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Characterization of a Compound Heterozygous SLC2A9 Mutation That Causes Hypouricemia

  1. Author:
    Yoon,Jaeho [ORCID]
    Cachau,Raul
    David,Victor
    Thompson,Mary
    Jung, Wooram
    Jee, Sun-Ha
    Daar,Ira [ORCID]
    Winkler,Cheryl
    Cho, Sung-Kweon

  2. Author Address

    Cancer & Developmental Biology Laboratory, Center for Cancer Research, National Cancer Institute, Frederick, MD 21701, USA., Advanced Biomedical Computational Science, Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, MD 21701, USA., Molecular Genetic Epidemiology Section, Basic Research Laboratory, National Cancer Institute, Frederick, MD 21701, USA., Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA., Department of Epidemiology and Health Promotion, Institute for Health Promotion, Graduate School of Public Health, Yonsei University College of Medicine, Seoul 03722, Korea., Department of Pharmacology, Ajou University School of Medicine, 164, Worldcup-ro, Yeongtong-gu, Suwon 16499, Korea.,
    1. Year: 2021
    2. Date: Sep 06
  2. Journal: Biomedicines
    1. 9
    2. 9
  4. Type of Article: Article
  5. Article Number: 1172
  6. ISSN: 2227-9059
  1. 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.

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External Sources

  1. View Full Text
  2. DOI: 10.3390/biomedicines9091172
  3. PMID: 34572357
  4. PMCID: PMC8471325
  5. View record in Web of Science®
  6. WOS: 000699048800001
  7. PII : biomedicines9091172

Library Notes

  1. Open Access Publication
  2. Fiscal Year: FY2020-2021
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