ABCMdb

PMID: 17329911

Fukushima-Uesaka H, Saito Y, Tohkin M, Maekawa K, Hasegawa R, Kawamoto M, Kamatani N, Suzuki K, Yanagawa T, Kajio H, Kuzuya N, Yasuda K, Sawada J
Genetic variations and haplotype structures of the ABC transporter gene ABCC1 in a Japanese population.
Drug Metab Pharmacokinet. 2007 Feb 25;22(1):48-60., 2007-02-25 [PubMed]

Sentences

No. Mutations Sentence Comment

11 ABCC1 p.Ser656Thr ABCC1 p.Asp1501Gly ABCC1 p.Arg1301Cys ABCC1 p.Val1164Ile ABCC1 p.Ile400Thr ABCC1 p.Trp242Cys ABCC1 p.Glu1184Lys ABCC1 p.Gly844Ser Of these, eight novel nonsynonymous variations, 726GÀT (Trp242Cys), 1199TÀC (Ile400Thr), 1967GÀC (Ser656Thr), 2530GÀA (Gly844Ser), 3490GÀA (Val1164Ile), 3550GÀA (Glu1184Lys), 3901CÀT (Arg1301Cys), and 4502AÀG (Asp1501Gly), were detected with an allele frequency of 0.003. Login to comment 26 ABCC1 p.Arg723Gln ABCC1 p.Arg723Gln ABCC1 p.Gly671Val ABCC1 p.Arg433Ser ABCC1 p.Arg433Ser ABCC1 p.Arg633Gln ABCC1 p.Ser1512Leu In Caucasian populations, 1299GÀT (Arg433Ser), 1898GÀA (Arg633Gln), 2012GÀT (Gly671Val), and 4535CÀT (Ser1512Leu) have been reported.79) In addition, Arg433Ser decreases the transport activity for LTC4 and estrone sulfate, but not for estradiol 17b-glucuronide, in vitro.10) Ito et al. found 16 genetic polymorphisms, including 4 nonsynonymous and 8 synonymous ones, in 48 Japanese subjects.11) An in vitro functional study showed that one of the non-synonymous variations, 2168GÀA (Arg723Gln), leads to reduced transport activity for LTC4, estradiol 17b-glucuronide and methotrexate.12) However, no haplotype analysis has been reported for the Japanese population. Login to comment 62 ABCC1 p.Ser656Thr ABCC1 p.Asp1501Gly ABCC1 p.Arg1301Cys ABCC1 p.Val1164Ile ABCC1 p.Ile400Thr ABCC1 p.Trp242Cys ABCC1 p.Glu1184Lys ABCC1 p.Gly844Ser Eight novel nonsynonymous variations, 726GÀT (Trp242Cys), 1199TÀC (Ile400Thr), 1967GÀC (Ser656Thr), 2530GÀA (Gly844Ser), 3490GÀA (Val1164Ile), 3550GÀA (Glu1184Lys), 3901CÀT (Arg1301Cys), and 4502AÀG (Asp1501Gly), were found heterozygously in dierent subjects with an allele frequency of 0.003. Login to comment 63 ABCC1 p.Ile400Thr ABCC1 p.Trp242Cys All substituted amino acids were located in the cytoplasmic regions of the MRP1 protein.1,2,12) Two of the changes occurred in the loop between TM5 and TM6 (Trp242Cys) and between TM7 and TM8 (Ile400Thr). Login to comment 64 ABCC1 p.Ser656Thr ABCC1 p.Gly844Ser Ser656Thr and Gly844Ser were found 22 residues upstream of the Walker A motif and 52 residues downstream of the Walker B motif in the nucleotide binding domain 1 in the loop between TM11 and TM12, respectively. Login to comment 65 ABCC1 p.Val1164Ile ABCC1 p.Glu1184Lys Both Val1164Ile and Glu1184Lys resided in the loop between TM15 and TM16. Login to comment 66 ABCC1 p.Asp1501Gly ABCC1 p.Arg1301Cys Arg1301Cys was located 26 residues upstream of the Walker A motif, while and Asp1501Gly was 47 residues downstream of the Walker B motif, in the nucleotide binding domain 2 in the C-terminal. Login to comment 67 ABCC1 p.Trp242Cys ABCC1 p.Gly844Ser Using PolyPhen program (http:WWwww.bork.embl-heider- berg.deWPolyPhen) to predict the functional eects of amino acid substitutions, two substitutions, Trp242Cys and Gly844Ser, were expected to alter the protein function based on the PSIC (position specic independent count) prole score dierences derived from multiple alignments. Login to comment 68 ABCC1 