ABCMdb

ABCB1 p.Ile1196Ser

None has been submitted yet.

Publications

PMID: 17373578 [PubMed] Yoshioka S et al: "The identification of two germ-line mutations in the human breast cancer resistance protein gene that result in the expression of a low/non-functional protein."

No. Sentence Comment

152 In our T3587G MDR1 transfectants, I1196S P-gp also did not appear on the cell surface, and the transfected cells were drug sensitive. Login to comment

PMID: 14646693 [PubMed] Sai K et al: "Haplotype analysis of ABCB1/MDR1 blocks in a Japanese population reveals genotype-dependent renal clearance of irinotecan."

No. Sentence Comment

89 The SNP 3587T.G is non-synonymous (I1196S), and the other novel SNPs were intronic or 59-flanking. Login to comment
102 Unauthorized reproduction of this article is prohibited. Copyright(c)LippincottWilliams&Wilkins.Unauthorizedreproductionofthisarticleisprohibited. Table 2 List of SNPs and deletion/insertion of the ABCB1 gene found in a Japanese population SNP IDÃ Position Nucleotide Effect on Block Site Our SNP ID NCBI IMS-JST NT_007933.10 cDNA-based change protein Frequency Block À1 59-Flanking MPJ6_AB1057 12472341 À8104 T.C 0.003 59-Flanking MPJ6_AB1059 12472207 À7970 C.T 0.007 Block 1 59-Flanking MPJ6_AB1002 rs2188524 ssj0000008 12464608 À371 A.G 0.128 Exon 1 (59-UTR) MPJ6_AB1003 12464382 À145 C.G 0.024 Exon 1 (59-UTR) MPJ6_AB1004 rs3213619 ssj0000009 12464366 À129 T.C 0.093 Intron 1 MPJ6_AB1005 rs3214119 ssj0000010 12463753 IVS1-74 delG 0.121 Intron 3 MPJ6_AB1008 rs2235074 12459219 IVS3+36 C.T 0.093 Intron 4 MPJ6_AB1010 rs2235014 12433788 IVS4-76 T.C 0.017 Intron 4 MPJ6_AB1011 rs2235015 12433737 IVS4-25 G.T 0.086 Exon 5 MPJ6_AB1012 12433674 325 G.A E109K 0.010 Intron 5 MPJ6_AB1013 rs2235016 12433585 IVS5+76 T.G 0.055 Block 2 Intron 5 MPJ6_AB1014 rs2235018 12433538 IVS5+123 A.G 0.141 Intron 5 MPJ6_AB1015 rs2235020 12433438 IVS5+223 A.T 0.548 Intron 5 MPJ6_AB1016 rs2235021 12433437 IVS5+224 G.T 0.548 Intron 6 MPJ6_AB1017 12429839 IVS6-109 G.T 0.007 Intron 7 MPJ6_AB1018 12429545 IVS7+14 G.A 0.010 Intron 8 MPJ6_AB1020 rs1922240 ssj0000016 12417527 IVS8-106 A.G 0.348 Intron 9 MPJ6_AB1021 12414371 IVS9-44 G.A 0.445 Intron 10 MPJ6_AB1023 rs2235029 12414108 IVS10-41 T.G 0.017 Exon 12 MPJ6_AB1025 rs1128503 12413774 1236 C.T G412G (silent) 0.555 Intron 12 MPJ6_AB1052 12413643 IVS12+17 G.A 0.010 Intron 13 MPJ6_AB1026 rs2235033 ssj0000018 12413316 IVS13+24 T.C 0.445 Intron 13 MPJ6_AB1027 rs2235035 ssj0000019 12413259 IVS13+81 C.T 0.348 Intron 14 MPJ6_AB1028 rs2235013 ssj0000020 12412799 IVS14+38 G.A 0.445 Intron 15 MPJ6_AB1029 12408557 IVS15-69 T.C 0.014 Intron 16 MPJ6_AB1030 rs2235046 12408239 IVS16+73 A.G 0.452 Intron 16 MPJ6_AB1031 rs1922242 12407840 IVS16-76 T.A 0.369 Intron 18 MPJ6_AB1034 12402869 IVS18-35 G.C 0.003 Intron 20 MPJ6_AB1035 rs2235040 ssj0000027 12399923 IVS20+24 G.A 0.090 Exon 21 MPJ6_AB1036 12394791 2677 G.A A893T 0.200 Exon 21 MPJ6_AB1037 rs2032582 12394791 2677 G.T A893S 0.403 Intron 21 MPJ6_AB1038 rs2032583 ssj0000031 12394734 IVS21+49 