ABCMdb

ABCB1 p.Ile1196Ser

Predicted by SNAP2:	A: D (63%), C: N (61%), D: D (80%), E: D (75%), F: D (59%), G: D (75%), H: D (71%), K: D (80%), L: N (87%), M: N (72%), N: D (75%), P: D (80%), Q: D (71%), R: D (75%), S: D (66%), T: D (63%), V: N (93%), W: D (75%), Y: D (71%),
Predicted by PROVEAN:	A: D, C: D, D: D, E: D, F: D, G: D, H: D, K: D, L: N, M: N, N: D, P: D, Q: D, R: D, S: D, T: D, V: N, W: D, Y: D,

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[hide] The identification of two germ-line mutations in t... Pharm Res. 2007 Jun;24(6):1108-17. Epub 2007 Mar 21. Yoshioka S, Katayama K, Okawa C, Takahashi S, Tsukahara S, Mitsuhashi J, Sugimoto Y
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.
Pharm Res. 2007 Jun;24(6):1108-17. Epub 2007 Mar 21., [PMID:17373578]

Abstract [show]
PURPOSE: We examined the effects of the nine nonsynonymous germ-line mutations/SNPs in the breast cancer resistance protein (BCRP/ABCG2) gene on the expression and function of the protein. MATERIALS AND METHODS: We generated cDNAs for each of these mutants (G151T, C458T, C496G, A616C, T623C, T742C, T1291C, A1768T, and G1858A BCRP) and compared the effects of their exogenous expression in PA317 cells with a wild-type control. RESULTS: PA/F208S cells (T623C BCRP-transfectants) expressed marginal levels of a BCRP protein species (65kDa), which is slightly smaller than wild-type (70kDa), but this mutant did not appear on the cell surface or confer drug resistance. PA/F431L cells (T1291C BCRP-transfectants) were found to express both 70 kDa and 65 kDa BCRP protein products. In addition, although PA/F431L cells expressed 70 kDa BCRP at comparable levels to PA/WT cells, they showed only marginal resistance to SN-38. PA/T153M cells (C458T BCRP-transfectants) and PA/D620N cells (G1858A BCRP-transfectants) expressed lower amounts of BCRP and showed lower levels of resistance to SN-38 compared with PA/WT cells. CONCLUSIONS: We have shown that T623C BCRP encodes a non-functional BCRP and that T1291C BCRP encodes a low-functional BCRP. Hence, these mutations may affect the pharmacokinetics of BCRP substrates in patients harboring these alleles.

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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

[hide] Haplotype analysis of ABCB1/MDR1 blocks in a Japan... Pharmacogenetics. 2003 Dec;13(12):741-57. Sai K, Kaniwa N, Itoda M, Saito Y, Hasegawa R, Komamura K, Ueno K, Kamakura S, Kitakaze M, Shirao K, Minami H, Ohtsu A, Yoshida T, Saijo N, Kitamura Y, Kamatani N, Ozawa S, Sawada J
Haplotype analysis of ABCB1/MDR1 blocks in a Japanese population reveals genotype-dependent renal clearance of irinotecan.
Pharmacogenetics. 2003 Dec;13(12):741-57., [PMID:14646693]

Abstract [show]
We performed comprehensive haplotyping of ABCB1/MDR1 gene blocks using 49 genetic polymorphisms, including seven novel ones, obtained from 145 Japanese subjects. The ABCB1/MDR1 gene was divided into four blocks (Blocks -1, 1, 2, and 3) based on linkage disequilibrium analysis of polymorphisms. Using an expectation-maximization based program, 1, 2, 8, and 3 haplotype groups (3, 12, 32, and 18 haplotypes) were identified in Blocks -1, 1, 2, and 3, respectively. Within Block 2, haplotype groups *1, *2, *4, *6, and *8 reported by Kim and colleagues (Clin Pharmacol Ther 2001; 70:189-199) were found, and additional three groups (*9 to *11) were newly defined. We analyzed the association of haplotypes with the renal clearance of irinotecan and its metabolites in 49 Japanese cancer patients given irinotecan intravenously. There was a significant association of the *2 haplotype in Block 2, which includes 1236C>T, 2677G>T and 3435C>T, with a reduced renal clearance of those compounds. Moreover, tendencies of reduced and increased renal clearance were also observed with *1f in Block 2 and *1b in Block 3, respectively. These findings suggest that the P-glycoprotein encoded by ABCB1/MDR1 in the proximal tubules plays a substantial role in renal exclusion of drugs and, moreover, that block-haplotyping is valuable for pharmacogenetic studies.

