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Abstract: TH-PO731

Human Gout Risk Variant ABCG2 Q141K Results in Profound Hyperuricemia and Significant Changes to Kidney Function in a New Mouse Model

Session Information

Category: Genetic Diseases of the Kidney

  • 1002 Genetic Diseases of the Kidney: Non-Cystic


  • Woodward, Owen M., University of Maryland School of Medicine, Baltimore, Maryland, United States
  • Kazi, Mirajul H., University of Maryland School of Medicine, Baltimore, Maryland, United States
  • Dixon, Eryn E., University of Maryland School of Medicine, Baltimore, Maryland, United States
  • Lewis, Raychel Morgan, University of Maryland School of Medicine, Baltimore, Maryland, United States

Gout is the most common inflammatory arthritic disease and is a consequence of having elevated circulating urate (UA) levels (hyperuricemia). GWAS studies have identified a number of key urate transporter genes that contribute to gout risk and are expressed in the kidney and the intestines. Yet recent work from others has shown individuals carrying the most common gout risk variant, Q141K ABCG2, have no measureable difference in their renal fractional excretion of urate (FEUA). These data beg the question of whether or not ABCG2 has a role in the renal urate excretion pathway.


We have made a new mouse knock-in model of the human gout risk variant, Q141K ABCG2 (in mice, Q140K) on a C57BL6J mouse background using CRISPR Cas9 gene editing techniques, and have used biochemical, Immunofluorescence,and renal physiological measurements to described the renal phenotypes of a human risk variant carried by 500 million individuals world-wide.


We first confirmed and localized the ABCG2 protein in the mouse and human tubule, confirming unambiguously that ABCG2 expression in apical membrane of the human proximal tubule is robust. The Q140K ABCG2 mutant male mice proved to be profoundly hyperuricemic, and although the mutant mice displayed both a slight decrease in renal protein abundance and a decrease in FEUA, it was significantly less than observed in the intestines, with female mice showing no defect at all. In addition to the decrease in FEUA, the male mutant mice exhibited other hallmarks of declining renal function including, reduced eGFR, signs of metabolic acidosis, impaired ammonium secretion, and evidence of more wide spread metabolic alterations, including increased blood glucose and insulin levels.


Our new mouse model of the common human gout risk variant, Q141K ABCG2, shows that a single loss of function point mutation in a single urate transporter has significant phenotypic effects on mammalian physiology, and this work provides evidence that alterations in urate homeostasis alone can effect kidney function, consistent with the hypothesized causal role of urate in renal and metabolic diseases.


  • NIDDK Support