reduced transport activity [149] c.1175C>T p.T392I N/A Reduced Vmax [148] For more information on members of the SLC superfamily of transporters please consult [301] and for more information of ABC transporters please consult [302]. Login to comment
538 131 Lee YM, Cui Y, Konig J et al.: Identification and functional characterization of the natural variant MRP3-Arg1297His of human multidrug resistance protein 3 (MRP3/ ABCC3). 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: 18484914 [PubMed] Nies AT et al: "Interplay of conjugating enzymes with OATP uptake transporters and ABCC/MRP efflux pumps in the elimination of drugs."

No. Sentence Comment

477 Lee YMA, Cui Y, König J, et al. Identification and functional characterization of the natural variant MRP3-Arg1297His of human multidrug resistance protein 3 (MRP3/ABCC3). Login to comment

PMID: 21606946 [PubMed] Ansari M et al: "Polymorphism in multidrug resistance-associated protein gene 3 is associated with outcomes in childhood acute lymphoblastic leukemia."

No. Sentence Comment

52 A false discovery rate correction was performed to adjust for multiple comparisons using Q-value Table 1 Identity of polymorphisms, details of PCR and ASO hybridization Polymorphisms PCR ASO Gene dbSNP Position Variation Primers Probes MRP2 rs1885301 À1519 A/G F: 50 -TCATATACCTGTTGGCCATT-30 50 -TATAGTATGTTGTGGATA-30 R: 50 -GTATGGACCTTGTTACTGAT-30 50 -TATAGTATATTGTGGATA-30 rs7910642 À993 G/A F: 50 -TTAGCTAGGATACCGCATGG-30 50 -AGGCCAAGGCAGAAGGA-30 R: 50 -ATGTTTTCTGTAGGGACGGG-30 50 -AGGCCAAGACAGAAGGA-30 rs2804402 À989 C/T F: 50 -ATGTTTTCTGTAGGGACGGG-30 50 -AACAATCCTTCTGCCTTG-30 R: 50 -TTAGCTAGGATACCGCATGG-30 50 -AACAATCCTCCTGCCTTG-30 rs717620 À24 G/A F: 50 -CCACTTGTTCTGAGTCTGAG-30 50 -TCTGGAACGAAGACTC-30 R: 50 -GGTCATCCTTTACGGAGAAC-30 50 -TCTGGAACAAAGACTC-30 rs2273697 1249 G/A (Val417Ile) F: 50 -GTGTCCATATGGAGCACATC-30 50 -AGTACACCGTTGGAGA-30 R: 50 -TACAAGCACCATCACCCCAA-30 50 -AGTACACCATTGGAGA-30 rs17222723 3563 T/A (Val1188Glu) F: 50 -ATGGTGGATGCCTCATGACT-30 50 -CAATGAGGTGAGGATTG-30 R: 50 -GTGTGTGGCCAGAGTGAATT-30 50 -CAATGAGGAGAGGATTG-30 rs8187710 4544 A/G (Cys1515Tyr) F: 50 -TCAGGGTAATGGTCCTAGAC-30 50 -TATAGAGTGCGGCAGCC-30 R: 50 -TCCTTTTCTAACCCATGGGG-30 50 -TATAGAGTACGGCAGCC-30 MRP3 rs1989983 À1696 A/G F: 50 -CATGACCAGGGTCATGGAAG-30 50 -TCCCAGAGGCATCAAGG-30 R: 50 -GCTAATCTGAGAGGTCCCCA-30 50 -TCCCAGAGACATCAAGG-30 rs9895420 À189 A/T F: 50 -GTGGGAGCGCCTGTGTATCC-30 50 -TCCCCCTGGCTTGGCCCA-30 R: 50 -AGTGCCTCTGGGTCCGGTCT-30 50 -TCCCCCTGGCATGGCCCA-30 rs4793665 À140 C/T F: 50 -GTGGGAGCGCCTGTGTATCC-30 50 -AAGGGCCCCCCCACCTCT-30 R: 50 -AGTGCCTCTGGGTCCGGTCT-30 50 -AAGGGCCCCCCTACCTCT-30 rs11568591 3890 G/A (Arg1297His) F: 50 -ATCTGCCCCTCCTGCCAGGC-30 50 -TATTCTGTGCGCTACCG-30 R: 50 -CGCCTACCCCACGCGTACCT-30 50 -TATTCTGTGCACTACCG-30 MRP5 rs7627754 À1629 A/T F: 50 -GAACTTGGGAGTAGGAAAGA-30 50 -GAATAATAAATATTCAAA-30 R: 50 -GGCTGCTCAAGTTTCCTATT-30 50 -GAATAATAATTATTCAAA-30 rs1520195 À1155 T/C F: 50 -TGGATGCACCAGTCTGTTTG-30 50 -ACTAGCTAGCTGTTATAA-30 R: 50 -CTCACCCCGCCGTATTTTTT-30 50 -ACTAGCTAGTTGTTATAA-30 rs562 5638 C/T F: 50 -CACTCCCTTCCCAGAGAATT-30 50 -CCATTCAATTGATGACAG-30 R: 50 -AAGAGACCTACCTCAGGTTG-30 50 -CCATTCAACTGATGACAG-30 Abbreviations: ASO, allele-specific oligonucleotide; F, forward; MRP, multidrug resistance-related protein; R, reverse; SNP, single-nucleotide polymorphism. Login to comment
118 Several non-synonymous polymorphisms of which some were shown to have functional consequences have been identified in MRP3 gene.30,31 All except Arg1297His replace- *1 *2 *3 pGL3Basic * ** ** ** * Relativepromoteractivity 0 HeLa Jeg-3 HepG2 1 2 3 4 5 6 7 8 9 Figure 3 Relative promoter activity in relation to multidrug resistance-related protein (MRP)3 promoter haplotypes. Login to comment

PMID: 18698235 [PubMed] Kobayashi K et al: "Functional analysis of nonsynonymous single nucleotide polymorphism type ATP-binding cassette transmembrane transporter subfamily C member 3."

