Functional Characterization of Clinically-Relevant Rare Variants in ABCG2 Identified in a Gout and Hyperuricemia Cohort.

Toyoda Toyoda,Pavlíková Pavlíková,Pavelka Pavelka,Matsuo Matsuo,Stiburkova Stiburkova,Suzuki Suzuki,Krylov Krylov,Bohatá Bohatá,Pavelcová Pavelcová,Morimoto Morimoto,Takada Takada,Mančíková Mančíková

doi:10.3390/cells8040363

Abstract

ATP-binding cassette subfamily G member 2 (ABCG2) is a physiologically important urate transporter. Accumulating evidence demonstrates that congenital dysfunction of ABCG2 is an important genetic risk factor in gout and hyperuricemia; recent studies suggest the clinical significance of both common and rare variants of ABCG2. However, the effects of rare variants of ABCG2 on the risk of such diseases are not fully understood. Here, using a cohort of 250 Czech individuals of European descent (68 primary hyperuricemia patients and 182 primary gout patients), we examined exonic non-synonymous variants of ABCG2. Based on the results of direct sequencing and database information, we experimentally characterized nine rare variants of ABCG2: R147W (rs372192400), T153M (rs753759474), F373C (rs752626614), T421A (rs199854112), T434M (rs769734146), S476P (not annotated), S572R (rs200894058), D620N (rs34783571), and a three-base deletion K360del (rs750972998). Functional analyses of these rare variants revealed a deficiency in the plasma membrane localization of R147W and S572R, lower levels of cellular proteins of T153M and F373C, and null urate uptake function of T434M and S476P. Accordingly, we newly identified six rare variants of ABCG2 that showed lower or null function. Our findings contribute to deepening the understanding of ABCG2-related gout/hyperuricemia risk and the biochemical characteristics of the ABCG2 protein.

Highlights

Gout—a common disease with increasing global occurrence, typically causing severe pain and physical disability—results from hyperuricemia characterized by elevated serum uric acid (SUA)Cells 2019, 8, 363; doi:10.3390/cells8040363 www.mdpi.com/journal/cellsCells 2019, 8, 363 concentrations [1]
Considering that ATP-binding cassette subfamily G member 2 (ABCG2) is one of the most influential genetic risk factors for gout and hyperuricemia, we examined a relationship between non-synonymous mutations in ABCG2 and the risk of such diseases in our gout/hyperuricemia cohort
Considering that a previous study with a small cohort had found only borderline significance (P = 0.053) for this association [23], our result can be considered to be a strength of this study. These findings suggest the epidemiological importance of ABCG2 common and rare variants for gout/hyperuricemia risk in the Czech population, supporting a “Common Disease, Multiple Common and Rare variant” hypothesis for the association between ABCG2 and gout, which was proposed in our previous study on Japanese gout patients [22]

Summary

Introduction

Gout—a common disease with increasing global occurrence, typically causing severe pain and physical disability—results from hyperuricemia characterized by elevated serum uric acid (SUA)Cells 2019, 8, 363; doi:10.3390/cells8040363 www.mdpi.com/journal/cellsCells 2019, 8, 363 concentrations [1]. Gout—a common disease with increasing global occurrence, typically causing severe pain and physical disability—results from hyperuricemia characterized by elevated serum uric acid (SUA). Uric acid accumulation in the body causes hyperuricemia and subsequently increases the risk of gout. Not all individuals with hyperuricemia develop symptomatic gout, the risk of gout increases in proportion to the elevation of urate in circulation. Humans do not have a functional uricase (urate-degrading enzyme) [2], so uric acid is the final metabolite in the purine catabolic pathway in humans. Urate excretion from the body is necessary for the maintenance of uric acid homeostasis. Accumulating evidence suggests that the net amount of excreted uric acid is regulated mainly by urate transporters, such as urate transporter 1

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