ABCMdb

PMID: 16377077

Wada M
Single nucleotide polymorphisms in ABCC2 and ABCB1 genes and their clinical impact in physiology and drug response.
Cancer Lett. 2006 Mar 8;234(1):40-50. Epub 2005 Dec 27., [PubMed]

Sentences

No. Mutations Sentence Comment

41 ABCC2 p.Arg768Trp ABCC2 p.Arg1150His ABCC2 p.Arg1066* ABCC2 p.Ile1173Phe ABCC2 p.Gln1382Arg ABCC2 p.Gly676Arg ABCC2 p.Arg100* ABCC2 p.Arg1310* In Japan, the expected number of Table 1 Summary of mutations identified in Dubin-Johnson syndrome (DJS) Mutation Exon IVS Amino acid alteration Reference 298COT 3 R100X a,b 1815C 2TOA 13 Exon13 skip [38] 1967C 2TOC 15 Exon15 skip [62] 2026GOC 16 G676R [92] 2302COT 18 R768W [49,91]c 2439C 2TOC 18 Exon18 skip [38]a,c 3196COT 23 R1066X [47] 3449GOA 25 R1150H [52] 3517AOT 25 I1173F [52] 3928COT 28 R1310X [50] 4145AOG 29 Q1382R [38] 4175- 4180del 30 RM1392-1393del [48] a Adachi and Wada, unpublished data. b Houkibara and Wada, unpublished data. Login to comment 58 ABCC2 p.Arg768Trp ABCC2 p.Val417Ile ABCC2 p.Gly676Arg ABCC2 p.Ser281Asn Mor-Cohen analyzed in vitro two novel missense mutations identified in exon 25 in DJS [52] (Tables 1 Table 2 Naturally occurring base-change in ABCC2 gene accompanied by amino acid substitution Location (exon) Nucleic acid substitution Amino acid substitution Domain Pathogenetic consequence (biochemical defect) Frequency (%) Jews Japanese Reference 7 842GOA S281N Linker Unkown 2.4 Not reported [52] 10 1249GOA V417I MSD2 Unkown 22.7 10.9 [42,43,52]a 16 2026GOC G676R NBD1 DJSb Not reported Not reported [92] 18 2302COT R768W NBD1 DJS (protein maturation) Not reported 0.4? Login to comment 59 ABCC2 p.Arg1150His ABCC2 p.Lys1299Gln ABCC2 p.Ser789Phe ABCC2 p.Ile1173Phe [42,49,53,91]c 18 2366COT S789F NBD1 (Transport activity) Not reported 0.9 [42]a 25 3449GOA R1150H MSD3 DJS (transport activity) 0.3 Not reported [52] 25 3517AOT I1173F MSD3 DJS (protein maturation) 1.4 Not reported [52] 28 3895AOC K1299Q NBD2 Unkown Not reported 1? Login to comment 60 ABCC2 p.Gln1382Arg [42] 29 4145AOG Q1382R NBD2 DJS (ATP hydrilysis) Not reported 0.1? Login to comment 61 ABCC2 p.Ala1450Thr [38,53] 31 4348GOA A1450T NBD2 (Transport activity) Not reported 0.4? Login to comment 66 ABCC2 p.Arg1150His Immunoblot analysis and immunocytochemistry showed that one mutant ABCC2 (R1150H) matured properly and localized at the plasma membrane of transfected cells. Login to comment 67 ABCC2 p.Ile1173Phe In contrast, expression of another mutant ABCC2 (I1173F) was low and mislocated to the ER of the transfected cells. Login to comment 68 ABCC2 p.Arg768Trp ABCC2 (R768W), being mutated in the C motif of NBD1, was localized in the cytoplasm with an ER-like distribution [53]. Login to comment 72 ABCC2 p.Arg768Trp ABCC2 p.Arg768Trp MG132, an inhibitor of the cytosolic proteasome, blocked the degradation of the precursor form of ABCC2 (R768W), suggesting that ABCC2 (R768W) is degraded by the proteasome pathway, which is involved in the degradation of newly synthesized, misfolded and unassembled proteins in the ER [54]. Login to comment 73 ABCC2 p.Gln1382Arg Another missense mutation Q1382R in NBD2 was found in one DJS patient with compound heterozygous mutations (Table 2) [38]. Login to comment 74 ABCC2 p.Gln1382Arg The precursor form of the ABCC2 (Q1382R) was rapidly converted to the mature form, and sorted to the apical membrane of the LLC-PK1 cells as the wild type ABCC2. Login to comment 75 ABCC2 p.Arg768Trp ABCC2 p.Gln1382Arg These results suggested that, unlike the R768W mutation, the Q1382R mutation does not affect either the maturation process or the subcellular localization of ABCC2. Login to comment 76 ABCC2 p.Gln1382Arg However, efflux of glutathione conjugate of mono- chlorobimane (GS-MCLB) and ATP-dependent LTC4 uptake into plasma membrane vesicles derived from HEK293 cells expressing ABCC2 (Q1382R) was markedly reduced compared to that from cells expressing wild type ABCC2. Login to comment 77 ABCC2 p.Gln1382Arg This indicated that ABCC2 (Q1382R), although localized on the apical membrane, was nonfunctional. Login to comment 80 ABCC2 p.Gln1382Arg Vanadate-induced nucleotide trapping in the wild type ABCC2 was stimulated by the transporter substrate estradiol-glucuronide (E217bG), but that in ABCC2 (Q1382R) was not. Login to comment 83 ABCC2 p.Gln1382Arg These results suggest that 8-azido-[a-32 P]ATP is trapped together with vanadate after hydrolysis, and that the Q1382R mutation impaired substrate-induced ATP hydrolysis (Table 2). Login to comment 87 ABCC7 p.Gln1291Arg The comparable amino acid substitution, Q1291R, in CFTR was observed in patients suffering from cystic fibrosis [60]. Login to comment 88 ABCC7 p.Gln1291Arg It has also been reported that the CFTR (Q1291R) shows no chloride channel function although it reaches the plasma membrane as a fully glycosylated mature protein. Login to comment 90 ABCC2 p.Gln1382Arg In our study, the lack of substrate-induced vanadate trapping in the ABCC2 (Q1382R) may suggest that Q1382 is directly involved in ATP hydrolysis [53]. Login to comment