No. Sentence Comment

188 Lee et al. [32] focused on SNP R1297H, one of the nonsynonymous ABCC3 SNPs frequently observed in Caucasians with an allele frequency of 8%, although this SNP did not affect ABCC3 protein localization and function when expressed in MDCK cells [32]. Login to comment

PMID: 18313914 [PubMed] Campa D et al: "Could polymorphisms in ATP-binding cassette C3/multidrug resistance associated protein 3 (ABCC3/MRP3) modify colorectal cancer risk?"

No. Sentence Comment

2 In this report, we investigated the hypothesis that a functional missense variant, namely the Arg1297His, and a polymorphism in the promoter region, namely the -211 C > Tof the ABCC3 gene, could be associated with colorectal cancer risk. Login to comment
15 In this report, we investigated the hypothesis that a functional missense variant, namely the Arg1297His, and a polymorphism in the promoter region, namely the -211 C > T of the ABCC3 gene could be associated with colorectal cancer risk (CRC). Login to comment
62 We did not find any significant association between ABCC3 Arg1297His or the -211 C > T polymorphisms and CRC risk, either overall or when subjects were stratified on the basis of gender. Login to comment
68 3.1. Statistical power Our study has 80% power to detect a minimum odds ratio of 2 for the Arg1297His SNP, present with a minor allele frequency (MAF) of 0.04 in our controls, and a minimum odds ratio of 1.4 for the -211 C > T (MAF = 0.46 in the controls of our study), assuming a = 0.05, two-sided test and a codominant model. Login to comment
71 Non-synonymous mutations in NBDs, which are highly conserved domains amongst ABC transporters, may cause deficient maturation and impaired trafficking.16 The Arg1297His SNP of ABCC3 has been postulated to exert such an effect.17 Lang and coworkers14 showed that the -211 C > T polymorphism of ABCC3 alters mRNA expression affecting the binding of nuclear factors to the promoter. Login to comment
75 Considering the low frequency of the Arg1297His SNP and the available sample size in this study, we cannot exclude that this polymorphism may be associated with a small alteration of risk. Login to comment
77 In conclusion, our study does not support a major role of Arg1297His and -211 C > T polymorphisms of ABCC3 gene in risk of CRC. Login to comment
83 Table 1 - Associations of ABCC3 functional polymorphisms with colorectal cancer risk Casesa Controlsa,b OR (95%)c P value P trend rs11568591 (Arg1297His) A/A 590 548 1 0.74 A/G 67 43 1.44 (0.96-2.11) 0.07 G/G 1 1 0.92 (0.51-14.44) 0.64 A/G+G/G 68 44 1.43 (0.97-2.13) 0.07 rs4793665 (-211 C > T) T/T 152 151 1 0.16 C/T 339 280 1.20 (0.91-1.58) 0.18 C/C 132 104 1.26 (0.89-1.77) 0.18 C/T + CC 471 384 1.22(0.94-1.58) 0.13 a Numbers may not add up to 100% of subjects due to genotyping failure. Login to comment
147 Lee YM, Cui Y, Konig J, et al. Identification and functional characterization of the natural variant MRP3-Arg1297His of human multidrug resistance protein 3 (MRP3/ABCC3). Login to comment
63 We did not find any significant association between ABCC3 Arg1297His or the -211 C > T polymorphisms and CRC risk, either overall or when subjects were stratified on the basis of gender. Login to comment
69 3.1. Statistical power Our study has 80% power to detect a minimum odds ratio of 2 for the Arg1297His SNP, present with a minor allele frequency (MAF) of 0.04 in our controls, and a minimum odds ratio of 1.4 for the -211 C > T (MAF = 0.46 in the controls of our study), assuming a = 0.05, two-sided test and a codominant model. Login to comment
72 Non-synonymous mutations in NBDs, which are highly conserved domains amongst ABC transporters, may cause deficient maturation and impaired trafficking.16 The Arg1297His SNP of ABCC3 has been postulated to exert such an effect.17 Lang and coworkers14 showed that the -211 C > T polymorphism of ABCC3 alters mRNA expression affecting the binding of nuclear factors to the promoter. Login to comment
76 Considering the low frequency of the Arg1297His SNP and the available sample size in this study, we cannot exclude that this polymorphism may be associated with a small alteration of risk. Login to comment
78 In conclusion, our study does not support a major role of Arg1297His and -211 C > T polymorphisms of ABCC3 gene in risk of CRC. Login to comment
84 Table 1 - Associations of ABCC3 functional polymorphisms with colorectal cancer risk Casesa Controlsa,b OR (95%)c P value P trend rs11568591 (Arg1297His) A/A 590 548 1 0.74 A/G 67 43 1.44 (0.96-2.11) 0.07 G/G 1 1 0.92 (0.51-14.44) 0.64 A/G+G/G 68 44 1.43 (0.97-2.13) 0.07 rs4793665 (-211 C > T) T/T 152 151 1 0.16 C/T 339 280 1.20 (0.91-1.58) 0.18 C/C 132 104 1.26 (0.89-1.77) 0.18 C/T + CC 471 384 1.22(0.94-1.58) 0.13 a Numbers may not add up to 100% of subjects due to genotyping failure. Login to comment
144 Lee YM, Cui Y, Konig J, et al. Identification and functional characterization of the natural variant MRP3-Arg1297His of human multidrug resistance protein 3 (MRP3/ABCC3). Login to comment

PMID: 17495421 [PubMed] Fukushima-Uesaka H et al: "Genetic variations of the ABC transporter gene ABCC3 in a Japanese population."

