The Function of ABCG2 in hyperuricemia and gout

Madhavi Bhatia,NIPER Guwahati

Hyperuricemia is a condition with increased uric acid levels in the blood which results in the deposition of monosodium urate crystals in synovial fluid of joints resulting in gout. Increased levels may be caused due to increased hepatic biosynthesis or reduced renal or intestinal excretion of urate. Most of the urate is eliminated from the body by glomerular filtration in the kidney or by extrarenal excretion by the intestine. During the reabsorption or excretion of urate, various transporters are utilized. Transporters involved in reabsorption  (URAT1 at apical, GLUT9 at basolateral membrane) and in excretion(NPT1/4 at apical, OAT1/3 at basolateral membrane, ABCG2 at apical brush border).

ABCG2 role in renal urate elimination-

 The ATP binding cassette (ABC) transporter ABCG2 is a multi-drug efflux pump that is located in the apical brush border membrane of renal proximal tubule cell. It consists of an ATP-hydrolyzing nucleotide-binding domain, which is in the cytoplasm and provides energy for the transport process. A transmembrane domain is responsible for the binding of substrates and their transport across the membrane. The function of this urate transporter is affected by single nucleotide polymorphism (SNP). A missense SNP in the ABCG2 gene (Q141K) reduces the surface expression of the transporter and decreases cellular urate excretion thus increasing uric acid levels in the blood.Q141K polymorphism occurs at the nucleotide-binding domain, it forms a hydrogen bond to N158 of an α-helix. This results in conformational changes in the transporter resulting in partial loss of the activity. However, there are conflicting results found for the involvement of ABCG2 in renal urate elimination. In the kidney, there are many renal transporters involved in urate excretion, so ABCG2 function loss is compensated by other transporters. Thus, only a little change in renal urate excretion is observed.

ABCG2 role in extrarenal urate elimination

The intestine is the main site for extrarenal urate excretion.ABCG2 plays a role in extrarenal urate excretion as it is located at the villi brush border of epithelial cells of the ileum and jejunum. When Q141K polymorphism occurred in the ABCG2 transporter there was a rise in serum urate levels due to decreased/complete lack of intestinal renal excretion. There was an indirect increase in the fraction of filtered urate load (FEUA).

ABCG2 polymorphism in Pediatric-onset Hyperuricemia and Early-onset gout

Gout and Hyperuricemia pathology has often been related to genetic predisposition. Thus it is affected by SNPs that occur in the genes which encode for the urate transporter. Polymorphism in protein sequences –Q126X, M131I, Q141K, R236X may result in changes in the ABCG2 transporter and decrease its surface expression. Polymorphism in the transmembrane domain causes impairment in the substrate transport abilities of the transporter. The importance of polymorphism in the development of hyperuricemia and gout might be related to its minor allele frequency in humans and its functional impact on the protein of interest.

Conclusion-Gout is a major healthcare concern as it is the most common cause of inflammatory arthritis in men. The major site of action of the ABCG2 transporter is the intestine through which it regulates urate homeostasis.

Also read: ORFik: a new toolkit for analysing translation

Source: Eckenstaler, R., & Benndorf, R. A. (2021). The Role of ABCG2 in the Pathogenesis of Primary Hyperuricemia and Gout—An Update. International Journal of Molecular Sciences, 22(13), 6678. doi:http://10.3390/ijms22136678

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