ABCMdb

PMID: 21554546

Woodward OM, Kottgen A, Kottgen M
ABCG transporters and disease.
FEBS J. 2011 Sep;278(18):3215-25. doi: 10.1111/j.1742-4658.2011.08171.x. Epub 2011 Jun 13., [PubMed]

Sentences

No. Mutations Sentence Comment

59 ABCG2 p.Gln141Lys ABCG2 p.Val12Met ABCG2 p.Ser441Asn ABCG2 p.Gln126* ABCG2 p.Gly268Arg R L L A A M AT T T R V S G G G F I T Q R R V K K S G E A D RR V V K K L L G E E E I IN NN D H Q Q R V V V V V L L S G F E N M TT QD D S K R V K L L G F P C Y R K S G F P P C N N A V L L S G G G I N A D R K P P S GG G R V VK K KK L L L LL L S S S GG G PPE E IIII N NN M A A A T D D Y N E A I P E S I D L L F T LS G EI MT D I I P FC L R IH A N T T T T T G L D S S K K K L L L S G G G F F F F Q P P I M M A A A A D H G G LS S S V L L L L L R R RQ Q I I Y Y YS S HE E A T V V V V L Q I S F I I II A A L G G Y K F R S S E E I I L G Y YY Y V V K H S P C M M D R T I II L L L F F YV S S P F N T I A Q Q L L L G F Y Y H S S PR W C N M I I A A A L L G F V V K H W T L I F F C C C D D D A A A QQ Q Q Q G G G G G G G G G G FF FF F F FF Y Y Y Y Y V V V V V VVV K KKK KK K K E E E E P P P P R W W TT TT T TT T T NNNN N N N N N M MM M L L L L L L L L LL LL I I I I I I AA A A A A A S S S S S S S S SS L L L L LL L L LL V V F G GCC T Q Q Q Q Y Y Y KK K K K H H EE E E E E EEE E P P P P R R RW N N N II I I I I I I A AAA A A A S SS S S S S L L LL L L L V V V V F F F F F F F G GG G C TT T T T T K K K K KKKK N NN LL D DDD DS S 395 469 565 644 414 450 495 505 584 625 Signature Walker A WalkerBQ EP MI A V V VF FG GTN N NS S S S P F HE V FG CTT K NN LLD SS AAA I V12M N-terminus C-terminus M MM MM T A A A A L F F Y V V S S S F 524476 Y Q126X G268R S441N F506fs Q141K 44 288 PP AA DD Fig. 2. Login to comment 66 ABCG2 p.Gln141Lys We therefore investigated whether urate is a physiological substrate of ABCG2, and whether the Q141K variant, encoded by rs2231142, leads to altered urate transport and as a consequence to elevated serum urate levels and increased risk of gout. Login to comment 81 ABCG2 p.Gln141Lys Q141K is a functional variant in ABCG2 Several lines of evidence in the initial genome-wide association study by Dehghan et al. [21] suggested that the rs2231142 variant may be functional. Login to comment 83 ABCG2 p.Gln141Lys Effect sizes of the ABCG2 rs2231142 (Q141K) variant on risk of gout and mean urate levels in study populations of different ancestry. Login to comment 85 ABCG2 p.Gln141Lys the variant is located in exon 5 of ABCG2 and leads to a glutamine-to-lysine amino acid substitution (Q141K) in ABCG2. Login to comment 90 ABCG2 p.Gln141Lys To test whether the rs2231142 is such a functional variant, the transport capacity of the encoded Q141K mutation was compared with that of wild-type ABCG2. Login to comment 91 ABCG2 p.Gln141Lys Oocytes expressing ABCG2 Q141K showed 54% reduced urate transport rates compared with oocytes expressing wild-type ABCG2 (Fig. 3C). Login to comment 92 ABCG2 p.Gln141Lys This is consistent with previous studies showing impaired transport of chemotherapeutic agents by ABCG2 Q141K [35,36] (and reviewed in [37]). Login to comment 93 ABCG2 p.Gln141Lys While it is difficult to compare the results from different transport assays and substrates, the reduction of transport of the Q141K variant compared with wild-type ABCG2 appears to be of similar magnitude. Login to comment 94 ABCG2 p.Gln141Lys The Q141 residue is located in the nucleotide binding domain of ABCG2 (Fig. 2), and Q141K ABCG2 expression is significantly lower than wild-type when overexpressed in mammalian cells [35,36,38,39]. Login to comment 96 ABCG2 p.Gln141Lys And like the Q141K ABCG2 mutation, expression of the deleted F508 CFTR mutant is significantly lower than wild-type suggesting a common pathophysiology (Woodward, unpublished observations). Login to comment 97 ABCG2 p.Gln141Lys 0.0 0.5 1.0 1.5 Urateaccumulation pmolperoocyte·120min-1 Urateaccumulation pmolperoocyte·120min-1 H2O ABCG2 ** A 0 20 40 60 0.4 0.6 0.8 1.0 Relativeurateremaining Time (min) ** ** ** ** ** B Lumen Blood 0.0 0.3 0.6 0.9 WT Q141K ** C Others3 Others4 SLC2A9 URAT1 SLC2A9 Others1 Others2 UU- UU- UU-UU- UU- UU- UU- UU- U-UU- D ABCG2 Fig. 3. Login to comment 101 ABCG2 p.Gln141Lys (C) Urate accumulation in oocytes expressing either the wild-type ABCG2 or the mutant Q141K ABCG2. Login to comment 108 ABCG2 p.Gln141Lys ABCG2 p.Gln126* In addition to Q141K, Q126X was identified as a novel loss-of-function variant. Login to comment 109 ABCG2 p.Gln141Lys ABCG2 p.Gln141Lys ABCG2 p.Gln126* Q126X was assigned to a different haplotype than Q141K and shown to increase gout risk (odds ratio 5.97) to an even greater extent than the Q141K variant. Login to comment 110 ABCG2 p.Gln141Lys ABCG2 p.Gln126* In addition, 10% of the gout patients studied had genotype combinations of the Q141K and Q126X variants that resulted in more than a 75% reduction of ABCG2 function compared with patients that were homozygous for the non-risk allele at both variants (odds ratio 25.8, 95% confidence interval 10.3-64.6). Login to comment