ABCB1 p.Ala999Trp
| Predicted by SNAP2: | C: D (71%), D: D (85%), E: D (80%), F: D (85%), G: D (66%), H: D (75%), I: D (71%), K: D (80%), L: D (80%), M: D (53%), N: D (66%), P: D (85%), Q: D (66%), R: D (75%), S: N (78%), T: N (66%), V: D (71%), W: D (85%), Y: D (85%), |
| Predicted by PROVEAN: | C: D, D: D, E: D, F: D, G: D, H: D, I: D, K: D, L: D, M: D, N: D, P: D, Q: D, R: D, S: N, T: D, V: D, W: D, Y: D, |
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[hide] Identification of functionally variant MDR1 allele... Clin Pharmacol Ther. 2001 Aug;70(2):189-99. Kim RB, Leake BF, Choo EF, Dresser GK, Kubba SV, Schwarz UI, Taylor A, Xie HG, McKinsey J, Zhou S, Lan LB, Schuetz JD, Schuetz EG, Wilkinson GR
Identification of functionally variant MDR1 alleles among European Americans and African Americans.
Clin Pharmacol Ther. 2001 Aug;70(2):189-99., [PMID:11503014]
Abstract [show]
MDR1 (P-glycoprotein) is an important factor in the disposition of many drugs, and the involved processes often exhibit considerable interindividual variability that may be genetically determined. Single-strand conformational polymorphism analysis and direct sequencing of exonic MDR1 deoxyribonucleic acid from 37 healthy European American and 23 healthy African American subjects identified 10 single nucleotide polymorphisms (SNPs), including 6 nonsynonymous variants, occurring in various allelic combinations. Population frequencies of the 15 identified alleles varied according to racial background. Two synonymous SNPs (C1236T in exon 12 and C3435T in exon 26) and a nonsynonymous SNP (G2677T, Ala893Ser) in exon 21 were found to be linked (MDR1*2 ) and occurred in 62% of European Americans and 13% of African Americans. In vitro expression of MDR1 encoding Ala893 (MDR1*1 ) or a site-directed Ser893 mutation (MDR1*2 ) indicated enhanced efflux of digoxin by cells expressing the MDR1-Ser893 variant. In vivo functional relevance of this SNP was assessed with the known P-glycoprotein drug substrate fexofenadine as a probe of the transporter's activity. In humans, MDR1*1 and MDR1*2 variants were associated with differences in fexofenadine levels, consistent with the in vitro data, with the area under the plasma level-time curve being almost 40% greater in the *1/*1 genotype compared with the *2/*2 and the *1/*2 heterozygotes having an intermediate value, suggesting enhanced in vivo P-glycoprotein activity among subjects with the MDR1*2 allele. Thus allelic variation in MDR1 is more common than previously recognized and involves multiple SNPs whose allelic frequencies vary between populations, and some of these SNPs are associated with altered P-glycoprotein function.
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No. Sentence Comment
136 Previously, a G2955C transversion in exon 24 (Ala999Trp) had been reported to be common in both tumor and normal tissues10; however, neither this study nor an earlier one,13 collectively involving a total of 84 healthy subjects, identified this SNP.
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ABCB1 p.Ala999Trp 11503014:136:46
status: NEW