No. Sentence Comment

66 We did not detect previously reported variations with Æ0.01 frequencies in Caucasians: 202CÀT (His68Tyr, at 0.016), and 3890GÀA (Arg1297His; at 0.052).14) Thus, it is likely that these SNPs are ethnic-specic. Another known polymorphism in the 5?-anking region, |211CÀT, was reported to be signicantly associated with reduced hepatic mRNA expression.14) The allele frequency of |211CÀT in Japanese was 0.837, which is 66z higher than that in Caucasians (frequency: 0.505). Login to comment

PMID: 17300812 [PubMed] Gradhand U et al: "Functional analysis of the polymorphism -211C>T in the regulatory region of the human ABCC3 gene."

No. Sentence Comment

26 While the polymorphism 3890ANG (Arg1297His) has no effect on the protein localization or the transport function (Lee et al., 2004), the polymorphism -211CNT, located in the 5'-regulatory region of the ABCC3 gene, was associated with significantly lower ABCC3 transcript levels and a trend towards lower protein expression in human liver. 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

0 Identification and functional characterization of the natural variant MRP3-Arg1297 His of human multidrug resistance protein 3 (MRP3/ABCC3) Young-Min A. Leea , Yunhai Cuia , Jo¨rg Ko¨niga , Angela Rischb , Birgit Ja¨gerb , Peter Dringsc , Helmut Bartschb , Dietrich Kepplera and Anne T. Niesa The human multidrug resistance protein 3 (MRP3, symbol ABCC3) is an ATP-binding cassette transporter that mediates the efflux of organic anions, including lipophilic substances conjugated with glucuronate, sulphate or glutathione, across the basolateral membrane of polarized cells (e.g. hepatocytes) into blood. Login to comment
4 The 3890G>A mutation, resulting in MRP3-Arg1297 His, was introduced into the ABCC3 cDNA which was stably transfected into MDCKII cells. Login to comment
5 For the functional characterization of MRP3-Arg1297 His in comparison with MRP3, ATP-dependent transport was analysed in isolated membrane vesicles. Login to comment
6 Two non-synonymous MRP3 variants were identified with an allele frequency of 0.003 for 1643T>A (MRP3-Leu548 Gln) and 0.08 for 3890G>A (MRP3-Arg1297 His). Login to comment
7 Because of the high frequency of the 3890G>A mutation, and because of the close proximity of Arg1297 to the second nucleotide-binding domain, we pursued the functional characterization of the MRP3-Arg1297 His polymorphic variant. Login to comment
8 MRP3-Arg1297 His was correctly localized to the basolateral membrane of polarized MDCKII cells. Login to comment
9 We identified monoglucuronosyl bilirubin, bisglucuronosyl bilirubin and leukotriene C4 as substrates for both MRP3 and MRP3-Arg1297 His. Login to comment
10 Dehydroepiandrosterone-3-sulphate and 17â-glucuronosyl oestradiol were transported with similar kinetics by MRP3 and MRP3-Arg1297 His. Login to comment
44 In addition to characterizing human MRP3 as a transporter for bilirubin glucuronosides, we identified two SNPs in the human ABCC3 gene that resulted in non-synonymous amino acid changes (i.e. MRP3-Leu548 Gln and MRP3-Arg1297 His). Login to comment
45 We functionally characterized the polymorphic variant MRP3-Arg1297 - His because of its high frequency in the Caucasian population and because amino acid Arg1297 is located close to the second nucleotide-binding domain (NBD). Login to comment
75 Site-directed mutagenesis The nucleotide exchange 3890G.A, leading to the amino acid exchange Arg1297 His, was introduced into the ABCC3 cDNA (GenBank/EBI data bank accession no. Login to comment
87 The fragment was then subcloned into the mammalian expression vector MRP3/pcDNA3.1(+) [8] between the restriction sites SanDI and AgeI, resulting in MRP3-Arg1297 His/pc DNA3.1. Login to comment
90 For stable transfection, parental MDCKII cells were grown in 10-cm diameter dishes until reaching confluency and transfected with the MRP3/pcDNA3.1-vector, MRP3-Arg1297 His/ pcDNA3.1-vector, or pcDNA3.1-vector (¼ control) using the polybrene method [36]. Login to comment
95 MRP3 and MRP3-Arg1297 His were detected with the FDS antiserum diluted 1 : 500 in Tris-buffered saline/Tween20 (20 mM Tris, 145 mM NaCl, 2.7 mM KCl, 0.05% Tween 20, pH 7.6) containing 5% milk powder. Login to comment
142 Because of the high frequency of the 3890G.A mutation in the Caucasian population, we analysed the functional consequence of the MRP3-Arg1297 His polymorphism. Login to comment
