Gout, genetics and ABC transporters

Abstract

Gout is a chronic arthritic disease associated with high levels of urate in blood. Recent advances in research have permitted the identification of several new and common genetic factors underlying the disease. Among them, a polymorphism in the ABC transporter gene ATP-binding cassette transporter isoform G2 has been highlighted. ATP-binding cassette transporter isoform G2 was found to be involved in renal urate elimination, and the presence of the Q141K polymorphism to induce a 2-fold decrease in urate efflux. The Q141K variant has been shown to have impaired trafficking, leading to its intracellular retention, whereas the wild type protein is expressed on the cell surface. Several agents are being studied for the purpose of improving folding, trafficking and function of various ABC transporters, including ATP-binding cassette transporter isoform G2. If successful, this strategy opens doors to potential new therapies for gout.

Figure 1.. Urate transporters in proximal tubule epithelial cells

Urate transporters are involved in both urate tubular secretion and postsecretory reabsorption, which determine the net urate excretion. In the urate secretion mechanism, the anion transporters OAT1 and OAT3 (organic anion transporter 1 and 3), localized on the basolateral membrane, have been shown to have the ability to transport urate depending on the gradients for exchanged anions. On the apical membrane, 4 transporters are involved in secretion: UAT (uric acid transporter), NPT1 (sodium phosphate transport protein 1), and the ATP-binding cassette transporters MRP4 (multidrug resistance related protein 4) and ABCG2 (ATP-binding cassette transporter isoform G2). Various ABCG2 and NPT1 variants with impaired function have been linked to increased risk of gout, and were described to decrease urate excretion, explaining the hyperuricemia. In renal reabsorption, the apical urate-anion exchanger URAT1 is considered to be essential in urate homeostasis and has been estimated to be responsible for 50% of urate reabsorption. OAT4 and OAT10 (organic anion transporter 4 and 10) are also apical mediators of this. In addition to these transporters, GLUT9 (glucose transporter 9) may play a dominant role in reabsorption. The short isoform, s-GLUT9, localizes exclusively to the apical membrane while the long isoform, l-GLUT9, is thought to mediate basolateral efflux of urate. GLUT9 and URAT1 single nucleotide polymorphisms (SNPs) have been identified by GWAS to be significantly associated with decreased and increased risk of gout, respectively. While some GLUT9 SNPs would be linked to the decrease in urate reabsorption leading to hypouricemia, the mechanism by which the URAT1 SNPs cause hyperuricemia and gout remains to be elucidated.

Figure 2.. Impact of mitoxantrone on ABCG2 T402L-G406L-G410L mutant localization

HEK293 cells transfected with the ABCG2 (ATP-binding cassette transporter isoform G2) T402L-G406L-G410L dimerization mutant were submitted to 24-hour exposure of 5 µM mitoxantrone before indirect immunostaining with the anti-ABCG2 antibody bxp21 according to the manufacturer’s instructions (Kamiya Biomedical, Seattle, WA), and DAPI nuclear stain. An overlay of the two stains is shown by confocal microscopy in the lower panels. Before treatment, the ABCG2 variant is partly retained in the cytoplasm. Mitoxantrone rescued the trafficking defect of the variant, leading to a significant increase in the amount of ABCG2 on the cell surface.