Characterization of a Compound Heterozygous SLC2A9 Mutation That Causes Hypouricemia.

Jaeho Yoon,Wooram Jung,Ira O Daar,Raul Cachau,Sung-Kweon Cho,Mary Thompson,Victor A David,Cheryl A Winkler,Sun-Ha Jee

doi:10.3390/biomedicines9091172

Abstract

Renal hypouricemia is a rare genetic disorder. Hypouricemia can present as renal stones or exercise-induced acute renal failure, but most cases are asymptomatic. Our previous study showed that two recessive variants of SLC22A12 (p.Trp258*, pArg90His) were identified in 90% of the hypouricemia patients from two independent cohorts: the Korean genome and epidemiology study (KoGES) and the Korean Cancer Prevention Study (KCPS-II). In this work, we investigate the genetic causes of hypouricemia in the rest of the 10% of unsolved cases. We found a novel non-synonymous mutation of SLC2A9 (voltage-sensitive uric acid transporter) in the whole-exome sequencing (WES) results. Molecular dynamics prediction suggests that the novel mutation p.Met126Val in SLCA9b (p.Met155Val in SLC2A9a) hinders uric acid transport through a defect of the outward open geometry. Molecular analysis using Xenopus oocytes confirmed that the p.Met126Val mutation significantly reduced uric acid transport but does not affect the SLC2A9 protein expression level. Our results will shed light on a better understanding of SLC2A9-mediated uric acid transport and the development of a uric acid-lowering agent.

Highlights

The homeostasis of serum uric acid (SUA) levels can be achieved by the dynamic processes of production and elimination
We identify a novel variant in SLC2A9 by whole-exome sequencing (WES) of the unsolved cases of hypouricemia
The corresponding residues for SLC2A9b are p.Met126Val and p.Arg351Gly, respectively. p.Arg380Gly was previously reported by HGMD (The Human Gene Mutation Database)

Summary

Introduction

The homeostasis of serum uric acid (SUA) levels can be achieved by the dynamic processes of production and elimination. Hypouricemia, with a low uric acid level, is defined as an SUA concentration < 2 mg/dL. Hypouricemia is generally asymptomatic in the general population; most hypouricemia patients are identified by chance in regular health examinations [1]. Renal hypouricemia (RUHC) is a rare genetic disorder diagnosed by hypouricemia and increased fractional excretion of uric acid (UA > 10%) [2]. RHUC is sometimes accompanied by severe complications, such as exercise-induced acute kidney injury (EIAKI) and urolithiasis [3]. In the case of urolithiasis, RUHC is 6–7 times more prevalent than in those with normal levels of SUA [4]

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Results

Conclusion