ABCMdb

PMID: 16006996

Conseil G, Deeley RG, Cole SP
Polymorphisms of MRP1 (ABCC1) and related ATP-dependent drug transporters.
Pharmacogenet Genomics. 2005 Aug;15(8):523-33., [PubMed]

Sentences

No. Mutations Sentence Comment

56 ABCC1 p.Arg1435Gln ABCC1 p.Gly1382Ser ABCC6 p.Arg1268Gln ABCC6 p.Arg1314Trp ABCC6 p.Gln1347His ABCC6 p.Gly1321Ser ABCC6 p.Gly1302Arg ABCC6 p.Val1298Phe ABCC6 p.Arg1339Cys ABCC6 p.Ala1303Pro ABCC6 p.Thr1301Ile ABCC6 p.Gly1354Arg ABCC7 p.Gly1244Glu ABCC7 p.Ser1255Pro ABCC7 p.Asn1303Lys ABCC7 p.Ser1251Asn ABCC7 p.Arg1283Lys ABCC7 p.Gln1291Arg ABCC7 p.Gly1249Arg ABCC7 p.Gln1352His ABCC7 p.Lys1351Glu ABCC7 p.Glu1228Gly ABCC7 p.Gly1247Arg ABCC7 p.Glu1321Gln ABCC7 p.Trp1282Gly ABCC7 p.Gln1382Arg ABCC7 p.Gln1238Arg ABCC7 p.Tyr1307Cys ABCC2 p.Ala1450Thr ABCC8 p.Gly1477Arg ABCC3 p.Arg1492Trp ABCC2 p.Arg1392His ABCC2 p.Ile1350Leu ABCC3 p.Asp1361Asn In the kidney, glomeruli and distal collecting tubules express MRP1, and, in the brain, MRP1 appears to form part of the drug permeability barrier Fig. 1 CF (CFTR/ABCC7) Q1291R E1228G Q1238R G1244E/V G1247R G1249R S1251N S1255P/L W1282G/R/C R1283K/M N1303K Y1307C E1321Q K1351E Q1352H R1268Q V1298F T1301I G1302R A1303P R1314W/Q G1321S R1339C Q1347H I1350L G1354R D1361N Q1382R A1450T R1347E R1351P V1359G/M S1368A G1377R G1382S R1392H R1419C R1435Q G1477R G1479R R1492W E1505K DJS (MRP2/ABCC2) NBD1 NBD2 COOH MEMBRANE MSD MSD MSD 12131415161710116 7 8 91 23 4 5TM H2 N Extracellular Intracellular PXE (ABCC6) PHHI (SUR1/ABCC8) Two-dimensional structure of MRP-related proteins. Login to comment 139 ABCC1 p.Cys1047Ser For example, the SNP G3140C in exon 23 which causes a Ser substitution of Cys1047 in CL6 appears to occur at a much higher frequency (4.5%) in African-American populations than in Caucasian populations where it has not been detected in any of the individuals screened thus far. To date, none of the reported MRP1 polymorphisms have been associated with any medical condition or unusual drug responses, although it should be borne in mind that the number of individuals screened is still relatively low and clinical information is scant. Login to comment 143 ABCC1 p.Gly671Val 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 146 ABCC1 p.Cys43Ser Resistance of transfected HeLa cells expressing the MRP1-Cys43Ser mutant to doxorubicin and sodium arsenite was also diminished. Login to comment 148 ABCC1 p.Cys43Ser ABCC1 p.Arg723Gln ABCC1 p.Thr73Ile ABCC1 p.Arg1058Gln ABCC1 p.Gly671Val ABCC1 p.Arg433Ser ABCC1 p.Cys1047Ser ABCC1 p.Arg633Gln ABCC1 p.Arg230Gln ABCC1 p.Val353Met ABCC1 p.Ala989Thr ABCC1 p.Ser1512Leu ABCC1 p.Ser92Phe ABCC3 p.Gly689Ala 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 152 ABCC1 p.Cys43Ser ABCC1 p.Cys43Ser Fig. 4 Wild-type MRP1 MRP1-Cys43Ser Confocal micrographs of transfected HeLa cells expressing recombinant Cys43Ser mutant and wild-type MRP1 proteins. Login to comment 153 ABCC1 p.Cys43Ser Recombinant wild-type MRP1 (left panel) and mutant MRP1-Cys43Ser (right panel) proteins expressed in stably transfected HeLa cells were detected with human MRP1-specific murine monoclonal antibody QCRL-3 and visualized with Alexa488-tagged secondary antibody (green); nuclei are stained with propidium iodide (red). Login to comment 154 ABCC1 p.Cys43Ser Note the extensive amount of the MRP1-Cys43Ser mutant that has not localized properly to the plasma membrane [44]. Login to comment 157 ABCC2 p.Arg768Trp ABCC2 p.Gln1382Arg For example, homozygous DJS mutations Arg768Trp (C2302T) and Gln1382Arg (A4145G) are located in NBD1 and NBD2, respectively, and in vitro studies have shown that both mutations have substantial phenotypic consequences [40]. Login to comment 158 ABCC2 p.Arg768Trp ABCC2 p.Gln1382Arg Thus, the Arg768Trp mutation impairs maturation and sorting of MRP2 to the apical membrane, whereas the Gln1382Arg mutation decreases organic anion (LTC4) transport and substrate-induced ATP hydrolysis [45]. Login to comment 159 ABCC7 p.Gln1291Arg MRP2-Gln1382 is located in the highly conserved Q-loop of NBD2 and a comparable substitution (Gln1291Arg) has been reported in CFTR (ABCC7) in cystic fibrosis patients. Login to comment 162 ABCC2 p.Ser789Phe ABCC2 p.Ala1450Thr Two other missense variants that affect conserved residues in the NBDs of MRP2 are Ser789Phe (exon 18 C2366T) and Ala1450Thr (exon 31 G4348A) [30,31]. Login to comment 167 ABCC2 p.Arg1150His ABCC2 p.Ile1173Phe The G3449A mutation (which results in a substitution of His for Arg1150 ) is found in Moroccan- Jewish DJS patients whereas the MRP2-Ile1173Phe (A3517T) mutation is mainly found in Iranian-Jewish patients. Login to comment 168 ABCC2 p.Arg1150His ABCC2 p.Ile1173Phe ABCC2 p.Ile1173Phe Although both the Arg1150His and Ile1173Phe mutations eliminate MRP2 transport activity in vitro, the Ile1173Phe variant protein also exists predominantly in an underglycosylated form that is retained in the endoplasmic reticulum [47,48]. Login to comment 179 ABCC3 p.Arg1297His 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 266 ABCC1 p.Gly671Val 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 267 ABCC3 p.Arg1297His 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