Background/Purpose: ABCG2 is a high-capacity urate transporter gene. Common dysfunctional variants of ABCG2 that result in decreased urate excretion in humans are major causes of hyperuricemia and gout – especially in pediatric-onset patients [1]. In the present study, we identified and functionally characterized a novel ABCG2 variant in a family with early-onset hyperuricemia and gout.

Methods: Fifty-three years old woman was examined for intermittent pain of distal interphalangeal joints and plants of non-inflammatory character. At age of 9, she was found to have hyperuricemia and then she started a strict low-purine diet. Nor medical reports either the levels of uric acid from that period are unfortunately available. At clinical examination, Heberden´s nodes and palpable resistance on plants were observed. In laboratory findings, there was a slightly elevated level of uric acid (371 μmol/L) and low level of vitamin D in her serum. Her son, a 33-year-old man, has the first gout attack at the age of 30 in the first metatarsal joint and since then the gout attack repeats twice a year. In biochemical characterization, hyperuricemia (569 μmol/L of uric acid), hyperglycaemia (5.9 mmol/L of glucose) and low level of vitamin D were found.

To explore the cause of this familial hyperuricemia and gout, we performed a metabolic investigation. The results of purine metabolism suggested that their hyperuricemia were mainly due to a defect in the urate excretion system and did not result from an excess production of urate. Based on two separate measurements of the patients’ fractional excretion of urate and urinary urate excretion, their hyperuricaemia could be classified as renal underexcretion type. Since this type of hyperuricemia is reportedly related to ABCG2 dysfunction, we analyzed ABCG2 coding regions of our patients using their genomic DNA, as described previously [2].  Prediction of the possible impact of allelic variant on protein function was determined using PolyPhen, Provean, Mutation Taster, and SIFT predictive software. Functional validation of an ABCG2 variant we found was performed using ABCG2-expressing plasma membrane vesicles as we report previously [3].

Results: We identified a novel heterozygous variant c.725T >C (p.I242T) in ABCG2 gene in the proband and her son. In silico predictions of the possible impact of this variant on protein function were consistent as strong deleterious. Cell-based functional assays showed that this novel variant has little effect on the expression and subcellular localization of ABCG2 protein, whereas I242T variant had no urate transport activity.

Conclusion: In conclusion, our findings suggest a causal relationship between the hitherto undescribed variant of ABCG2 and very early familiar onset of hyperuricemia/gout.  Our identification of novel dysfunctional ABCG2 variant confirmed a key role of ABCG2 transporter as a a key genetic determinant in the onset of hyperuricemia/gout.

References

1. Stiburkova B, et al. Arthritis Res Ther. 2019 Mar 20;21(1):77.
2. Stiburkova B, et al. Rheumatology (Oxford). 2017 Nov 1;56(11):1982-1992.
3. Toyoda Y, et al. Cells. 2019 Apr 18;8(4). pii: E363.

Supported by the grant from the Czech Republic Ministry of Health: AZV 15-26693A.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/identification-and-characterization-of-a-novel-dysfunction-variant-p-i242t-in-abcg2-transporter-in-a-family-with-early-onset-hyperuricamia-and-gout/