ABCG2 p.Val508Leu
| Predicted by SNAP2: | A: N (78%), C: N (87%), D: D (66%), E: D (59%), F: N (61%), G: D (63%), H: N (53%), I: N (87%), K: D (63%), L: N (72%), M: N (66%), N: N (53%), P: D (66%), Q: D (63%), R: D (63%), S: N (57%), T: N (87%), W: D (66%), Y: D (63%), |
| Predicted by PROVEAN: | A: N, C: D, 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, |
[switch to compact view]
Comments [show]
None has been submitted yet.
[hide] Functional assessment of ABCG2 (BCRP) gene polymor... Drug Metab Dispos. 2005 Jan;33(1):94-101. Epub 2004 Oct 8. Kobayashi D, Ieiri I, Hirota T, Takane H, Maegawa S, Kigawa J, Suzuki H, Nanba E, Oshimura M, Terakawa N, Otsubo K, Mine K, Sugiyama Y
Functional assessment of ABCG2 (BCRP) gene polymorphisms to protein expression in human placenta.
Drug Metab Dispos. 2005 Jan;33(1):94-101. Epub 2004 Oct 8., [PMID:15475413]
Abstract [show]
The aim of the present study was to assess the contribution of polymorphisms in the breast cancer resistance protein/ATP-binding cassette transporter G2 (BCRP/ABCG2) gene to the placental expression from a new perspective, allelic imbalance. Polymorphisms were screened by polymerase chain reaction (PCR)-single-strand conformation polymorphism analysis followed by sequencing with DNA extracted from 100 placentas. To examine whether polymorphisms of the BCRP gene correlate with the placental BCRP expression, we determined mRNA and protein levels by quantitative real-time PCR and Western blotting, respectively. In placentas, G34A (Val(12)Met) and C421A (Gln(141)Lys) were frequently observed (18-36%), but C376T, which creates a stop codon (Gln(126) stop codon), was found with an allelic frequency of 1%. The mean of the BCRP protein level was significantly lower (p < 0.05) in homozygotes for the A421 allele than in those for the C421 allele, and heterozygotes had an intermediate value. To evaluate whether the C421A polymorphism acts as a cis-element in BCRP transcription, allelic imbalance was determined using informative lymphoblasts and 56 samples of placental cDNA. In most of the placental samples we tested, the difference in expression levels between the two alleles was small, and only two samples indicated a monoallelic expression (i.e., preferential expression of one allele). These results suggest that 1) the predominant allelic expression pattern of BCRP in placental samples is biallelic, and 2) the mutation C421A is not a genetic variant acting in cis, but is considered to influence the translation efficiency.
Comments [show]
None has been submitted yet.
No. Sentence Comment
112 C376T, which is associated with an amino acid substitution from Gln to a stop codon at codon 126 (Gln126stop), was detected in only two placental samples (1.0%) as TABLE 1 Genetic polymorphism in the BCRP gene in Japanese placentas (n ϭ 100) Location Positiona Reference Alleleb Variant Allele Amino Acid Substitution Genotype Frequency of Variant Allele R/R R/V V/V 5Ј-Flanking region -20445 gtctCctcc gtctTctcc 98 2 0 0.010 -20296 agctAttaa agctGttaa 80 18 2 0.110 -19781 aaaaAttat aaaaGttat 99 1 0 -19572_-19569 ctcaCTCAcaaa ctca--caaa 60 33 7 0.235 Exon 2 34 cccaGtgtc cccaAtgtc Val12Met 70 24 6 0.180 Intron 2 203 ϩ 16 tttaAttta tttaGttta 70 24 6 0.180 Intron 3 263 ϩ 10 tataAgaga tataGgaga 85 14 1 0.080 263 ϩ 72 ttttGtgtg ttttTGtgtg 99 1 0 0.005 Exon 4 376 ggtaCaagt ggtaTaagt Gln126stop 98 2 0 0.010 Exon 5 421 cttaCagtt cttaAagtt Gln141Lys 42 45 13 0.355 Intron 5 532-16 ttatAatat ttatGatat 99 1 0 0.005 Exon 9 1098 aggaGatca aggaAatca Synonymous 98 2 0 0.010 Intron 10 1277 ϩ 95 atagTgtaa atagAgtaa 97 3 0 0.015 Exon 11 1322 agcaGtgtt agcaAtgtt Ser441Asn 99 1 0 0.005 Intron 11 1367 ϩ 20 ttctAggaa ttctGggaa 71 25 4 0.165 Exon 12 1465 tataTttac tataCttac Phe489Leu 99 1 0 0.005 Intron 12 1492 ϩ 49 ctatGggtg ctatCggtg 44 45 11 0.335 Exon 13 1515 atgcCttct atgc-ttct Phe506Ser 99 1 0 0.005 Phe507Leu Val508Leu Met509stop Intron 13 1648-42 tgaaAttac tgaaTttac 99 1 0 0.005 1648-21 gactCttag gactTttag 71 25 4 0.165 Intron 14 1738-46 tcttAaaat tcttGaaat 24 52 24 0.500 3Ј-UTR 2332 cttcAgtct cttcTAgtct 86 14 0 0.070 2364 tgccAttat tgccCttat 99 1 0 0.005 2512 agaaCttac agaaTttac 99 1 0 0.005 R, reference allele; V, variant allele.
