ABCMdb

ABCC3 p.Arg1381Ser

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Publications

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

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: 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

4 Results After transient transfection of cDNA into HeLa cells, it was found that R1381S ABCC3 exhibits intracellular accumulation of immature protein, the localization of which was mostly merged with a marker for the endoplasmic reticulum. Login to comment
7 Conclusion The results of this study suggest that the possession of R1381S, S346F, and S607N types of ABCC3 sequences may be a possible risk factor for the acquisition of hepatotoxicity, due to their poor ability to transport toxic compounds across the sinusoidal membrane. Login to comment
40 Using site-directed mutagenesis, SNP-type ABCC3 (G11D, R99Q, S346F, S607N, V765L, P920S, R923Q, R1286G, R1348C, Q1365R, and R1381S ABCC3) was constructed on a pBluescript SK ( - ) vector. Login to comment
81 In contrast, R1381S was only found in the Mexican population, but not in other populations (Table 1). Login to comment
86 Except for R1381S ABCC3, other all SNP-type ABCC3 were localized on the plasma membrane of HeLa cells, as observed for the wild-type ABCC3. Login to comment
87 R1381S ABCC3 was mostly located intracellularly (Fig. 2a). Login to comment
88 Although the localization of R1381S ABCC3 on the plasma membrane was observed in some HeLa cells, this cell population accounted for only approximately 20% of the transfected cells, which was in marked contrast to the wild-type ABCC3. Login to comment
89 Then, we examined the localization of R1381S ABCC3 by double-label experiments with anti-ABCC3 antiserum and anti-calnexin antibody, which allows staining of the endoplasmic reticulum (ER) (Fig. 2b). Login to comment
91 In contrast, the localization of R1381S ABCC3 mostly merged with that of calnexin. Login to comment
92 It was found that a fraction of the R1381S molecules were located on intracellular organelles other than ER in HeLa cells (Fig. 2b). Login to comment
93 Protein expression of ATP-binding cassette transmembrane transporter subfamily C member 3 in HeLa cells The protein expression and modification of ABCC3 in HeLa cells were determined by Western blot analysis Fig. 1 G11D 0.18% R99Q 0.54% S346F 0.91% S607N 0.99% V765L 1.09% P920S 3.88% R923Q 0.55% R1286G 0.18% R1348C 1.65% R1381S 0.22% Q1365R 0.33% Outside Inside NBD2 NBD1 Predicted secondary structure of ATP-binding cassette transmembrane transporter subfamily C member 3 showing the position of the eleven nonsynonymous variants. Login to comment
103 Similar band patterns were observed for other SNP-type ABCC3 except for R1381S ABCC3. Login to comment
104 For R1381S ABCC3, the shortest 160-kDa band was the major product (Fig. 3a). Login to comment
107 As shown in Fig. 3b, a strong 160-kDa band and faint higher molecular weight bands were observed in R1381S without any treatment. Login to comment
108 In addition, treatment of R1381S ABCC3 with PNGase F gave a single 160-kDa band, whereas treatment with Endo H did not affect the band pattern. Login to comment
109 These results may be accounted for by assuming that the major 160-kDa band for R1381S ABCC3 may represent the nonglycosylated form and faint higher molecular weight bands of R1381S ABCC3 may represent the fully N-glycosylated form, thereby confirming resistance to Endo H treatment. Login to comment
110 Collectively, R1381S ABCC3 molecules are trapped mostly in the ER as the immature form, whereas only a minor population of R1381S ABCC3, which is resistant to Endo H digestion, may be located in cellular compartments other than ER. Login to comment
117 As observed for R1381S ABCC3, mutated rat Abcc2 provided substantial colocalization with calnexin in HEK293 cells. Login to comment
