ABCMdb

PMID: 18974617

Ho WF, Koo SH, Yee JY, Lee JD
Genetic variations of the ABCC2 gene in the Chinese, Malay, and Indian populations of Singapore.
Drug Metab Pharmacokinet. 2008;23(5):385-91., [PubMed]

Sentences

No. Mutations Sentence Comment

13 ABCC2 p.Gln1523Pro ABCC2 p.His1414Tyr ABCC2 p.Glu896Lys Three novel nonsynonymous variations: 2686GÀA (Glu896Lys), 4240CÀT (His1414Tyr) and 4568AÀC (Gln1523Pro) were detected in single heterozygous Malay, Chinese, and Indian subjects, respectively. Login to comment 44 ABCC2 p.Gln1523Pro ABCC2 p.His1414Tyr ABCC2 p.Glu896Lys Of the 8 nonsynonymous variations, 3 variations were novel: 2686GÀA (Glu896Lys), 4240CÀT (His1414Tyr), and 4568AÀC (Gln1523Pro), each was found as heterozygotes in Malay, Chinese, and Indian subjects, respectively. Login to comment 46 ABCC2 p.Gln1523Pro ABCC2 p.His1414Tyr MRP2 comprises 17 transmembrane segments organized in three membrane-spanning domains (MSD).2) Among the novel nonsynonymous variations, 4240CÀT (His1414Tyr) is located between Walker A and Walker C motifs of the ABC, and 4568AÀC (Gln1523Pro) is located just adjacent to the ABC.5) Mutations that are likely to affect function or alter phenotype have been found to localize within the ABC or its adjacent regions.5) This is consistent with the results obtained using the PolyPhen program (http://genetics.bwh.harvard.edu/pph/) to predict the functional effects of the amino acid substitutions. Login to comment 47 ABCC2 p.Gln1523Pro ABCC2 p.His1414Tyr 4240CÀT (His1414Tyr) and 4568AÀC (Gln1523Pro) were expected to be probably damaging based on the position-specific independent count score differences derived from multiple alignments. Login to comment 48 ABCC2 p.Glu896Lys 2686GÀA (Glu896Lys) which resides outside the ABC region was predicted to be benign. Login to comment 49 ABCC2 p.Gln1523Pro ABCC2 p.His1414Tyr ABCC2 p.Glu896Lys This is also well in agreement with the fact that His1414Tyr and Gln1523Pro involve a larger degree of structural modification than Glu896Lys. Login to comment 50 ABCC2 p.His1414Tyr The polar histidine of His1414Tyr is replaced by the non-polar tyrosine. Login to comment 51 ABCC2 p.Gln1523Pro Similarly, the polar glutamine of Gln1523Pro is substituted with non-polar proline. Login to comment 52 ABCC2 p.Glu896Lys Glu896Lys is the variant with the least drastic change, with both charged amino acid residues glutamate (acidic) and lysine (basic) having polar side chains, and thus likely to produce the mildest effect. Login to comment 54 ABCC2 p.Val417Ile ABCC2 p.Val417Ile ABCC2 p.Cys1515Tyr ABCC2 p.Cys1515Tyr ABCC2 p.Val1188Glu ABCC2 p.Val1188Glu ABCC2 p.Val1188Glu ABCC2 p.Val1188Glu ABCC2 p.Thr486Ile Among the reported variations, the ones that may be of functional relevance include -24CÀT,7,25) 1249GÀA (Val417Ile),5) 3563TÀA (Val1188Glu),5,26-28) 3972CÀT (Ile1324Ile),25) and 4544GÀA (Cys1515Tyr).26,28) The -24CÀT polymorphism was found to associate with increased plasma methotrexate concentrations in pediatric leukemia patients.7) We have also previously observed a trend for a genotypic-phenotypic correlation between -24CÀT polymorphism and increased irinotecan AUC(0, /).29) -24CÀT and 3972CÀT (Ile1324Ile) were linked to higher response rates to irinotecan and longer progression-free survival in patients with advanced non-small cell lung cancer.25) However, a study on the disposition of nitrocamptothecin and its aminocamptothecin metabolite in relation to the 3972CÀT variation revealed no significant association.30) 3563TÀA (Val1188Glu) and 4544GÀA (Cys1515Tyr) were correlated with high MRP2 expression,28) and increased susceptibility for anthracycline-induced cardiotoxicity.26) 3563TÀA (Val1188Glu) was also significantly associated with pruritus in primary biliary cirrhosis.27) Genetic polymorphisms in ABCC2 might thus constitute a risk factor for the development of acquired forms of cholestatic liver diseases.28) Mutations in the transmembrane domain: 1249GÀA (Val417Ile), 1457CÀT (Thr486Ile), and 3563TÀA (Val1188Glu) could affect their substrate specificities though their transporter activities might not be completely disrupted.5) All reported nonsynonymous variations detected in this study were predicted to be benign using the PolyPhen program. Login to comment 67 ABCC2 p.Gln1523Pro ABCC2 p.His1414Tyr ABCC2 p.Glu896Lys Population Genetic Variations of ABCC2 Gene SNP20 (389) el nonsynonymous variations, 2686GÀA (Glu896Lys) was speculated to be benign, and 4240CÀT (His1414Tyr) and 4568AÀC (Gln1523Pro) were speculated to be potentially damaging in function. Login to comment