ABCC3 p.Val799Met
| Predicted by SNAP2: | A: N (87%), C: N (93%), D: D (66%), E: N (66%), F: N (57%), G: D (53%), H: N (53%), I: N (97%), K: D (59%), L: N (97%), M: N (93%), N: D (63%), P: D (66%), Q: D (59%), R: D (59%), S: N (57%), T: N (82%), W: D (63%), Y: N (57%), |
| Predicted by PROVEAN: | A: N, C: N, D: D, E: D, F: N, G: D, H: D, I: N, K: D, L: N, M: N, N: D, P: D, Q: D, R: D, S: D, T: N, W: D, Y: N, |
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[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.
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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.
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ABCC3 p.Val799Met 18464048:172:357
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.
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ABCC3 p.Val799Met 18464048:174:989
status: NEW[hide] Xenobiotic, bile acid, and cholesterol transporter... Pharmacol Rev. 2010 Mar;62(1):1-96. Epub 2010 Jan 26. Klaassen CD, Aleksunes LM
Xenobiotic, bile acid, and cholesterol transporters: function and regulation.
Pharmacol Rev. 2010 Mar;62(1):1-96. Epub 2010 Jan 26., [PMID:20103563]
Abstract [show]
Transporters influence the disposition of chemicals within the body by participating in absorption, distribution, and elimination. Transporters of the solute carrier family (SLC) comprise a variety of proteins, including organic cation transporters (OCT) 1 to 3, organic cation/carnitine transporters (OCTN) 1 to 3, organic anion transporters (OAT) 1 to 7, various organic anion transporting polypeptide isoforms, sodium taurocholate cotransporting polypeptide, apical sodium-dependent bile acid transporter, peptide transporters (PEPT) 1 and 2, concentrative nucleoside transporters (CNT) 1 to 3, equilibrative nucleoside transporter (ENT) 1 to 3, and multidrug and toxin extrusion transporters (MATE) 1 and 2, which mediate the uptake (except MATEs) of organic anions and cations as well as peptides and nucleosides. Efflux transporters of the ATP-binding cassette superfamily, such as ATP-binding cassette transporter A1 (ABCA1), multidrug resistance proteins (MDR) 1 and 2, bile salt export pump, multidrug resistance-associated proteins (MRP) 1 to 9, breast cancer resistance protein, and ATP-binding cassette subfamily G members 5 and 8, are responsible for the unidirectional export of endogenous and exogenous substances. Other efflux transporters [ATPase copper-transporting beta polypeptide (ATP7B) and ATPase class I type 8B member 1 (ATP8B1) as well as organic solute transporters (OST) alpha and beta] also play major roles in the transport of some endogenous chemicals across biological membranes. This review article provides a comprehensive overview of these transporters (both rodent and human) with regard to tissue distribution, subcellular localization, and substrate preferences. Because uptake and efflux transporters are expressed in multiple cell types, the roles of transporters in a variety of tissues, including the liver, kidneys, intestine, brain, heart, placenta, mammary glands, immune cells, and testes are discussed. Attention is also placed upon a variety of regulatory factors that influence transporter expression and function, including transcriptional activation and post-translational modifications as well as subcellular trafficking. Sex differences, ontogeny, and pharmacological and toxicological regulation of transporters are also addressed. Transporters are important transmembrane proteins that mediate the cellular entry and exit of a wide range of substrates throughout the body and thereby play important roles in human physiology, pharmacology, pathology, and toxicology.
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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.
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ABCC3 p.Val799Met 20103563:7118:1007
status: NEW7115 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.
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ABCC3 p.Val799Met 20103563:7115:991
status: NEW[hide] Genetic variations of the ABC transporter gene ABC... Drug Metab Pharmacokinet. 2007 Apr;22(2):129-35. Fukushima-Uesaka H, Saito Y, Maekawa K, Hasegawa R, Suzuki K, Yanagawa T, Kajio H, Kuzuya N, Noda M, Yasuda K, Tohkin M, Sawada J
Genetic variations of the ABC transporter gene ABCC3 in a Japanese population.
Drug Metab Pharmacokinet. 2007 Apr;22(2):129-35., [PMID:17495421]
Abstract [show]
An ATP-binding cassette transporter, multidrug resistance-related protein 3 (MRP3), is encoded by the ABCC3 gene. The MRP3 protein is expressed in several tissues, and functions as an efflux transporter for conjugated as well as unconjugated substrates. In this study, the 31 ABCC3 exons and their flanking introns were comprehensively screened for genetic variations in 89 Japanese subjects. Forty-six genetic variations, including 21 novel ones, were found: 8 were located in the 5'-flanking region, 14 in the coding exons (8 synonymous and 6 nonsynonymous variations), and 24 in the introns. Of these 46 variations, five novel nonsynonymous variations, 2221C>T (Gln741Stop), 2395G>A (Val799Met), 2798_2799delAG (Gln933ArgfsX64), 3657C>A (Ser1219Arg), and 4217C>T (Thr1406Met), were found as heterozygous variations. The allele frequencies were 0.011 for Ser1219Arg and 0.006 for the other four variations. Gln741Stop induces a stop codon at codon 741. Gln933ArgfsX64 causes a frame-shift at codon 933, resulting in early termination at codon 997. Both variations result in loss of 6 transmembrane helices (from the 12th to 17th helices) in the C-terminus and all regions of nucleotide binding domain 2. Thus, both variant proteins are assumed to be inactive. These data provide fundamental and useful information for pharmacogenetic studies on MRP3-transported drugs in Japanese.
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12 Of these 46 variations, ve novel nonsynonymous variations, 2221CÀT (Gln741Stop), 2395GÀA (Val799Met), 2798ä2799delAG (Gln933ArgfsX64), 3657CÀA (Ser1219Arg), and 4217CÀT (Thr1406Met), were found as heterozygous variations.
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ABCC3 p.Val799Met 17495421:12:106
status: NEW50 Five novel nonsynonymous variations, 2221CÀT (Gln741Stop), 2395GÀA (Val799Met), 2798ä2799delAG (Gln933ArgfsX64), 3657CÀA (Ser1219Arg), and 4217CÀT (Thr1406Met), were found as heterozygous variations.
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ABCC3 p.Val799Met 17495421:50:78
status: NEW61 The other three variations, Val799Met, Ser1219Arg, and Thr1406Met, were located 24 bases downstream of the Walker B motif in NBD1, in the extracellular loop between TM16 and TM17, and 20 bases upstream of the signature sequence in NBD2, respectively.
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ABCC3 p.Val799Met 17495421:61:28
status: NEW