ABCC3 p.Lys13Asn
| Predicted by SNAP2: | A: N (57%), C: D (53%), D: D (59%), E: N (78%), F: D (59%), G: N (57%), H: N (57%), I: D (53%), L: D (53%), M: N (53%), N: N (61%), P: N (57%), Q: N (82%), R: N (87%), S: N (87%), T: N (82%), V: N (57%), W: D (80%), Y: D (63%), |
| Predicted by PROVEAN: | A: N, C: N, D: N, E: N, F: D, G: N, H: N, I: N, L: N, M: N, N: N, P: N, Q: N, R: N, S: N, T: N, V: N, W: D, Y: N, |
[switch to compact view]
Comments [show]
None has been submitted yet.
[hide] Pharmacogenomics of MRP transporters (ABCC1-5) and... Drug Metab Rev. 2008;40(2):317-54. Gradhand U, Kim RB
Pharmacogenomics of MRP transporters (ABCC1-5) and BCRP (ABCG2).
Drug Metab Rev. 2008;40(2):317-54., [PMID:18464048]
Abstract [show]
Elucidation of the key mechanisms that confer interindividual differences in drug response remains an important focus of drug disposition and clinical pharmacology research. We now know both environmental and host genetic factors contribute to the apparent variability in drug efficacy or in some cases, toxicity. In addition to the widely studied and recognized genes involved in the metabolism of drugs in clinical use today, we now recognize that membrane-bound proteins, broadly referred to as transporters, may be equally as important to the disposition of a substrate drug, and that genetic variation in drug transporter genes may be a major contributor of the apparent intersubject variation in drug response, both in terms of attained plasma and tissue drug level at target sites of action. Of particular relevance to drug disposition are members of the ATP Binding Cassette (ABC) superfamily of efflux transporters. In this review a comprehensive assessment and annotation of recent findings in relation to genetic variation in the Multidrug Resistance Proteins 1-5 (ABCC1-5) and Breast Cancer Resistance Protein (ABCG2) are described, with particular emphasis on the impact of such transporter genetic variation to drug disposition or efficacy.
Comments [show]
None has been submitted yet.
No. Sentence 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.
X
ABCC3 p.Lys13Asn 18464048:172:300
status: NEWX
ABCC3 p.Lys13Asn 18464048:172:489
status: NEWX
ABCC3 p.Lys13Asn 18464048:172:506
status: NEW174 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.
X
ABCC3 p.Lys13Asn 18464048:174:446
status: NEW[hide] Multidrug resistance associated proteins as determ... Curr Drug Metab. 2007 Dec;8(8):787-802. Yu XQ, Xue CC, Wang G, Zhou SF
Multidrug resistance associated proteins as determining factors of pharmacokinetics and pharmacodynamics of drugs.
Curr Drug Metab. 2007 Dec;8(8):787-802., [PMID:18220559]
Abstract [show]
The multidrug resistance associated proteins (MRP1, MRP2, MRP3, MRP4, MRP5, MRP6, MRP7, MRP8 and MRP9) belong to the ATP-binding cassette superfamily (ABCC family) of transporters. They are expressed differentially in the liver, kidney, intestine, brain and other tissues. These transporters are localized to the apical and/or basolateral membrane of the hepatocytes, enterocytes, renal proximal tubule cells and endothelial cells of the blood-brain barrier. Several MRPs (mainly MRP1-3) are associated with tumor resistance which is often caused by an increased efflux and decreased intracellular accumulation of natural product anticancer drugs and other anticancer agents. MRPs transport a structurally diverse array of important endogenous substances and xenobiotics and their metabolites (in particular conjugates) with different substrate specificity and transport kinetics. Most MRPs are subject to induction and inhibition by a variety of compounds. Several nuclear receptors, including pregnane X receptor (PXR), liver X receptor (LXR), and farnesoid receptor (FXR) participate in the regulation of MRPs. MRPs play an important role in the absorption, distribution and elimination of various drugs in the body and thus may affect their efficacy and toxicity and cause drug-drug interactions. MRPs located in the blood-brain barrier can restrict the penetration of compounds into the central nervous system. Mutation of MRP2 causes Dubin-Johnson syndrome, while mutations in MRP6 are responsible for pseudoxanthoma elasticum. More recently, mutations in mouse Mrp6/Abcc6 gene is associated with dystrophic cardiac calcification (DCC), a disease characterized by hydroxyapatite deposition in necrotic myocytes. A single nucleotide polymorphism, 538G>A in the MRP8/ABCC11 gene, is responsible for determination of earwax type. A better understanding of the function and regulating mechanism of MRPs can help minimize and avoid drug toxicity, unfavourable drug-drug interactions, and to overcome drug resistance.
Comments [show]
None has been submitted yet.
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.
X
ABCC3 p.Lys13Asn 18220559:406:87
status: NEW360 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).
X
ABCC3 p.Lys13Asn 18220559:360:179
status: NEW[hide] Genetic polymorphisms in the multidrug resistance-... Pharmacogenetics. 2004 Mar;14(3):155-64. Lang T, Hitzl M, Burk O, Mornhinweg E, Keil A, Kerb R, Klein K, Zanger UM, Eichelbaum M, Fromm MF
Genetic polymorphisms in the multidrug resistance-associated protein 3 (ABCC3, MRP3) gene and relationship to its mRNA and protein expression in human liver.
Pharmacogenetics. 2004 Mar;14(3):155-64., [PMID:15167703]
Abstract [show]
AIMS: To determine the genetic variability of multidrug resistance protein 3 (MRP3). METHODS: Genomic DNA samples from 103 Caucasians were systematically screened for genetic variations to find a potential relationship with hepatic MRP3 expression. Sequencing comprised all 31 exons, approximately 100 bp of the flanking intronic regions and 2 kb of the 5' UTR. RESULTS: In total, 51 mutations were identified. Fifteen SNPs were located in the coding exons of MRP3, six of which are nonsynonymous mutations. 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. A splice site mutation (1339-1G>T) was found at the intron 10-exon 11 boundary. To evaluate, whether mutations in the MRP3 gene correlate with human hepatic MRP3 expression, we analyzed the genetic variants in Caucasian liver samples, whose MRP3 mRNA (n = 84) and protein (n = 50) expression has been determined by real time quantitative PCR and Western Blot, respectively. We found a significant correlation of a polymorphism in the 5' promoter region (-211C>T) of MRP3 with mRNA expression. Individuals homozygous and heterozygous for the -211C>T promoter polymorphism had significantly lower MRP3 transcript levels compared to wild-type individuals (P < 0.05). Accordingly, electrophoretic mobility shift assay demonstrated that -211C>T polymorphism affected the binding of nuclear factors. CONCLUSIONS: Multiple genetic polymorphisms of MRP3 exist in Caucasians. The -211C>T promoter polymorphism appears to be associated with altered hepatic MRP3 mRNA expression.
Comments [show]
None has been submitted yet.
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.
X
ABCC3 p.Lys13Asn 15167703:5:192
status: NEW75 Six mutations located in exon 1 (39G.C; Lys13Asn; allele frequency: 0.5%), exon 2 (202C.T; His68Tyr; 1.6%), exon 9 (1037C.T; Ser346Phe; 0.5%), exon 12 (1537C.
X
ABCC3 p.Lys13Asn 15167703:75:40
status: NEW100 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].
X
ABCC3 p.Lys13Asn 15167703:100:1337
status: NEW104 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.
X
ABCC3 p.Lys13Asn 15167703:104:212
status: NEW