Session Type: ACR Concurrent Abstract Session
Session Time: 9:00AM-10:30AM
Gout is a common arthritic disease resulting from deposition of monosodium urate crystals in joints and is a consequence of having elevated circulating uric acid (UA) levels (hyperuricemia). Previously, we discovered that ABCG2 codes a high-capacity UA efflux transporter, that when dysfunctional causes hyperuricemia and significantly increases the risk for gout. Recent work from others has demonstrated ABCG2 mediated secretion is important in extra-renal, specifically, intestinal excretion of UA. Although ABCG2 is thought to be important for both renal and extra-renal UA excretion, in human cohort studies, ABCG2 dysfunction confers a disproportionate risk for the Renal Overload (ROL) type of hyperuricemia (Matsuo et al 2014), a finding highlighting a disconnect in our understanding of the ABCG2 risk alleles and extra-renal UA excretion.
To study the molecular and physiological consequences of a common gout causing ABCG2 mutation on intestinal UA excretion, we created a mouse model of the Q141K mutation (Q140K in mouse) using CRISPR Cas9 gene editing techniques on a C57BL6 mouse background.
In a comparison of wildtype and mutant litter mates, we found in the wild type mice ABCG2 expression varies along the GI track with the highest levels in the jejunum and ileum, but surprisingly low levels in the colon. These data are consistent with the observed low level of ABCG2 expression in the human colonic Caco-2 cell line. The localization of the wild type ABCG2 protein was exclusive to the brush border of villus cells and luminal membrane of the crypt cells, optimized to facilitate UA secretion into the intestinal lumen. In contrast, both one or two copies of the Q140K Abcg2 allele resulted in significant decreases (53% and 88% respectively) in total intestinal expression and apical membrane staining in villus cells. Using an intestinal ligation loop model, we tested the acute UA secretion of the small intestines and found the Q140K mutation reduced UA flux 40%. The reduction in the UA flux in the Q140K loop model was comparable to the reduction observed when the wild type ABCG2 loop was treated with the ABCG2 inhibitor FTC (30%), suggesting the Q140K mutation approximates a complete loss of ABCG2 function in the small intestines.
We conclude that the Q141K gout causing ABCG2 mutation (Q140K mouse) results in severe loss of ABCG2 mediated UA secretion in the small intestine, contrary to the current dogma that the Q141K ABCG2 is a less severe mutation with only partial (50%) loss of function. Our findings illustrate a potential explanation as to why just one copy of the Q141K ABCG2 allele dramatically increases risk of the ROL type of hyperuricemia.
To cite this abstract in AMA style:Hoque KM, Woodward OM. New Mouse Model of Gout Risk Variant, ABCG2 Q141K, Reveals Unexpectedly Severe Molecular and Functional Defect in ABCG2 Mediated Intestinal Uric Acid Secretion [abstract]. Arthritis Rheumatol. 2017; 69 (suppl 10). https://acrabstracts.org/abstract/new-mouse-model-of-gout-risk-variant-abcg2-q141k-reveals-unexpectedly-severe-molecular-and-functional-defect-in-abcg2-mediated-intestinal-uric-acid-secretion/. Accessed September 22, 2020.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/new-mouse-model-of-gout-risk-variant-abcg2-q141k-reveals-unexpectedly-severe-molecular-and-functional-defect-in-abcg2-mediated-intestinal-uric-acid-secretion/