Characterization of a Compound Heterozygous SLC2A9 Mutation That Causes Hypouricemia

• Main Authors: Jaeho Yoon, Raul Cachau, Victor A. David, Mary Thompson, Wooram Jung, Sun-Ha Jee, Ira O. Daar, Cheryl A. Winkler, Sung-Kweon Cho
• Format: Article
• Language: English
• Published: MDPI AG 2021-09-01
• Series: Biomedicines
• Subjects: <i>SLC2A9</i>; hypouricemia
• Online Access: https://www.mdpi.com/2227-9059/9/9/1172
• ISSN: 2227-9059

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 <i>SLC2A9</i> (voltage-sensitive uric acid transporter) in the whole-exome sequencing (WES) results. Molecular dynamics prediction suggests that the novel mutation p.Met126Val in <i>SLCA9b</i> (p.Met155Val in <i>SLC2A9a)</i> hinders uric acid transport through a defect of the outward open geometry. Molecular analysis using <i>Xenopus</i> oocytes confirmed that the p.Met126Val mutation significantly reduced uric acid transport but does not affect the <i>SLC2A9</i> protein expression level. Our results will shed light on a better understanding of <i>SLC2A9</i>-mediated uric acid transport and the development of a uric acid-lowering agent.