X
ABCG2 p.Val508Leu 15475413:112:1357
status: VERIFIED116 Another polymorphism, a C1515 deletion, which results in a frame shift (Phe506Ser, Phe507Ser, Val508Leu, and Met509stop), was extremely rare (0.5%) in our samples.
X
ABCG2 p.Val508Leu 15475413:116:94
status: VERIFIED[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
250 It should be noted that many xeno- and endobiotic BCRP Figure 5 Predicted membrance topology of BCRP (ABCG2) based on hydrophobicity analysis. Locations of the non-synonymous polymorphisms are indicated with arrows. See Table 5 for allele frequencies and description of funtional consequences. NH2 COOH NBD Val12Met Gly51Cys Gln126* Ala149Pro Gln141Lys Thr153Met Arg160Gln Arg163Lys Gln166Glu Phe506Ser Phe507Leu Val508Leu Met509* Phe489Leu Ser441Asn Phe431Leu Glu334* Ile206Leu Ala315del Thr316del Phe208Ser Asp296His Ser248Pro Pro269Ser Phe571Ile Arg575* Asn590Tyr Asp620Asn in out Membrane BCRP (ABCG2) NBD Val12Met NBDNBD Val12Met substrates are also transported by other efflux transporters, especially P-glycoprotein, thus extrapolating BCRP related in vitro data to the in vivo situation may be difficult.
X
ABCG2 p.Val508Leu 18464048:250:413
status: VERIFIED290 In addition, loss or 339 Table5BCRP(ABCG2)singlenucleotidepolymorphisms.Location,allelefrequencyandfunctionaleffects. Positionin coding sequence Amino acidexchangeLocation Allelefrequency Effect NCBIID ReferenceAfCaJpothers 34G>AVal12MetExon26[1] 4[2] 4[1] 2[2] 2[3] 10[4] 17[1] 18[5] 15[2] See[2]noinfluenceonproteinexpression,localization[6] andtransportintransfectedcells[5-8] rs2231137 noassociationwithmRNAexpressioninventricular andauricularheardtissue[9] increaseddrugaccumulationandlossofdrug resistanceinvitro[4] lossinmembranelocalization[4] higherdrugresistanceinvitro(SN-38)[7] 151G>TGly51CysExon2---Originnotcitedin[10]impactonMTXandporphyrintransportin transfectedcellsunclear[11] 376C>TGln126*Exon40[1]0[1] 0[4] 1[1] 1[5] -expressionoftruncatedproteinintransfectedcells,lossof MTXandporphyrintransportintransfectedcells[11] 421C>AGln141LysExon52[1] 0[2] 1-5 [12] 11[1] 14[2] 10-12 [12] 9[4] 30[1] 26[5] 35[2] See[2,13] 34Chinese[12] lowerproteinexpressioninplacenta[1]rs2231142 noassociationwithmRNAexpressioninheart[9] ormRNAandproteinexpressioninintestine[2] lowerproteinexpressionintransfectedcells[5-7] conflictingdataonmembranelocalizationin transfectedcells[7,8] decreaseinin-vitrotransport[8,14] increaseddrugaccumulationandlossofdrug resistanceinvitro[4,7] higherdiflomotecanplasmalevels[15] nosignificantchangesinirinotecanpharmacokinetics [12,13] greateraccumulationofgefitinib[16]andassociation withgefitinib-induceddiarrhea[17]increaseAUC andcmaxofrosuvastatin[18] (Continued) Table5(Continued) Positionin coding sequence Amino acidexchangeLocation Allelefrequency Effect NCBIID ReferenceAfCaJpothers 445G>CAla149ProExon5---originnotcitedin[6]noinfluenceonproteinexpressionandtransportin transfectedcells[6] 458C>TThr153MetExon5-0[4]--noeffectonMTXandporphyrintransportin transfectedcells[11] 479G>AArg160GlnExon5-0.5c[19]--- 488G>AArg163LysExon5---originnotcitedin[6]noinfluenceonproteinexpressionandtransport intransfectedcells[6] 496C>GGln166GluExon5----noinfluenceonproteinexpressionandtransport intransfectedcells[6] rs1061017 616A>CIle206LeuExon60[2]0[2]0[2]10inHispaniclivers[2], see[2] noinfluenceonmembranelocalizationintransfected