143 Immunoblot and immunofluorescence analysis of MRP3 and MRP3-Arg1297 His stably expressed in MDCK cells In line with previous studies [6,8], recombinant MRP3 appeared as a fully glycosylated form of 190 kDa and of a less glycosylated form of approximately 170 kDa in immunoblot analysis (Fig. 2a), the ratio of the 190 to the 170 kDa form being 1.8 Æ 0.3 (n ¼ 3) for this membrane vesicle preparation. Login to comment
145 The MRP3-Arg1297 His protein was also present in a 190 and a 170 kDa form, their ratio being 1.4 Æ 0.1 (n ¼ 3) in this preparation. Login to comment
146 Two other MRP3-Arg1297 His membrane vesicle preparations had ratios of 1.3 and 1.4. Login to comment
147 In the given blot (Fig. 2a), the level of the synthesized 190 kDa form of MRP3-Arg1297 His was 1.04 of that of MRP3 and 1.15 when both glycosylated forms were taken into account. Login to comment
149 Using confocal laser scanning microscopy (Fig. 2b-e), MRP3 and MRP3-Arg1297 His were localized to the basolateral membrane of MDCKII cells, indicating the synthesis of a full-length MRP3-Arg1297 His and its correct basolateral routing. Login to comment
151 ATP-dependent transport of 17â-glucuronosyl [3 H]oestradiol, [3 H]LTC4 and [3 H]DHEAS by MRP3 and MRP3-Arg1297 His For the functional characterization of MRP3-Arg1297 His, transport assays with [3 H]E217âG, [3 H]LTC4 and [3 H]DHEAS were performed. Login to comment
152 ATP-dependent transport of all three substances was detected for MRP3 and MRP3-Arg1297 His. Login to comment
153 Transport by MRP3-Arg1297 His showed similar transport kinetics as MRP3 (Fig. 3). Login to comment
156 Unauthorized reproduction of this article is prohibited. Table 4 Allelic variations in human MRP3 Exon Nucleotide variation Amino acid variation Allele frequency Type of mutation 13 1643T.A Leu548 Gln T ¼ 0.997 Non-synonymous A ¼ 0.003 22 3039C.T Gly1013 Gly C ¼ 0.94 Synonymous T ¼ 0.06 27 3890G.A Arg1297 His G ¼ 0.92 Non-synonymous A ¼ 0.08 27 3942C.T His1314 His C ¼ 0.76 Synonymous T ¼ 0.24 29 4266C.T Gly1422 Gly C ¼ 0.99 Synonymous T ¼ 0.01 31 4509A.G Glu1503 Glu A ¼ 0.80 Synonymous G ¼ 0.20 (c) (e) (d) MRP3MRP3-Arg1297 His(b) 180 kDa M RP3-Arg1297 H is C o M RP3 (a) Fig. 2 Analysis of the synthesis of MRP3 and MRP3-Arg1297 His in polarized MDCKII cells. Login to comment
157 (a) Immunoblot analysis using the FDS antiserum directed against the C-terminus of human MRP3 [8] indicates synthesis of full-length and fully glycosylated MRP3 and MRP3-Arg1297 His in transfected MDCKII cells. Login to comment
160 (b-e) Confocal laser scanning micrographs after reaction with the FDS antiserum showed basolateral localization of MRP3-Arg1297 His (b,c) and MRP3 (d,e) in polarized MDCKII cells. Login to comment
162 Scale bar ¼ 20 ìm. values) of vesicles from MRP3-, MRP3-Arg1297 His-transfected and control cells for E217âG were 24.2 Æ 5.8 ìM (71.5 Æ 6.3 pmol/mg protein per min), 16.0 Æ 10.9 ìM (72.3 Æ 19.5 pmol/mg protein per min) and 13.4 Æ 7.5 ìM (25.0 Æ 5.2 pmol/mg protein per min), respectively. Login to comment
164 Km values (and Vmax values) for vesicles from MRP3- and MRP3-Arg1297 His-transfected cells for DHEAS were 46.3 Æ 7.3 (281 Æ 21 pmol/mg protein per min) and 34.6 Æ 5.7 ìM (269 Æ 19 pmol/mg protein per min), respectively. Login to comment
165 ATP-dependent transport of [3 H]-monoglucuronosyl bilirubin and [3 H]-bisglucuronosyl bilirubin by MRP3 and MRP3-Arg1297 His Membrane vesicles from MRP3- or MRP3-Arg1297 His-transfected MDCKII cells showed significant ATP-dependent transport (P , 0.001 compared to controls) of [3 H]MGB (12 nM) with a transport rate of 0.12 pmol/ Copyright (c) Lippincott Williams & Wilkins. Login to comment
167 Time (min) MRP3 MRP3-Arg1297 His Control 9 6 3 0 ATP-dependent[3 H]LTC4transport (pmol/mgprotein) (b) 0 2 4 6 8 10 MRP3 MRP3-Arg1297 His Control 120 80 40 0 ATP-dependent[3 H]DHEAStransport (pmol/mgprotein) (c) 0 2 4 6 8 10 MRP3 MRP3-Arg1297 His Control 290 150 100 50 0 ATP-dependent[3H]E217βGtransport (pmol/mgprotein) (a) 0 2 4 6 8 10 Fig. 3 ATP-dependent transport of (a) 17â-glucuronosyl oestradiol (E217âG), (b) leukotriene C4 (LTC4) and (c) dehydroepiandrosterone-3-sulphate (DHEAS) into membrane vesicles from MRP3-, MRP3-Arg1297 His-transfected and control MDCKII cells. Login to comment