118 Transport activities of the ATP-binding cassette transmembrane transporter subfamily C member 3 variants The transport function of wild-type and SNP-type ABCC3 was studied by examining the ATP-dependent uptake of [3 H]E217bG into membrane vesicles isolated from Sf9 cells infected with recombinant baculoviruses Table 1 Allele frequency of ABCC3 SNPs examined in this study Ethnic population SNP sequence Asian (%) African-American (%) Pacific islander (%) Mexican (%) Caucasian (%) SubSaharan- African (%) Total (%) Reference G11D 0.83 (120) 0 (160) 0 (12) 0 (100) 0 (160) 0.18 (552) PharmGKB 0.6 (178)a Fukushima-Uesaka et al. 0.5 (206) Lang et al. R99Q 0 (120) 1.88 (160) 0 (12) 0 (100) 0 (160) 0.54 (552) PharmGKB S346F 0 (120) 0.62 (160) 0 (12) 0 (100) 2.5 (160) 0.91 (552) PharmGKB 0.5 (206) Lang et al. S607N 0 (296) 2.76 (290) 0 (10) 1 (100) 0 (210) 0.99 (906) PharmGKB 11.7 (120) dbSNP V765L 0 (120) 3.12 (160) 0 (12) 1 (100) 0 (160) 1.09 (552) PharmGKB P920S 0 (292) 10.3 (290) 0 (12) 0 (100) 2.4 (280) 3.88 (902) PharmGKB R923Q 0 (108) 0.62 (160) 0 (12) 0 (100) 1.25 (160) 0.55 (550) PharmGKB R1286G 0 (120) 0.62 (160) 0 (12) 0 (100) 0 (160) 0.18 (552) PharmGKB R1348C 0 (298) 5.17 (290) 0 (12) 0 (100) 0 (210) 1.65 (910) PharmGKB 7.5 (120) dbSNP Q1365R 0 (298) 1.05 (286) 0 (12) 0 (100) 0 (208) 0.33 (904) PharmGKB R1381S 0 (298) 0 (290) 0 (12) 2 (100) 0 (210) 0.22 (910) PharmGKB Allele frequencies (%) in individual ethnic population are shown. Login to comment
124 ABCC3 SNP analysis Kobayashi et al. 827 Fig. WT R1381S G11D R99Q S346F S607N V765L P920S R923Q R1286G WT ABCC3 Calnexin Calnexin merge R1381S merge ABCC3 R1348C Q1365R (a) (b) Subcellular localization of ATP-binding cassette transmembrane transporter subfamily C member 3 (ABCC3) in HeLa cells. Login to comment
140 Discussion On account of its inducible nature under cholestatic conditions, ABCC3/Abcc3 is considered to provide a compensatory efflux pathway for endogenous and exo- Table 2 Corresponding amino acid residues in other ABCC family proteins Protein Species G11D R99Q S346F S607N V765L P920S R923Q R1286G R1348C Q1365R R1381S ABCC3 Human G R S S V P R R R Q R Abcc3 Mouse G S T N V T K R V Q R Abcc3 Rat G S T N V P K S F Q R ABCC1 Human S I D S V R N V I K R ABCC2 Human - A L G T K R K I K R ABCC4 Human - - L L V Q R E W K R ABCC5 Human - - L L L - D E K K R Amino acid residues in other ABCC family proteins at the corresponding positions to 11 amino acid residues in human ABCC3 examined in this study. Login to comment
142 Fig. 3 (a) (b) Treatment WT R1381S Endo HPNGaseEndo HPNGase 190 kDa 180 kDa 170 kDa 160 kDa 190 kDa 170 kDa 160 kDa WT G11D S346F R99Q S607N V765L P920S R923Q R1286G R1348C Q1365R R1381S pcDNA3.1(+) Western blot analysis of wild-type and single nucleotide polymorphism-type ATP-binding cassette transmembrane transporter subfamily C member 3 (ABCC3) proteins expressed in HeLa cells. Login to comment
150 It was found that R1381S ABCC3 accumulates in the ER as an immature form with a molecular weight of 160 kDa (Figs 2 and 3), whereas S346F and S607N ABCC3 lost their transport function (Fig. 7). Login to comment
151 It is possible that R1381S could not fold properly and, consequently was trapped in the ER with calnexin, a molecular chaperon in the ER. Login to comment
152 Altered transport activity was expected for such misfolded protein; however, R1381S ABCC3 exhibited apparently normal transport activity for E217bG when expressed in insect Sf9 cells. Login to comment
153 To account for the unaltered transport activity of R1381S ABCC3 expressed in Sf9 cells, two hypotheses may be postulated. Login to comment
154 One possibility is that R1381S ABCC3 may be properly folded in Sf9 cells and the other is that the R1381S ABCC3 is still functional even if this molecule is not properly folded. Login to comment
160 Fig. 5 WT 170 kDa Band density 1.00 1.01 0.77 1.21 1.16 0.95 1.00 1.01 0.91 1.29 1.10 G11D S346F S607N V765L P920S R923Q R1286G R1348C Q1365R R1381S GFP Western blot analysis of wild-type or single nucleotide polymorphisms-type ATP-binding cassette transmembrane transporter subfamily C member 3 (ABCC3) proteins in membrane vesicles isolated from Sf9 cells. Login to comment
171 The cellular localization of R1381S ABCC3 should also be discussed in more detail. Login to comment
172 Although R1381S ABCC3 exhibited altered localization in HeLa cells, this should be regarded with caution, because sorting machinery is sometimes cell type-specific. Login to comment
190 These are Q741Stop and Fig. 7 10 8 ATP-dependentuptakenormalizedbyrelative ABCC3expressionlevel(pmol/mgprotein/2min) 6 * * ** ** ** ** ** ** ** 4 2 WT G11D S346F S607N V765L P920S R923Q R1286G R1348C Q1365R R1381S GFP 0 Uptake of [3 H]estradiol-17b-D-glucuronide (E217bG) by ATP-binding cassette transmembrane transporter subfamily C member 3 (ABCC3) variants. 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