p.Ile400Thr The loop between TM5 and TM 6 where Trp242 resides is known to be important for interaction with glutathione.17) Furthermore, Trp242 is located near the regions important for LTC4 binding (residues 260274)18) and LTC4 transporting activity of MRP1 proteins (amino acids 223232).19) As for Ile400Thr, Lys396 mutation to Glu or Ile, located 4 residues upstream, was shown to cause a reduced transport activity.20) The functional signicance of these 8 novel variations should be claried in the future studies. Login to comment 69 ABCC1 p.Arg723Gln ABCC1 p.Arg723Gln ABCC1 p.Thr73Ile ABCC1 p.Arg1058Gln ABCC1 p.Gly671Val ABCC1 p.Cys1047Ser ABCC1 p.Ser1512Leu We also detected three known nonsynonymous variations, 218CÀT (Thr73Ile), 2168GÀA (Arg723Gln), and 3173GÀA (Arg1058Gln) at frequencies of 0.007, 0.065 and 0.003, respectively. These frequencies were similar to those found in the earlier reports for Japanese11) and Chinese.21) One of the variations, Arg723Gln, leads to reduced transport activities for LTC4, estradiol 17b-glucuronide and methotrexate.12) We did not detect three previously reported variations: 2012GÀT (Gly671Val; found with approximately 0.03 frequency in Caucasians), 3140GÀC (Cys1047Ser; 0.05 in African-Americans), and 4535CÀT (Ser1512Leu; 0.03 in Caucasians).8,9,12) These SNPs might be ethnic- specic. Login to comment 109 ABCC1 p.Thr73Ile ABCC1 p.Ile400Thr ABCC1 p.Trp242Cys In Block 1 (Table 3), 4 haplotype groups (*1 to *4) were inferred, and the *2 to *4 groups were represented by the nonsynonymous variations, 218CÀT (Thr73Ile) (*2), 726GÀT (Trp242Cys) (*3), and 1199TÀC (Ile400Thr) (*4). Login to comment 113 ABCC1 p.Thr73Ile ABCC1 p.Ile400Thr ABCC1 p.Trp242Cys In addition to these 8 htSNPs, 3 nonsynonymous variations, 218CÀT (Thr73Ile), 726GÀT (Trp242Cys), and 1199TÀC (Ile400Thr) may be included in the htSNPs in order to detect *2 to *4 haplotypes because they might have the functional signicance. Login to comment 115 ABCC1 p.Arg723Gln ABCC1 p.Ser656Thr ABCC1 p.Gly844Ser The *2 to *4 haplotypes were dened by the nonsynonymous variations, 2168GÀA (Arg723Gln) (*2), 1967GÀC (Ser656Thr) (*3), and 2530GÀA (Gly844Ser) (*4). Login to comment 118 ABCC1 p.Arg723Gln To distinguish these 7 haplotypes, the 6 htSNPs, IVS1285GÀA, 1684CÀT (Leu562Leu), IVS13 { 105CÀT, 2007CÀT (Pro669Pro), IVS16{181CÀT, and 2168GÀA (Arg723Gln), can be used. Login to comment 119 ABCC1 p.Ser656Thr ABCC1 p.Gly844Ser In addition to them, 2 nonsynonymous variations, 1967GÀC (Ser656Thr) (*3) and 2530GÀA (Gly844Ser) (*4), may be added to the htSNPs for Block2. Login to comment 120 ABCC1 p.Arg1058Gln ABCC1 p.Arg1301Cys ABCC1 p.Val1164Ile ABCC1 p.Glu1184Lys As for Block 3 (Table 5), the haplotypes with 3550GÀA (Glu1184Lys), 3901CÀT (Arg1301Cys), 3490GÀA (Val1164Ile) and 3173GÀA (Arg1058Gln) were dened as *2, *3, *4 and *5, respectively. Login to comment 124 ABCC1 p.Arg1058Gln ABCC1 p.Arg1301Cys ABCC1 p.Val1164Ile ABCC1 p.Glu1184Lys In addition, the variations 3550GÀA (Glu1184Lys, *2), 3901CÀT (Arg1301Cys, *3), 3490GÀA (Val1164Ile, *4) and 3173GÀA (Arg1058Gln, *5) could be included in the Block 3 htSNPs. Login to comment 125 ABCC1 p.Asp1501Gly Regarding Block 4 (Table 6), the haplotype containing the nonsynonymous variation 4502AÀG (Asp1501Gly) was designated as *2. Login to comment 137 ABCC1 p.Asp1501Gly The *2 marker, 4502AÀG (Asp1501Gly), may also be included. Login to comment