ABCC2 p.Val1188Gln
| Predicted by SNAP2: | A: N (61%), C: N (57%), D: D (59%), E: N (72%), F: D (59%), G: D (59%), H: D (63%), I: N (53%), K: D (53%), L: D (53%), M: N (53%), N: N (53%), P: D (75%), Q: N (53%), R: D (63%), S: N (61%), T: N (66%), W: D (91%), Y: D (80%), |
| Predicted by PROVEAN: | A: N, C: N, D: N, E: N, F: N, G: N, H: N, I: N, K: N, L: N, M: N, N: N, P: N, Q: N, R: N, S: N, T: N, W: N, Y: N, |
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[hide] Functional defect caused by the 4544G>A SNP in ABC... Pharmacogenet Genomics. 2011 Dec;21(12):884-93. Elens L, Tyteca D, Panin N, Courtoy P, Lison D, Demoulin JB, Haufroid V
Functional defect caused by the 4544G>A SNP in ABCC2: potential impact for drug cellular disposition.
Pharmacogenet Genomics. 2011 Dec;21(12):884-93., [PMID:22027652]
Abstract [show]
OBJECTIVES: ABCC2 contributes to the active cellular efflux of several endogenous and exogenous compounds. The 4544G>A (rs8187710) single nucleotide polymorphism (SNP), which is coding for a C1515Y substitution, has been previously associated with susceptibility to cholestatic liver disease, doxorubicin cardiotoxicity, nonalcoholic fatty liver disease, decreased graft function after renal transplantation and tenofovir-induced proximal nephropathy. It is also involved in differential flavopiridol disposition and increased lopinavir (LPV) cellular accumulation in vivo. The aim of the present study was to investigate whether the 4544G>A SNP causes alterations in ABCC2-mediated transport towards different substrates and to explore the underlying molecular mechanisms. METHODS: Human embryonic kidney cells (HEK293) were stably transfected with full-length ABCC2 cDNA coding the wild-type (4544G) or the variant (4544A) ABCC2 allele. Accumulation and efflux assays were carried out with three different substrates and kinetic parameters were then compared between wild-type and variant HEK293-transfected clones. The vanadate-sensitive ATPase activity of the wild-type and the variant ABCC2-transfected clones was assayed in isolated membranes vesicles. RESULTS: At a comparable expression level, the ABCC2 4544A clone showed higher accumulation of LPV, calcein and carboxyfluorescein diacetate as well as reduced ABCC2-mediated efflux of LPV compared with the ABCC2 4544G clone. The 4544G>A SNP impaired ABCC2 ATPase activity, which likely explains the reduced efflux activity of the 4544A clone. CONCLUSION: The C1515Y amino acid substitution caused by the 4544G>A SNP in ABCC2 impairs its ATPase activity and is associated with higher cellular accumulation of ABCC2 substrates.
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No. Sentence Comment
220 Of considerable interest for further studies, the 4544G > A SNP is in strong linkage disequilibrium in vivo with the ABCC2 rs17222723 SNP, which leads to a glutamine to valine substitution at position 1188 in ABCC2: the functional consequences of this SNP remain unexplored.
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ABCC2 p.Val1188Gln 22027652:220:156
status: NEW