ABCMdb

PMID: 18855611

Zhou SF, Di YM, Chan E, Du YM, Chow VD, Xue CC, Lai X, Wang JC, Li CG, Tian M, Duan W
Clinical pharmacogenetics and potential application in personalized medicine.
Curr Drug Metab. 2008 Oct;9(8):738-84., [PubMed]

Sentences

No. Mutations Sentence Comment

487 ABCB1 p.Asn21Asp ABCB1 p.Phe103Leu Exon 2 contains a polymorphism that changes Asn21 to Asp, and the mutation at exon 5 changes Phe103 to Leu. Login to comment 489 ABCB1 p.Ser400Asn The 1199G>A polymorphism is located at exon 11, which changes Ser400 to Asn. Login to comment 532 ABCB1 p.Gly185Val ABCB1 p.Asn183Ser ABCB1 p.Ser400Asn ABCB1 p.Asn21Asp ABCB1 p.Gln1107Pro ABCB1 p.Ser893Ala ABCB1 p.Ser1141Thr ABCB1 p.Pro1051Ala ABCB1 p.Arg669Cys ABCB1 p.Thr1256Lys ABCB1 p.Leu662Arg ABCB1 p.Val1251Ile ABCB1 p.Ile849Met ABCB1 p.Met89Thr ABCB1 p.Trp1108Arg ABCB1 p.Ile261Val ABCB1 p.Asn44Ser ABCB1 p.Ile829Val ABCB1 p.Gly1063Ala ABCB1 p.Ala80Glu ABCB1 p.Ala599Thr ABCB1 p.Val801Met ABCB1 p.Phe17Leu ABCB1 p.Arg593His ABCB1 p.Arg593Cys ABCB1 p.Asp613Tyr ABCB1 p.Ser992Asn ABCB1 p.Ile60Leu ABCB1 p.Ser1137Ile ABCB1 p.Ile836Val ABCB1 p.Asp800Asn ABCB1 p.Lys1168Glu ABCB1 p.Ile144Thr ABCB1 p.Asp1088Asn ABCB1 p.Val168Ile ABCB1 p.Lys1099Glu ABCB1 p.Glu1223Asp ABCB1 p.Ile736Lys ABCB1 p.Glu566Lys Nucleotide change rs number Amino acid change 49T>C rs28381804 F17L 61A>G rs61615398; rs9282564 N21D 131A>G rs1202183 N44S 178A>C rs41315618 I60L 239C>A rs9282565 A80E 266T>C Rs35810889 M89T 431T>C rs61607171 I144T 502G>A rs61122623 V168I 548A>G rs60419673 N183S 554G>T rs1128501 G185V 781A>G rs36008564 I261V 1199G>A rs2229109 S400N 1696G>A rs28381902 E566K 1777C>T rs28381914 R593C 1778G>A rs56107566 R593H 1795G>A rs2235036 A599T 1837G>T rs57001392 D613Y 1985T>G rs61762047 L662R 2005C>T rs35023033 R669C 2207A>T rs41316450 I736K 2398G>A rs41305517 D800N 2401G>A rs2235039 V801M 2485A>G rs2032581 I829V 2506A>G rs28381967 I836V 2547A>G rs36105130 I849M 2677T>A/G rs2032582 S893A/T 2975G>A rs56849127 S992N 3151C>G rs28401798 P1051A 3188G>C rs2707944 G1063A 3262G>A rs57521326 D1088N 3295A>G rs41309225 K1099E 3320A>C rs55852620 Q1107P 3322T>C rs35730308 W1108R 3410G>T rs41309228 S1137I 3421T>A rs2229107 S1141T 3502A>G rs59241388 K1168E 3669A>T rs41309231 E1223D 3751G>A rs28364274 V1251I 3767C>A r35721439 T1256K Data are from NCBI dbSNP (access date: 2 August 2008). Login to comment 614 ABCG2 p.Arg482Thr ABCG2 p.Arg482Gly It was discovered that the first cloned BCRP cDNA [265] encoded a mutant BCRP that differs from the wild-type BCRP at Arg482 (R482), which was substituted with either threonine (R482T) or glycine (R482G) [269]. Login to comment 618 ABCG2 p.Gln141Lys ABCG2 p.Val12Met ABCG2 p.Ile206Leu ABCG2 p.Gln166Glu ABCG2 p.Phe208Ser ABCG2 p.Ser248Pro ABCG2 p.Phe571Ile ABCG2 p.Asp296His ABCG2 p.Ala528Thr ABCG2 p.Leu525Arg Only a small portion of them are non-synonymous (V12M, Q141K, Q166E, I206L, F208S, S248P, D296H, L525R, A528T, F571I, and Y590N) and there is one frameshift (1515delC) mutation observed in the coding region of ABCG2. Login to comment 619 ABCG2 p.Gln141Lys ABCG2 p.Val12Met Among the above variations, 34G>A (V12M) AND 421C>A (Q141K) have been testified to be polymorphic in numerous populations [267, 271]. Login to comment 620 ABCG2 p.Val12Met The V12M polymorphism located in exon 2 influenced the N-terminal intracellular region of the protein. Login to comment 622 ABCG2 p.Val12Met The V12M polymorphism was discovered in all ethnic groups tested, found with the highest allele frequency in Mexican-Indians (90%, but only 10 individuals were tested), while only 2% in a Swedish population [272]. Login to comment 623 ABCG2 p.Val12Met Upon the combination of several population studies, a consistent and significant difference can be seen between the overall allele frequencies of V12M in Caucasian, African American and Japanese populations [271]. Login to comment 624 ABCG2 p.Gln141Lys The Q141K polymorphism located