T.C 0.090 Intron 24 MPJ6_AB1040 12379982 IVS24+16 C.T 0.031 Exon 26 MPJ6_AB1041 rs1045642 ssj0000040 12372818 3435 C.T I1145I (silent) 0.441 Intron 26 MPJ6_AB1042 rs2235047 ssj0000048 12372705 IVS26+59 T.G 0.403 Intron 26 MPJ6_AB1043 rs2235048 ssj0000049 12372684 IVS26+80 T.C 0.448 Block 3 Exon 27 MPJ6_AB1068 12369435 3587 T.G I1196S 0.003 Intron 27 MPJ6_AB1044 12369323 IVS27+63 C.G 0.003 Intron 27 MPJ6_AB1053 12368127 IVS27-189 A.G 0.007 Intron 27 MPJ6_AB1045 rs1186745 ssj0000051 12368120 IVS27-182 G.T 0.200 Intron 27 MPJ6_AB1054 12368110 IVS27-172 G.A 0.010 Intron 27 MPJ6_AB1047 rs1186744 12368106 IVS27-168 T.C 0.010 Intron 27 MPJ6_AB1048 12368105 IVS27-167 A.G 0.014 Intron 27 MPJ6_AB1055 12368090 IVS27-152 A.G 0.003 Intron 27 MPJ6_AB1049 12368057 IVS27-119 C.T 0.021 Intron 27 MPJ6_AB1056 rs2235049 12368025 IVS27-87 A.G 0.007 Intron 27 MPJ6_AB1070 12368024 IVS27-86 T.C 0.003 Intron 27 MPJ6_AB1071 12368018 IVS27-80 ins C 0.003 Exon 28 MPJ6_AB1051 12367824 3751 G.A V1251I 0.010 ÃSNP ID assigned by our project team (MPJ-6). Login to comment
103 746Pharmacogenetics2003,Vol13No12 Copyright(c)LippincottWilliams&Wilkins.Unauthorizedreproductionofthisarticleisprohibited. Table 3 Classification of major ABCB1 haplotypes Site Exon 2 Exon 5 Exon 7 Exon 11 Exon 12 Exon 13 Exon 21 Exon 21 Exon 21 Exon 26 Exon 26 Exon 27 Exon 28 PositionÃ Exon 1 Exon 1 61A.G 325G.A 548A.G 1199G.A 1236C.T 1474C.T 2650C.T 2677G.T 2677G.A 3421T.A 3435C.T 3587T.G 3751G.A Effect on protein À4C.T À1G.A N21D E109K N183S S400N G412G R492C L884L A893S A893T S1141T I1145I I1196S V1251I Classification by Kim et al. [12] Ã1 - - - - - - - - - - - Ã1A - - - - A - - - - - - Ã1B T - - - - - - - - - - Ã1C - - - - - - - - - A - Ã1D - - - G - - - - - - - Ã2 - - - - - T - - T - T Ã2A - - G - - T - - T - T Ã2B - - - - - T - T T - T Ã2C - - - - - T T - T - T Ã3 - - - - - - - - T - T Ã4 - - - - - T - - - - T Ã5 - A - - - - - - - - T Ã6 - - - - - - - - - - T Ã7 - - - - - - - - T - - Ã8 - - - - - T - - - - - Classification of haplotype group detected in this paperÃÃ Block 1 Ã1 - - - - Ã2 - - G - Block 2 Ã1 - - - - - - - - - Ã2 - - T - - T - - T Ã4 - - T - - - - - T Ã6 - - - - - - - - T Ã8 - - T - - - - - - Ã9 - - - - - - - - - Ã10 - - - - - - A - - Ã11 - - T - - - A - - Block 3 Ã1 - - Ã2 - A Ã3 G - ÃAdenine of the initiation codon ATG in exon 2 was numbered +1. Login to comment
154 The Ã2 and Ã3 haplotypes had a nonsynonymous SNP of 3751G.A (V1251I) and 3587T.G (I1196S), respectively. Login to comment
162 *1b Block 3 Site Position Nucleotide change Effect on protein Exon 27 3587 TϾG I1196S Diplotype *1a/*1a Intron 27 Intron 27 IVS27 ϩ63 Intron 27 Intron 27 Intron 27 Intron 27 Intron 27 Intron 27 Intron 27 Intron 27 Intron 27 Exon 28 IVS27 -189 IVS27 -182 IVS27 -172 IVS27 -168 IVS27 -167 IVS27 -152 IVS27 -119 IVS27 -87 IVS27 -86 IVS27 -80 3751 CϾG AϾG GϾT GϾA TϾC AϾG AϾG CϾT AϾG TϾC ins C GϾA V1251I *1a/*1b *1a/*1c *1a/*1d *1a/*1e *1a/*1f *1a/*1g *1a/*1h *1a/*1i *1a/*1j *1a/*1k *1a/*1m *1a/*1n *1a/*1p *1a/*1q ? Login to comment

