The ABCG2 Q141K hyperuricemia and gout associated variant illuminates the physiology of human urate excretion

Kazi Mirajul Hoque, Eryn E. Dixon, Raychel M. Lewis, Jordyn Allan, Gregory D. Gamble, Amanda J. Phipps-Green, Victoria L. Halperin Kuhns, Anne M. Horne, Lisa K. Stamp, Tony R. Merriman, Nicola Dalbeth and Owen M. Woodward ()
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Kazi Mirajul Hoque: University of Maryland School of Medicine
Eryn E. Dixon: University of Maryland School of Medicine
Raychel M. Lewis: University of Maryland School of Medicine
Jordyn Allan: University of Auckland
Gregory D. Gamble: University of Auckland
Amanda J. Phipps-Green: University of Otago
Victoria L. Halperin Kuhns: University of Maryland School of Medicine
Anne M. Horne: University of Auckland
Lisa K. Stamp: University of Otago
Tony R. Merriman: University of Otago
Nicola Dalbeth: University of Auckland
Owen M. Woodward: University of Maryland School of Medicine

Nature Communications, 2020, vol. 11, issue 1, 1-15

Abstract: Abstract The pathophysiological nature of the common ABCG2 gout and hyperuricemia associated variant Q141K (rs2231142) remains undefined. Here, we use a human interventional cohort study (ACTRN12615001302549) to understand the physiological role of ABCG2 and find that participants with the Q141K ABCG2 variant display elevated serum urate, unaltered FEUA, and significant evidence of reduced extra-renal urate excretion. We explore mechanisms by generating a mouse model of the orthologous Q140K Abcg2 variant and find male mice have significant hyperuricemia and metabolic alterations, but only subtle alterations of renal urate excretion and ABCG2 abundance. By contrast, these mice display a severe defect in ABCG2 abundance and function in the intestinal tract. These results suggest a tissue specific pathobiology of the Q141K variant, support an important role for ABCG2 in urate excretion in both the human kidney and intestinal tract, and provide insight into the importance of intestinal urate excretion for serum urate homeostasis.

Date: 2020
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DOI: 10.1038/s41467-020-16525-w

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