171 MRP3 Km 24µM E217βG 60 40 20 0 [3H]E217βGtransport (pmol/mgproteinpermin) (a) 0 20 40 60 80 E217βG (µM) MRP3-Arg1297His Km 16µM E217βG 60 40 20 0 (b) 0 10 20 40 50 E217βG (µM) 30 MRP3-Arg1297His Km 35µM DHEAS250 150 50 0 (d) 0 30 60 90 120 DHEAS (µM) 200 100 MRP3 Km 46µM DHEAS250 200 100 0 (c) 0 30 60 90 120 DHEAS (µM) 150 50 [3H]DHEAStransport (pmol/mgproteinpermin) Fig. 4 Kinetic analysis of MRP3- and MRP3-Arg1297 His-mediated transport of (a,b) glucuronosyl oestradiol (E217âG) or (c,d) dehydroepiandrosterone-3-sulphate (DHEAS). Login to comment
172 Rates of ATP-dependent transport of [3 H]E217âG or [3 H]DHEAS were determined in membrane vesicles from MRP3- or MRP3-Arg1297 His-transfected MDCKII cells at the indicated substrate concentrations after 5 min. Login to comment
177 For each substrate, the transport kinetics of MRP3 and MRP3-Arg1297 His were similar. Login to comment
178 Only the 10-min value of the [3 H]BGB transport was significantly higher for MRP3-Arg1297 His than for MRP3 (Fig. 5f). Login to comment
181 ATP 5'-AMP MRP3 MGB (a) 2 1 0 [3 H]MGBtransport(pmol/mgprotein) 0 5 10 ATP 5'-AMP MRP3-Arg1297His MGB (b) 2 1 0 [3 H]MGBtransport(pmol/mgprotein) 0 5 10 MRP3 MRP3-Arg1297 His (c) 2 1 0 ATP-dependent[3H]MGBtransport (pmol/mgprotein) 0 5 10 Control Time (min) MRP3 MRP3-Arg1297 His (f) 2 1 0 ATP-dependent[3 H]BGBtransport (pmol/mgprotein) 0 5 10 Control Time (min) * ATP 5'-AMP MRP3-Arg1297 His BGB (e) 2 1 0 [3 H]BGBtransport(pmol/mgprotein) 0 5 10 ATP 5'-AMP MRP3 BGB (d) 2 1 0[3 H]BGBtransport(pmol/mgprotein) 0 5 10 Fig. 5 Transport of (a-c) [3 H]monoglucuronosyl bilirubin (MGB) and (d-f) [3 H]bisglucuronosyl bilirubin (BGB) into membrane vesicles from MRP3- and MRP3-Arg1297 His-transfected MDCKII cells. Login to comment
193 In addition to several synonymous mutations that have been described in a Japanese population [29], we identified two non-synonymous mutations in MRP3 (i.e. MRP3-Leu548 Gln and MRP3-Arg1297 His) (Fig. 1, Table 4). Login to comment
194 We pursued the functional characterization of MRP3-Arg1297 His because Arg1297 is located close to the Walker A motif of the second NBD (Fig. 1). Login to comment
196 Recombinant MRP3 and MRP3-Arg1297 His were present in 190- and 170-kDa forms (Fig. 2a), both of which are most likely differentially glycosylated forms [6,8]. Login to comment
197 The level of the less glycosylated form appeared to be higher for MRP3-Arg1297 His than for MRP3. However, the proportion of both forms may vary as observed for the different MRP3 membrane vesicle preparations. Login to comment
200 Therefore, the MRP3-Arg1297 His protein is probably also localized in the basolateral membrane of human hepatocytes. Login to comment
201 However, this remains to be proven because human liver samples were not available from patients with the MRP3-Arg1297 His polymorphic variant. Login to comment
202 Because the Arg1297 His polymorphism had no effect on maturation and basolateral localization of MRP3 (Fig. 2), we analysed whether MRP3-Arg1297 His differs in its transport properties from MRP3. Login to comment
211 In the case of MRP3-Arg1297 His, we also observed similar transport characteristics as for MRP3 (Fig. 3) with the established MRP3 substrates LTC4 and E217âG [1-4]. Login to comment
212 The Km values for E217âG of MRP3 and MRP3-Arg1297 His (Fig. 4) were in the range of those reported by Zeng et al. [2] (26 ìM) and Akita et al. [4] (43 ìM). Login to comment
213 We additionally examined the bilirubin glucuronosides MGB and BGB, and the steroid DHEAS as MRP3 substrates (Figs 3-5), and showed that they were transported with similar kinetic characteristics by MRP3-Arg1297 His as well as by MRP3. Login to comment
214 In the case of significant transport differences between MRP3-Arg1297 His and MRP3, studies would be of interest to elucidate whether interindividual variations of MRP3 affect the response of an individual to chemotherapy. Login to comment
227 In conclusion, we identified two non-synonymous SNPs and functionally characterized for the first time a natural variant of MRP3, MRP3-Arg1297 His. Login to comment
229 Thus, based on our membrane vesicle transport assays, individuals with the MRP3-Arg1297 His variant are not expected to be affected in their ability to export MRP3 substrates into blood. Login to comment

