ABCB1 p.Ile1196Tyr
| 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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No. Sentence Comment
154 Surprisingly, both the Ile residue of I1196Y P-gp and the Phe of F208S BCRP occupy the amino acid positions in the Walker B motifs of P-gp and BCRP, respectively. A number of ongoing studies in our laboratory are therefore currently focused on the mechanisms underlying the maturation and stability of mutant ABC transporters as this may have a significant impact upon the effectiveness of cancer chemotherapy regimens.
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ABCB1 p.Ile1196Tyr 17373578:154:38
status: NEW151 We recently examined the effects of a T3587G germ-line mutation in the human MDR1 gene and found that the resulting I1196Y P-glycoprotein (P-gp), that also contains an amino acid substitution within the Walker B domain, did not have ATP-binding activity (27).
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ABCB1 p.Ile1196Tyr 17373578:151:116
status: NEW