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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

[hide] A T3587G germ-line mutation of the MDR1 gene encod... Mol Cancer Ther. 2006 Apr;5(4):877-84. Mutoh K, Mitsuhashi J, Kimura Y, Tsukahara S, Ishikawa E, Sai K, Ozawa S, Sawada J, Ueda K, Katayama K, Sugimoto Y
A T3587G germ-line mutation of the MDR1 gene encodes a nonfunctional P-glycoprotein.
Mol Cancer Ther. 2006 Apr;5(4):877-84., [PMID:16648557]

Abstract [show]
The human multidrug resistance gene 1 (MDR1) encodes a plasma membrane P-glycoprotein (P-gp) that functions as an efflux pump for various structurally unrelated anticancer agents. We have identified two nonsynonymous germ-line mutations of the MDR1 gene, C3583T MDR1 and T3587G MDR1, in peripheral blood cell samples from Japanese cancer patients. Two patients carried the C3583T MDR1 allele that encodes H1195Y P-gp, whereas a further two carried T3587G MDR1 that encodes I1196S P-gp. Murine NIH3T3 cells were transfected with pCAL-MDR-IRES-ZEO constructs carrying either wild-type (WT), C3583T, or T3587G MDR1 cDNA and selected with zeocin. 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. H1195Y P-gp expression levels in 3T3/H1195Y cells were slightly lower than the corresponding WT P-gp levels in 3T3/WT cells. 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. 3T3/I1196S cells did not show any drug resistance unlike 3T3/H1195Y cells. Moreover, a vanadate-trap assay showed that the I1196S P-gp species lacks ATP-binding activity. Taken together, we conclude from these data that T3587G MDR1 expresses a nonfunctional P-gp and this is therefore the first description of such a germ-line mutation. We contend that the T3587G MDR1 mutation may affect the pharmacokinetics of MDR1-related anticancer agents in patients carrying this allele.

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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

[hide] Genetic variations and haplotype structures of the... Ann Hum Genet. 2006 Sep;70(Pt 5):605-22. Sai K, Itoda M, Saito Y, Kurose K, Katori N, Kaniwa N, Komamura K, Kotake T, Morishita H, Tomoike H, Kamakura S, Kitakaze M, Tamura T, Yamamoto N, Kunitoh H, Yamada Y, Ohe Y, Shimada Y, Shirao K, Minami H, Ohtsu A, Yoshida T, Saijo N, Kamatani N, Ozawa S, Sawada J
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.
Ann Hum Genet. 2006 Sep;70(Pt 5):605-22., [PMID:16907707]

Abstract [show]
As functional ABCB1 haplotypes were recently reported in the promoter region of the gene, we resequenced the ABCB1 distal promoter region, along with other regions (the enhancer and proximal promoter regions, and all 28 exons), in a total of 533 Japanese subjects. Linkage disequilibrium (LD) analysis based on 92 genetic variations revealed 4 LD blocks with the same make up as previously described (Blocks -1, 1, 2 and 3), except that Block 1 was expanded to include the distal promoter region, and that a new linkage between polymorphisms -1,789G>A in the distal promoter region and IVS5 + 123A>G in intron 5 was identified. We re-assigned Block 1 haplotypes, and added novel haplotypes to the other 3 blocks. The reported promoter haplotypes were further classified into several types according to tagging variations within Block 1 coding or intronic regions. Our current data reconfirm the haplotype profiles of the other three blocks, add more detailed information on functionally-important haplotypes in Block 1 and 2 in the Japanese population, and identified differences in haplotype profiles between ethnic groups. Our updated analysis of ABCB1 haplotype blocks will assist pharmacogenetic and disease-association studies carried out using Asian subjects.

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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

[hide] Very important pharmacogene summary: ABCB1 (MDR1, ... Pharmacogenet Genomics. 2011 Mar;21(3):152-61. Hodges LM, Markova SM, Chinn LW, Gow JM, Kroetz DL, Klein TE, Altman RB
Very important pharmacogene summary: ABCB1 (MDR1, P-glycoprotein).
Pharmacogenet Genomics. 2011 Mar;21(3):152-61., [PMID:20216335]

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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