PMID: 15167703 [PubMed] Lang T et al: "Genetic polymorphisms in the multidrug resistance-associated protein 3 (ABCC3, MRP3) gene and relationship to its mRNA and protein expression in human liver."

No. Sentence Comment

5 SNPs 39G>C (allele frequency: 0.5%, located in exon 1), 202C>T (1.6%, exon 2), 1037C>T (0.5%, exon 9), 1537C>A (0.5%, exon 12), 3890G>A (5.2%, exon 27) and 4267G>A (0.6%, exon 29) resulted in Lys13Asn, His68Tyr, Ser346Phe, Gln513Lys, Arg1297His and Gly1423Arg amino acid substitutions, respectively. Login to comment
76 A; Gln513Lys; 0.5%), exon 27 (3890G.A; Arg1297His; 5.2%) and exon 29 (4267G.A; Gly1423Arg; 0.6%) resulted in amino acid substitutions (Fig. 1). Login to comment
78 The most frequent amino acid exchange from Arg to His at position 1297 is located near the functionally important second ATP-binding domain (1323-1330). Login to comment
100 Table 2 Polymorphisms identified in the MRP3 gene and frequencies of MRP3 mutations estimated among 103 Caucasian individuals Frequency (%) SNP ID 5` Sequence Genetic variation 3` Sequence Region Effect Alleles n Heterozygous Homozygous NCBI SNP ID 1 GAAGCCGGTG À1942G.T GTAGACAAGG Promoter 186 2.2, 0.4-6.6 (2.2) 0.0, 0.0-3.2 (0.0) 2 AGTCCCAGAG À1767G.A CATCAAGGAG Promoter 186 22.6, 15.7-30.9 (21.7) 1.1, 0.1-5.0 (1.5) rs1989983 3 GAGGTGGCTT À1328G.A CCCCTTCTGC Promoter 190 12.6, 7.5-19.7 (11.8) 0, 0.0-3.1 (0.4) 4 GGCTCCCACC À1298C.G ACACCTGCCG Promoter 192 2.1, 0.4-6.4 (2.1) 0, 0.0-3.1 (0.0) 5 TGAAACTGGA À1213C.G AGACCTGTGG Promoter 184 21.7, 14.9-30.0 (21.1) 1.1, 0.1-5.1 (1.4) 6 CCCCAACAAG À1134C.T GGTGCTGAGT Promoter 190 4.2, 1.5-9.4 (4.1) 0.0, 0.0-3.1 (0.0) rs4148403 7 ACCTGTCCTT À897delC CCCCCCCAAC Promoter 196 45.9, 37.3-54.7 (43.7) 9.2, 4.9-15.5 (10.3) rs4148404 8 CAGAGGGAAT À860T.G CACACATGTT Promoter 188 1.1, 0.1-4.9 (1.1) 0.0, 0.0-3.1 (0.0) 9 TCCCCCTGGC À260T.A TGGCCCAGGG Promoter 180 23.9, 16.8-32.4 (20.9) 1.1, 0.1-5.1 (1.6) 10 AGGGCCCCCC À211C.T ACCTCTGCCC Promoter 198 58.6, 49.8-67.0 (50.0) 21.2, 13.8-28.0 (24.5) rs4793665 11 TGGGTCCGAC À35C.A GCGCTCGCCT Exon 1 non-coding 196 1.0, 0.1-4.7 (1.0) 0.0, 0.0-3.0 (0.0) 12 TCGGCTCCAA 39G.C TTCTGGGTAA Exon 1 K13N 198 1.0, 0.1-4.7 (1.0) 0.0, 0.0-3.0 (0.0) 13 TTCTCTGTGT 46-6C.T CCCAGGACTC Intron 1 192 1.0, 0.1-4.8 (1.0) 0.0, 0.0-3.1 (0.0) 14 ACCTGTGGGT 141C.T GCCCTGCCCT Exon 2 silent 192 1.0, 0.1-4.8 (1.0) 0.0, 0.0-3.1 (0.0) 15 CATCCTCTCC 202C.T ACCTGTCCAA Exon 2 H68Y 192 3.1, 0.9-7.9 (3.1) 0.0, 0.0-3.1 (0.0) 16 CCAACCTGTG 223-12C.T TCTCTTCGCA Intron 2 202 1.0, 0.1-4.6 (1.0) 0.0, 0.0-2.9 (0.0) 17 GGGAAGAAGA 349-102A.C GGGGGTGGCC Intron 3 192 1.0, 0.1-4.8 (1.0) 0.0, 0.0-3.1 (0.0) 18 GGGGTGGCCC 349-90C.T AGAAACTTCT Intron 3 192 1.0, 0.1-4.8 (1.0) 0.0, 0.0-3.1 (0.0) 19 GAGAAATGGA 349-53G.A GCAGGTCCAG Intron 3 196 5.1, 2.0-10.4 (5.0) 0.0, 0.0-3.0 (0.1) rs2301836 20 CAGCCCCCAA 612þ73C.A CCCTCCAGTT Intron 5 166 10.8, 5.8-18.2 (10.2) 0.0, 0.0-3.5 (0.2) 21 TGATTCCCCC 613-22G.A TCCTATTCTC Intron 5 168 45.2, 36.0-54.8 (40.8) 6.0, 2.4-12.1 (8.2) rs739923 22 ACCCACTGCT 807-18C.T CTTCCTCCCT Intron 7 176 12.5, 7.2-19.8 (13.6) 1.1, 0.1-5.3 (0.6) rs2301837 23 TCCACACTCC 998þ16G.A GCTCACTATA Intron 8 154 7.8, 3.4-14.8 (7.5) 0.0, 0.0-3.8 (0.1) 24 ATGGCCCCCT 1037C.T CTGGTGGGGC Exon 9 S346F 202 1.0, 0.1-4.6 (1.0) 0.0, 0.0-2.9 (0.0) 25 TGCTTCCTGC 1339-107C.G CATCTACACA Intron 10 170 1.2, 0.1-5.5 (1.2) 0.0, 0.0-3.5 (0.0) 26 TGCCTCCTCA 1339-1G.T AACCTAGGTC Intron 10/Exon 11 splice site 174 