cells[20] 623T>CPhe208SerExon6----lowproteinexpressionandnomembrane localizationintransfectedcells,drugresistance similartomock[7] rs1061018 lowproteinexpressionintransfectedcells,lossofMTX andporphyrintransportintransfectedcells[11] 742T>CSer248ProExon7----noinfluenceonproteinexpressionandlocalizationin transfectedcells,drugresistancesimilartoWT[7] rs3116448 decreaseinMTXandporphyrintransportin transfectedcells[11] 805C>TPro269SerExon7---4Chinese[21]noinfluenceonproteinexpressionandtransport intransfectedcells[6] 886G>CAsp296HisExon8-----rs41282401 944-49delAla315del Thr316del Exon8/9----noinfluenceonproteinexpressionandtransport intransfectedcells[5] 1000G>TGlu334*Exon9----expressionoftruncatedproteinintransfectedcells,loss ofMTXandporphyrintransportintransfectedcells[11] rs3201997 341 1291T>CPhe431LeuExon12--0.8[22]-noinfluenceonproteinexpressionandlocalizationin transfectedcells,drugresistancesimilartoWT[7] decreaseinMTXtransportintransfectedcells[11] 1322G>TSer441AsnExon11--0.5[1]-intracellularlocalizationanddecreaseintotalBCRP expressionintransfectedcells[6,7] lowerdrugresistance[7]anddecreaseinMTXand porphyrintransportintransfectedcells[11] 1465T>CPhe489LeuExon12--0.5[1]-noinfluenceonproteinexpressionandlocalizationin transfectedcells[7] 0.8[22] 1515CdelPhe506SerExon13--0.5[1]-- Phe507Leu Val508Leu Met509* 1711A>TPhe571IleExon14-----rs9282571 1723C>TArg575*Exon14-0.5c [19]--- 1768A>TAsn590TyrExon150[2]1[2] 0.3[4] --noinfluenceonmembranelocalizationin transfectedcells[20] 1858G>AAsp620AsnExon16-0.5c [19]--noinfluenceonmembranelocalizationortransport intransfectedcells[8,20] c Population93%Caucasian.
X
ABCG2 p.Val508Leu 18464048:290:3489
status: VERIFIED[hide] Structure and function of BCRP, a broad specificit... Arch Toxicol. 2014 Jun;88(6):1205-48. doi: 10.1007/s00204-014-1224-8. Epub 2014 Apr 29. Jani M, Ambrus C, Magnan R, Jakab KT, Beery E, Zolnerciks JK, Krajcsi P
Structure and function of BCRP, a broad specificity transporter of xenobiotics and endobiotics.
Arch Toxicol. 2014 Jun;88(6):1205-48. doi: 10.1007/s00204-014-1224-8. Epub 2014 Apr 29., [PMID:24777822]
Abstract [show]
The discovery and characterization of breast cancer resistance protein (BCRP) as an efflux transporter conferring multidrug resistance has set off a remarkable trajectory in the understanding of its role in physiology and disease. While the relevance in drug resistance and general pharmacokinetic properties quickly became apparent, the lack of a characteristic phenotype in genetically impaired animals and humans cast doubt on the physiological importance of this ATP-binding cassette family member, similarly to fellow multidrug transporters, despite well-known endogenous substrates. Later, high-performance genetic analyses and fine resolution tissue expression data forayed into unexpected territories concerning BCRP relevance, and ultimately, the rise of quantitative proteomics allows putting observed interactions into absolute frameworks for modeling and insight into interindividual and species differences. This overview summarizes existing knowledge on the BCRP transporter on molecular, tissue and system level, both in physiology and disease, and describes a selection of experimental procedures that are the most widely applied for the identification and characterization of substrate and inhibitor-type interactions.