in exon 5 leads to the replacement of the negatively charged glutamic acid residue with a positively charged lysine residue. Login to comment 626 ABCG2 p.Gln141Lys ABCG2 p.Gln141Lys The Q141K variant was detected in all ethnic groups tested; it was found that Q141K occurs frequently in Asian populations ranging from (~30-60%) and relatively low allele frequency in Caucasians and African American subjects (~5-10%) [273]. Login to comment 627 ABCG2 p.Gln141Lys For example, 60% are heterozygous for Q141 K in a Chinese population; 39-50% heterozygous for a Japanese population and 7% homozygous for the variant Q141K. Login to comment 628 ABCG2 p.Ile206Leu ABCG2 p.Asp620Asn Several other variants such as I206L, N520Y and D620N are much less frequent with allele frequencies of ~1%. Login to comment 630 ABCG2 p.Gln141Lys ABCG2 p.Val12Met Studies have discovered that the expression levels of Q141K ABCG2 protein is lower than the wild-type, or the V12M variant when expressed in PA317 or HEK-293 cells [273]. Login to comment 631 ABCG2 p.Gln141Lys ABCG2 p.Gln141Lys ABCG2 p.Val12Met It was also found that a portion of Q141K remained intracellular despite having a low level of expression, as both V12M and Q141K BCRP could reach the plasma membrane in the HEK-293 cells [273]. Login to comment 632 ABCG2 p.Gln141Lys Other reports quoted that there is a 30-40% reduction in expression of cell surface Q141K variant, despite having a similar mRNA level compared to the wild-type. Login to comment 633 ABCG2 p.Gln141Lys Individuals homozygous for the Q141K variant had significantly lower expression levels of BCRP in the placenta while the heterozygous samples displayed an intermediate expression level [274]. Login to comment 635 ABCG2 p.Gln141Lys ABCG2 p.Val12Met ABCG2 is expressed in polarized LLC-PKI cells, and a study has demonstrated that the V12M variant has an intracellular localization whereas the wild-type ABCG2 and Q141K show mainly apical staining [275]. Login to comment 636 ABCG2 p.Val12Met ABCG2 p.Gln166Glu ABCG2 p.Ser441Asn ABCG2 p.Ala149Pro ABCG2 p.Pro269Ser ABCG2 p.Arg163Lys The localization of other variants including V12M, A149P, R163K, Q166E, P269S and S441N was also examined. Login to comment 637 ABCG2 p.Gln141Lys ABCG2 p.Val12Met ABCG2 p.Ser441Asn All polymorphisms, including V12M and Q141K, had an apical localization, and only the S441N variant displayed an intracellular staining [275]. Login to comment 639 ABCG2 p.Gln141Lys ABCG2 p.Gln141Lys ABCG2 p.Val12Met Further studies are required to clarify the mechanism of a reduced protein expression for Q141K, and the change of cellular localization for the V12M and Q141K variants found under specific conditions. Login to comment 641 ABCG2 p.Gln141Lys ABCG2 p.Val12Met There was a 10-fold decrease in drug resistance compared with the wild-type ABCG2 when the V12M or Q141K-transfected LLC-PKI cells were challenged by mitoxantrone or topotecan [275]. Login to comment 642 ABCG2 p.Gln141Lys In contrast, when compared to wild-type ABCG2-transfected cells, Q141K variant alone had a fairly lower level resistance against mitoxantrone, topotecan or SN-38. Login to comment 644 ABCG2 p.Gln141Lys In the ATP-binding cassette region of ABCG2, Q141K is between the Walker A and the signature motifs; hence variant ATPase activity alteration is possible. Login to comment 645 ABCG2 p.Gln141Lys ABCG2 p.Val12Met Experiments were undertaken to observe between the vanadate-sensitive ATPase activity of ABCG2 V12M and Q141K variants, using Sf9 (Spodoptera frugiperda) cell membranes [276]. Login to comment 646 ABCG2 p.Gln141Lys ABCG2 p.Val12Met There was a 1.3 and 1.8-fold lower basal ATPase activity, respectively, for V12M and Q141K compared to wild-type [276]. Login to comment 647 ABCG2 p.Val12Met ABCG2 p.Asp620Asn On the other hand, the V12M (and D620N) ABCG2 displayed a comparable ATPase activity as the wild-type protein. Login to comment