1.1, 0.1-5.3 (1.1) 0.0, 0.0-3.4 (0.0) 27 TGAAGCTGTA 1512C.T GCCTGGGAGC Exon 12 silent 204 1.0, 0.1-4.6 (1.0) 0.0, 0.0-2.9 (0.0) 28 CTTCCTGAAG 1537C.A AGGTGGAGGG Exon 12 Q513K 204 1.0, 0.1-4.6 (1.0) 0.0, 0.0-2.9 (0.0) 29 GGAGGGCATC 1552A.C GGCAGGGTGA Exon 12 silent 202 6.9, 3.3-12.6 (6.7) 0.0, 0.0-2.9 (0.1) 30 CTTCCTGGTG 1635þ4delA GGCTTGGCAC Intron 12 splice site consenus 204 1.0, 0.1-4.6 (1.0) 0.0, 0.0-2.9 (0.0) 31 TGCTGGACGC 1695C.T GAGAAGGCCT Exon 13 silent 204 1.0, 0.1-4.6 (1.0) 0.0, 0.0-2.9 (0.0) 32 GTCCTCCTTT 1871-79C.T CCCTGCCCCC Intron 14 202 23.8, 17.0-31.8 (22.5) 75.2, 67.2-82.2 (75.8) rs879459 33 TTCCCTGCCC 1871-70C.G CCAGCCTCCC Intron 14 202 1.0, 0.1-4.6 (1.0) 0.0, 0.0-2.9 (0.0) 34 CTCCCTGACC 1871-22C.G TGCCCACCTT Intron 14 202 2.0, 0.4-6.1 (2.0) 0.0, 0.0-2.9 (0.0) 35 ACCTGCCCCC 1926C.A ACTCTGCACA Exon 15 silent 202 3.0, 0.8-7.5 (3.0) 0.0, 0.0-2.9 (0.0) 36 AGATTGGAGA 2238G.A AAGGTACAGA Exon 17 silent 166 1.2, 0.1-5.6 (1.2) 0.0, 0.0-3.5 (0.0) 37 AAGAGGCTAG 2241þ34G.C GCATAGAGCT Intron 17 166 41.0, 31.8-50.6 (42,0) 49.4, 39.9-58.9 (48.8) 38 TTCACACATT 2241þ97G.A GTGTAACGTT Intron 17 160 6.3, 2.5-12.7 (6.7) 1.3, 0.1-5.8 (0.3) 39 CCTTTCAATC 2600-123C.T CCCTCATTTT Intron 19 196 55.1, 46.3-63.7 (47.4) 11.2, 6.4-17.9 (15.0) rs4148415 40 CCAGCCCTCC 2714þ29C.T GGAGGCTGTA Intron 20 196 52.0, 43.3-60.7 (46.7) 11.2, 6.4-17.9 (13.9) rs2072365 41 GGCCTCCCCA 2714þ53A.G GCCCTGCCAG Intron 20 196 46.9, 38.3-55.7 (43.3) 8.2, 4.1-14.2 (10.0) rs2072366 42 TGAGGCTGGG 3039C.T GTCTATGCTG Exon 22 silent 156 10.3, 5.2-17.7 (12.1) 1.3, 0.1-5.9 (0.4) rs4148416 43 CCCCCCAAAC 3067þ71C.T GTGCCCTTGC Intron 22 180 20.0, 13.3-28.2 (19.8) 1.1, 0.1-5.2 (1.2) 44 TTATTGGGGC 3378þ47G.A GGGCAACACA Intron 23 202 11.9, 7.0-18.5 (11.2) 0.0, 0.0-2.9 (0.4) 45 ACACATGGGC 3378þ63G.T GGGGCAGCAG Intron 23 202 3.0, 0.8-7.5 (3.0) 0.0, 0.0-2.9 (0.0) 46 TCCCTCCTTT 3579-66C.T CCCTAAGCAG Intron 24 196 10.2, 5.6-16.7 (9.7) 0.0, 0.0-3.0 (0.3) rs967935 47 TATTCTGTGC 3890G.A CTACCGGCCG Exon 27 R1297H 192 10.4, 5.8-17.0 (9.9) 0.0, 0.0-3.1 (0.3) 48 TGCATGTGCA 3942C.T GGTGGCGAGA Exon 27 silent 192 30.2, 22.5-38.8 (31.1) 4.2, 1.4-9.3 (3.8) rs2277624 49 AGGTACGCGT 3954þ9G.T GGGTAGGCGG Intron 27 192 1.0, 0.1-4.8 (1.0) 0.0, 0.0-3.1 (0.0) 50 CTCAGAGGGC 4267G.A GGGAGAATCT Exon 29 G1423R 180 1.1, 0.1-5.2 (1.1) 0.0, 0.0-3.3 (0.0) 51 TAGTAGCTGA 4509A.G TTTGATTCTC Exon 31 silent 176 22.7, 15.6-31.3 (21.9) 1.1, 0.1-5.3 (1.6) rs1051640 SNPs with the ID 6, 7, 19, 21, 22, 32, 39, 40, 41, 42, 46, 48 and 51 previously reported by Saito et al. [13]. Login to comment
104 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 1 16 75 117 163 205 226 269 333 393 447 478 595 624 646 689 748 804 867 905 954 1023 1127 1199 1236 1270 1319 1372 1427 1493546 K13N H68Y S346F Q513K R1297H G1423R splice site mutation SNPs: P Exon: H2N out membrane in TMDs ATP TMDs ATP COOH Fig. 1 MRP3 gene and predicted two-dimensional protein structure using the MRP3 protein topology of Swiss-Prot O15438. Login to comment
112 No significant correlation was found between MRP3 protein variants and protein expression level including the most frequent Arg1297His protein variant. Login to comment
150 mutation found in this study was the SNP 3890G.A in exon 27 (Arg1297His) with an allele frequency of 5.2%, followed by SNP 202C.T in exon 2 (His68Tyr) with an allele frequency of 1.6%. Login to comment
153 Arg1297His did not significantly alter MRP3 protein expression. Login to comment