PMID: 16648557 [PubMed] Mutoh K et al: "A T3587G germ-line mutation of the MDR1 gene encodes a nonfunctional P-glycoprotein."

No. Sentence Comment

3 Two patients carried the C3583T MDR1 allele that encodes H1195Y P-gp, whereas a further two carried T3587G MDR1 that encodes I1196S P-gp. Login to comment
5 The resulting zeocin-resistant mixed populations of transfected cells were designated as 3T3/WT, 3T3/H1195Y, and 3T3/I1196S, respectively. The cell surface expression of I1196S P-gp in 3T3/I1196S cells could not be detected by fluorescence-activated cell sorting, although low expression of I1196S P-gp was found by Western blotting. Login to comment
7 By immunoblotting analysis, both WT P-gp and H1195Y P-gp were detectable as a 145-kDa protein, whereas I1196S P-gp was visualized as a 140-kDa protein. Login to comment
8 3T3/I1196S cells did not show any drug resistance unlike 3T3/H1195Y cells. Login to comment
9 Moreover, a vanadate-trap assay showed that the I1196S P-gp species lacks ATP-binding activity. Login to comment
32 April 2006 American Association for Cancer ResearchCopyright (c) 2006 on September , We have also reported previously the identification of a T3587G MDR1 germ-line mutation in a Japanese patient, which confers a serine substitution for Ile1196 in P-gp (I1196S P-gp; ref. 17). Login to comment
37 In our current study, we have established T3587G MDR1 and C3583T MDR1 cDNA transfectants and examined both expression levels and functional properties of I1196S P-gp and H1195Y P-gp. Login to comment
48 The zeocin-resistant mixed populations of the transfected cells were designated as 3T3/WT, 3T3/H1195Y, and 3T3/I1196S, respectively. Login to comment
49 Because 3T3/I1196S cells expressed only a small amount of P-gp, we isolated 30 T3587G MDR1 cDNA transfectant clones by limiting dilution and tested for P-gp expression. Login to comment
50 A clone with the highest I1196S P-gp expression, designated as 3T3/I1196S clone 23, was used in the evaluation of ATP-binding activity of mutant P-gps. Login to comment
79 The C3583T MDR1 and T3587G MDR1 alleles encode H1195Y P-gp and I1196S P-gp, respectively, and both of the His1195 and Ile1196 residues are located in the Walker B region of the second ATP-binding site of P-gp (Fig. 1A). Login to comment
87 Arrows, location of the H1195Y and I1196S substitutions. Login to comment
91 April 2006 American Association for Cancer ResearchCopyright (c) 2006 on September 29, P-gp Expression Levels in the MDR1 Transfectants To investigate the molecular functions of the H1195Y mutant P-gp and I1196S mutant P-gp, we generated 3T3/ WT, 3T3/H1195Y, and 3T3/I1196S cells, which were stably transfected with WT MDR1, C3583T MDR1, and T3587G MDR1 cDNA, respectively. The P-gp expression levels on the cell surfaces of these transfectants were subsequently examined by FACS analysis using the MRK16 antibody, which recognizes a cell surface epitope of human P-gp. Login to comment
93 Surprisingly, the 3T3/I1196S cells did not express P-gp on their cell surface (Fig. 2A). Login to comment
96 Moreover, both WT P-gp and H1195Y P-gp were detectable as a 145-kDa protein, whereas I1196S P-gp was observed as a 140-kDa protein (Fig. 2B). Login to comment
97 In addition, the expression levels of I1196S P-gp in 3T3/I1196S cells were at significantly lower levels than the other P-gp species. Login to comment
98 As the expression levels of I1196S P-gp were very low in 3T3/I1196S cells, we examined the copy number of exogenous MDR1 cDNA and the expression level of MDR1 mRNA in these transfectants. Login to comment
106 As shown in Fig. 3, P-gp expression was observed in NIH3T3 cells transduced with both WT and H1195Y MDR1 retroviruses but not in cells transduced with I1196S MDR1 retrovirus. Login to comment
