ABCMdb

PMID: 26136557

Woodward OM
ABCG2: the molecular mechanisms of urate secretion and gout.
Am J Physiol Renal Physiol. 2015 Sep 15;309(6):F485-8. doi: 10.1152/ajprenal.00242.2015. Epub 2015 Jul 1., [PubMed]

Sentences

No. Mutations Sentence Comment

12 ABCG2 p.Gln141Lys This review will highlight the recent work to identify the first important human uric acid secretory transporter, ABCG2, and the identification of a common causal ABCG2 variant, Q141K, for hyperuricemia and gout. Login to comment 13 ABCG2 p.Gln141Lys uric acid; kidney; ABCG2; Q141K; gout; hyperuricemia URIC ACID IS A TERMINAL METABOLITE of the purine metabolic pathway in humans and is only weakly soluble in water or blood. Login to comment 35 ABCG2 p.Ser187Ala Using a Xenopus oocyte expression system, we demonstrated ABCG2 to be a high-capacity urate transporter with ABCG2-mediated c-14 uric acid efflux highly dependent on the intracellular concentration, and could be blocked by a specific ABCG2 inhibitor, FTC, or with a single amino acid substitution, S187A. Login to comment 38 ABCG2 p.Gln141Lys ABCG2 p.Gln141Lys We found the Q141K variant had similar total and surface expression levels in the Xenopus oocytes but showed a 54% reduction in urate transport, marking Q141K as a loss-of-function mutation (17, 18, 30). Login to comment 39 ABCG2 p.Gln141Lys A population-based study of 14,783 individuals supported rs2231142 (Q141K) as a causal variant for gout and increased SUA levels, marking the rs2231142 as a rare example in support of the common disease-common variant hypothesis (30). Login to comment 42 ABCG2 p.Gln141Lys ABCG2 p.Gln126* Matsuo et al. compared gouty and normal cohorts of Japanese males and found two ABCG2 mutations, Q141K (50% function) and Q126X (no function), and used these to correlate ABCG2 function with age of gout onset. Login to comment 50 ABCG2 p.Gln141Lys Of the 28 loci, the ABCG2 loci (rs2231142/ Q141K mutation) resulted in the highest OR for gout risk (1.73) and contributed the largest increases in SUA (0.217 mg/dl) (12). Login to comment 51 ABCG2 p.Gln141Lys ABCG2 p.Gln141Lys ABCG2 p.Gln141Lys ABCG2 p.Gln141Lys ABCG2 p.Gln141Lys ABCG2 p.Gln141Lys ABCG2 p.Gln141Lys ABCG2 p.His155Ala ABCG2 p.His155Ala ABCG2 p.His155Ala ABCG2 p.His155Ala ABCG2 p.His155Ala Q141K Q141K / H155A 0.00 0.25 0.50 Q141K ABCG2 abundance relative to Wt Q141K ABCG2 H155A -- -- H155A GAPDH ABCG2 Wt ABCG2 Q141K H155 2 Q141K + H155A H155A ICL Q141K / Wt NBD B A C D ** Fig. 1. Login to comment 52 ABCG2 p.Gln141Lys Q141K gout-causing mutation changes NBD structure in a model of ABCG2. Login to comment 53 ABCG2 p.Gln141Lys ABCG2 p.Gln141Lys A: model comparing Wt and Q141K NBDs as described in Woodward et al. (32) reveals a shift in an adjacent loop (black arrow, Q141K in blue, Wt in green). Login to comment 55 ABCG2 p.Gln141Lys ABCG2 p.His155Ala C: biochemical confirmation of the model shows the Q141K mutant expression levels can be rescued with the secondary H155A substitution. Login to comment 63 ABCG2 p.Gln141Lys Recent work has focused on the molecular defect caused by the Q141K mutation of ABCG2 as both a potential therapeutic target and also as a model for understanding the basic structure/ function biology of ABC transporters. Login to comment 64 ABCG2 p.Gln141Lys The Q141K mutation occurs in a residue of the nucleotide-binding domain, a position believed critical for interactions with the intracellular loops of the transmembrane portion of the protein. Login to comment 67 ABCG2 p.Gln141Lys A comparative analysis between the Q141K ABCG2 mutant and the èc;F508 CFTR mutant reveals striking similarities. Login to comment 72 ABCG2 p.Gln141Lys The Q141K ABCG2 mutant appears to only cause instability in the NBD domain. Login to comment 73 ABCG2 p.Gln141Lys We recently demonstrated that artificially stabilizing the NBD domain of the Q141K mutant corrects the molecular defect. Login to comment 74 ABCG2 p.Gly188Glu Using either small molecules like the drug VRT-325 (11), or by using the suppressor mutation G188E to enhance NBD sandwich formation (25), we were able to rescue expression, trafficking, and function (32). Login to comment 79 ABCG2 p.Gln141Lys The specific source of the Q141K instability has remained unresolved. Login to comment 80 ABCG2 p.Gln141Lys ABCG2 p.Gln141Lys Recently, we have found that modeling the Q141K and Wt ABCG2 NBD domains (32) suggested a loop adjacent to the site of the Q141K substitution (see Fig. 1A) appears to be shifted outward, resulting from a clash between the mutant 141K residue and a histidine residue at the top of the loop. Login to comment 81 ABCG2 p.Gln141Lys ABCG2 p.His155Ala Replacing the histidine with an alanine appeared to resolve the shift and also significantly increased total Q141K (H155A) and mature, glycosylated protein abundance (Fig. 1, B-D) when expressed in HEK293 cells. Login to comment