PMID: 20799350 [PubMed] Kelly L et al: "Functional hot spots in human ATP-binding cassette transporter nucleotide binding domains."

No. Sentence Comment

72 Predictions of the Functional Effects of 40 nsSNPs in ABC Transporters Comon name HUGO name Mutation NBD Prediction BSEP ABCB11 E592Q NBD1 Neutral BSEP ABCB11 N591S NBD1 Neutral BSEP ABCB11 Q558H NBD1 Neutral BSEP ABCB11 V444A NBD1 Neutral BSEP ABCB11 E1186K NBD2 Disease MDR1 ABCB1 P1051A NBD2 Neutral MDR1 ABCB1 S1141T NBD2 Neutral MDR1 ABCB1 T1256K NBD2 Disease MDR1 ABCB1 V1251I NBD2 Neutral MDR1 ABCB1 W1108R NBD2 Disease MRP2 ABCC2 I670T NBD1 Disease MRP2 ABCC2 L849R NBD1 Disease MRP2 ABCC2 C1515Y NBD2 Disease MRP3 ABCC3 D770N NBD1 Neutral MRP3 ABCC3 K718M NBD1 Neutral MRP3 ABCC3 T809M NBD1 Disease MRP3 ABCC3 V765L NBD1 Disease MRP3 ABCC3 Q1365R NBD2 Disease MRP3 ABCC3 R1297H NBD2 Disease MRP3 ABCC3 R1348C NBD2 Disease MRP3 ABCC3 R1381S NBD2 Disease MRP4 ABCC4 G487E NBD1 Disease MRP4 ABCC4 K498E NBD1 Neutral MRP4 ABCC4 R1220Q NBD2 Neutral MRP4 ABCC4 T1142M NBD2 Neutral MRP4 ABCC4 V1071I NBD2 Neutral MRP6 ABCC6 I1330L NBD1 Neutral MRP6 ABCC6 I742V NBD1 Neutral MRP6 ABCC6 P664S NBD1 Neutral MRP6 ABCC6 R724K NBD1 Neutral MRP6 ABCC6 R769K NBD1 Neutral MRP6 ABCC6 A1291T NBD2 Neutral MRP6 ABCC6 E1369K NBD2 Neutral MRP6 ABCC6 G1327E NBD2 Disease MRP6 ABCC6 L1416R NBD2 Disease MRP6 ABCC6 R1268Q NBD2 Disease MRP6 ABCC6 R1461H NBD2 Disease MXR ABCG2 I206L NBD1 Neutral MXR ABCG2 P269S NBD1 Disease MXR ABCG2 Q141K NBD1 Neutral nsSNPs. Login to comment

PMID: 16504381 [PubMed] Kerb R et al: "Implications of genetic polymorphisms in drug transporters for pharmacotherapy."

No. Sentence Comment

209 Nonsynonymous SNPs that occur with a frequency of clearly more than 1% have only reported for ABCC2: Val471Ile (1249GOA; 14% in African American,13% in Asian,and 24% in Caucasian), Phe981Leu (2943COG; 4% in Caucasian), and Cys1515Tyr (4544GOA; 2% in Caucasian), as well as for ABCC3, His68Tyr (202COT; 2% in Caucasian) and Arg1297His (3890GOA, 5% in Caucasian). 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

199 3.1.2.3 ABCC3 - 5/MRP3 - 5 Only two ABCC3 non-synonymous polymorphisms (H68Y and R1297H) have a frequency higher than 1%. Login to comment

PMID: 17518506 [PubMed] Kock K et al: "Expression of adenosine triphosphate-binding cassette (ABC) drug transporters in peripheral blood cells: relevance for physiology and pharmacotherapy."

No. Sentence Comment

937 Guo Y, Kotova E, Chen ZS, et al. MRP8, ATP-binding cassette characterization of the natural variant MRP3-Arg1297His of C11 (ABCC11), is a cyclic nucleotide efflux pump and a human multidrug resistance protein 3 (MRP3/ABCC3). Login to comment
938 Guo Y, Kotova E, Chen ZS, et al. MRP8, ATP-binding cassette characterization of the natural variant MRP3-Arg1297His of C11 (ABCC11), is a cyclic nucleotide efflux pump and a human multidrug resistance protein 3 (MRP3/ABCC3). Login to comment
939 Guo Y, Kotova E, Chen ZS, et al. MRP8, ATP-binding cassette characterization of the natural variant MRP3-Arg1297His of C11 (ABCC11), is a cyclic nucleotide efflux pump and a human multidrug resistance protein 3 (MRP3/ABCC3). Login to comment

PMID: 24732756 [PubMed] Ulzurrun E et al: "Selected ABCB1, ABCB4 and ABCC2 polymorphisms do not enhance the risk of drug-induced hepatotoxicity in a Spanish cohort."

No. Sentence Comment

318 Lee YM, Cui Y, Ko &#a8;nig J, Risch A, Ja &#a8;ger B, et al. (2004) Identification and functional characterization of the natural variant MRP3-Arg1297His of human multidrug resistance protein 3 (MRP3/ABCC3). Login to comment

PMID: 24523126 [PubMed] Templeton I et al: "Case study 5. Deconvoluting hyperbilirubinemia: differentiating between hepatotoxicity and reversible inhibition of UGT1A1, MRP2, or OATP1B1 in drug development."

No. Sentence Comment

319 Identification and functional characterization of the natural variant MRP3-Arg1297His of human multidrug resistance protein 3 (MRP3/ ABCC3). Login to comment