Comments [show]
None has been submitted yet.
No. Sentence Comment
95 Histone deacetylase inhibitors rescue newly synthesized transporter proteins and prevent aggresome targeting by disturbing TableÊf;1ߒߙMajor non-synonymous single-nucleotide polymorphisms found in the ABCG2 coding region Allele frequencies presented in this table do not reflect interethnic differences Mutation Position in BCRP Cellular effects of SNP Allele frequency % References 34G>A, V12M (rs2231137) N-terminus Lower expression, no impact on function 0-29.8 Tamura et al. (2006), Bosch et al. (2005), Mizuarai et al. (2004), Imai et al. (2002), Kobayashi et al. (2005), Backstrom et al. (2003), Honjo et al. (2002), Kondo et al. (2004) 151G>T, G51C N-terminus Slightly overexpressed, decreased transport activity 0.1 Tamura et al. (2006), Yoshioka et al. (2007) 376C>T, Q126X (rs7255271) NBD No expression, no activity 0-1.7 Tamura et al. (2006), Mizuarai et al. (2004), Itoda et al. (2003), Imai et al. (2002), Kobayashi et al. (2005), Kondo et al. (2004) 421C>A, Q141K (rs2231142) NBD Lower expression, decreased transport activity, substrate specificity altered 0-35.7 Tamura et al. (2006), Bosch et al. (2005), Mizuarai et al. (2004), Imai et al. (2002), Kobayashi et al. (2005), Backstrom et al. (2003), Honjo et al. (2002), Kondo et al. (2004) 458C>T, T153 M NBD Slightly lower expression, no impact on function 3.3 Tamura et al. (2006), Mizuarai et al. (2004) 479G>A, R160Q NBD Not determined 0.5 Bosch et al. (2005), Tamura et al. (2006) 496C>G, Q166E (rs1061017) NBD Slightly lower expression, no impact on function 0-1.1 Tamura et al. (2006), Kondo et al. (2004), Yoshioka et al. (2007) 616A>C, I206L (rs12721643) NBD Well expressed, decreased transport activity 0-10.0 Tamura et al. (2006), Zamber et al. (2003), Vethanayagam et al. (2005), Ieiri (2012a) 623T>C, F208 (rs1061018) NBD No expression, no transport activity 0.9-3.9 Tamura et al. (2006) 742T>C, S248P (rs3116448) NBD Well expressed, no transport activity 0.5 Tamura et al. (2006), Yoshioka et al. (2007) 1000G>T, E334X (rs3201997) NBD No expression, no transport activity Not determined Tamura et al. (2006), Ishikawa et al. (2005) 1291T>C F431L ECL1 Lower expression, substrate specificity altered 0.6-0.8 Tamura et al. (2006), Itoda et al. (2003), Yoshioka et al. (2007) 1322G>A, S441 N ECL1 Slightly lower expression, no transport activity 0.5 Tamura et al. (2006), Kobayashi et al. (2005), Kondo et al. (2004) 1465T>C, F489L TM3 Slightly lower expression, no transport activity 0.5-0.8 Tamura et al. (2006), Itoda et al. (2003), Kobayashi et al. (2005) 1515delC, F506S TM4 Not determined 0.5 Itoda et al. (2003), Kobayashi et al. (2005) 1515delC, F507L 1515delC, V508L 1515delC, M509X 1711T>A, F571I (rs9282571) TM5 Well expressed, substrate specificity altered 0.5 Tamura et al. (2006) 1723C>T, R575X TM5 Not determined 0.5 Tamura et al. (2006) 1768A>T, N590Y (rs34264773) ECL3 Slightly overexpressed, substrate specificity altered 0-9.7 Tamura et al. (2006), Mizuarai et al. (2004), Zamber et al. (2003), Vethanayagam et al. (2005) 1858G>A, D620 N (rs34783571) ECL3 Slightly overexpressed, substrate specificity altered 0-11.1 Tamura et al. (2006), Bosch et al. (2005), Honjo et al. (2002), Vethanayagam et al. (2005) the trafficking along microtubules (Basseville et al. 2012).
X
ABCG2 p.Val508Leu 24777822:95:2665
status: NEW