124 Nonfunctional P-glycoprotein Mutant880 in these cells and it is also significant that 3T3/I1196S cells showed no increased resistance to these chemotherapeutic agents when compared with the parental cells (Fig. 4), although I1196S P-gp was found to be expressed at low levels in 3T3/I1196S cells. Login to comment
125 Loss of ATP-Binding Ability in I1196S P-gp Because H1195Y P-gp and I1196S P-gp have amino acid substitutions in the second ATP-binding site of P-gp, we examined the ATP-binding activities of these variants. Login to comment
126 3T3/ I1196S clones were isolated and screened for higher P-gp expression, and clone 23 was found to contain the highest expression levels of I1196S P-gp. Login to comment
127 3T3/I1196S clone 23 was thus used in these analyses (Fig. 5A). Login to comment
128 Because 3T3/I1196S clone 23 expressed f25% of the WT P-gp levels, and 3T3/H1195Y cells expressed f50% of the WT levels, we normalized these amounts in the relevant experiments (Fig. 5B and C). Login to comment
129 It was significant that the I1196S P-gp species showed no ATP-binding activity in either the absence or presence of 50 Amol/L verapamil (Fig. 5B and D). Login to comment
131 These results suggest that I1196S P-gp lacks ATP-binding activity and therefore cannot function as an efflux pump. Login to comment
137 The C3583T MDR1 substitutes a tyrosine for the His1195 residue of P-gp, whereas the T3587G MDR1 results in a serine substitution for Ile1196 . Login to comment
151 D, NIH3T3 cells transduced with I1196S MDR1 retrovirus. Login to comment
155 ), 3T3/WT (o), 3T3/H1195Y (4), and 3T3/I1196S (w ) cells were cultured for 5 d with various concentrations of vincristine or doxorubicin. Cell numbers were determined using a cell counter. Login to comment
182 B, ATP-binding activity of I1196S P-gp. Plasma membrane protein extracts of NIH3T3 (20 Ag), 3T3/WT (5 Ag), and 3T3/I1196S clone 23 (20 Ag) cells were incubated with 10 Amol/L 8-azido- [a-32 P]ATP and 200 Amol/L vanadate in the absence (À) or presence (+) of 50 Amol/L verapamil for 10 min at 37jC. Login to comment
194 We show in our current experiments that the I1196S P-gp also lacks ATP-binding activity and that its expression levels in 3T3/I1196S cells are markedly lower than in 3T3/WT cells. Login to comment
195 In addition, whereas the WT P-gp migrates as a 145-kDa protein, the I1196S P-gp migrates as a 140-kDa protein (Fig. 2B). Login to comment
196 The SDS-PAGE profile of I1196S P-gp is also very similar to the glycosylation-deficient P-gp that has the three amino acid substitutions, N91Q, N94Q, and N99Q (39). Login to comment
197 Taken together, these data suggest the possibility that I1196S P-gp does not undergo proper maturation, which results in low protein expression levels. Login to comment
198 Analyses of the biosynthesis and glycosylation status of I1196S P-gp are ongoing in our laboratory. Login to comment
200 Our present study also shows that substitution of serine for Ile1196 results in the loss of ATP-binding activity but that the substitution of tyrosine for His1195 does not affect P-gp function. Login to comment

PMID: 16907707 [PubMed] Sai K et al: "Genetic variations and haplotype structures of the ABCB1 gene in a Japanese population: an expanded haplotype block covering the distal promoter region, and associated ethnic differences."

No. Sentence Comment

159 As observed previously, the rare haplotype groups * 2 [3751G>A (V1251I)] and * 3 [3587T>G (I1196S)] were observed at frequencies of 0.014 and 0.001, respectively. Login to comment

PMID: 20216335 [PubMed] Hodges LM et al: "Very important pharmacogene summary: ABCB1 (MDR1, P-glycoprotein)."

No. Sentence Comment

40 In humans, spontaneous deletion of ABCB1 has not been described, but a nonfunctional variant was found in two heterozygous individuals in which a single nucleotide polymorphism (SNP), T3587G, results in an isoleucine to serine change at residue 1196 in the second ATP-binding domain of P-gp [39]. Login to comment