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Genetic analysis for mechanism of underexcretion type hyperuricemia

Research Project

Project/Area Number 14571041
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Kidney internal medicine
Research InstitutionJikei University School of Medicine

Principal Investigator

ICHIDA Kimiyoshi  The Jikei University School of Medicine, Lecturer, 医学部, 講師 (80183169)

Co-Investigator(Kenkyū-buntansha) HOSOYAMADA Makoto  Kyorin University, Medicine, Lecturer, 医学部, 講師 (00291659)
Project Period (FY) 2002 – 2004
Project Status Completed (Fiscal Year 2004)
Budget Amount *help
¥2,900,000 (Direct Cost: ¥2,900,000)
Fiscal Year 2004: ¥1,100,000 (Direct Cost: ¥1,100,000)
Fiscal Year 2003: ¥900,000 (Direct Cost: ¥900,000)
Fiscal Year 2002: ¥900,000 (Direct Cost: ¥900,000)
KeywordsUrate / URAT1 / Renal hypouricemia / SLC22A12 / ベンズブロマロン / プロベネシド / SLCA22A12
Research Abstract

Urate is reabsorbed and secreted bilaterally at the apical membrane in the tubules. We cloned urate transporter 1(URAT1 encoded by SLC22A12), located at the apical membrane in the proximal tubules. The estimated Michaelis constant (Km) for urate was 371±28mM. We found that the urate transport via URAT1 is inhibited selectively by organic anions such as lactate, nicotinate, acetoacetate, hydroxybutyrate and succinate. Aromatic monocarboxylates such as pyrazinecarboxylic acid, nicotinate and orotate at 1mM inhibited urate uptake more effectively than aliphatic monocarboxylates such as lactate. We also tested the influence of uricosuric substances known to reduce hyperuricemia. Probenecid, phenylbutazone, sulphinpyrazone, nonsteroidal anti-inflammatory drugs, and diuretic drugs at 1mM cis inhibited urate uptake ; benzbromarone was the most potent, completely inhibiting urate uptake at 50mM, with a 50%-inhibitory concentration(IC50) of less than 0.1mM.
We also demonstrated that URAT1 regula … More tes serum urate levels by showing that patients with renal hypouricemia have defects in SLC22A12. Renal hypouricemia is a heterogeneous disorder characterized by impaired tubular urate transport. We elucidated genetic features of renal hypouricemia and the significance of URAT1 in maintaining serum urate levels in vivo using 32 unrelated patients. Thirty out of 32 patients had SLC22A12 mutations (93.8%), while 2 patients had none in the URAT1-coding region. We detected SLC22A12 mutations in 54 out of 64 alleles (84.4 %). Ten mutations in SLC22A12 were identified. Mutations included two nonsense mutations, one splice-site mutation, a 5-bp deletion and 6 missense mutations. The G774A mutation was identified in 40 out of 54 affected SLC22A12 alleles (74.1 %). All of the missense mutations and the 5-bp deletion (1639-1643delGTCCT) were tested for urate transport activity by in vitro expression analysis in Xenopus oocytes. The urate transports of all URAT1 mutants were significantly decreased and similar to that of oocytes that were not injected with URAT1 cRNA. Less

Report

(4 results)
  • 2004 Annual Research Report   Final Research Report Summary
  • 2003 Annual Research Report
  • 2002 Annual Research Report
  • Research Products

    (19 results)

All 2004 2003 2002 Other

All Journal Article (12 results) Publications (7 results)

  • [Journal Article] Clinical and molecular analysis of patients with renal hypouricemia in Japan -influence of URAT1 gene on urinary urate excretion-.2004

    • Author(s)
      Ichida K et al.
    • Journal Title

      J Am Soc Nephrol. 15・1

      Pages: 164-173

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Function and localization of urate transporter 1 in mouse kidney.2004

    • Author(s)
      Hosoyamada M et al.
    • Journal Title

      J Am Soc Nephrol 15・2

      Pages: 261-268

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] A high prevalence of renal hypouricemia caused by inactive SLC22A12 in Japanese.2004

    • Author(s)
      Iwai N et al.
    • Journal Title

      Kidney Int 66・3

      Pages: 935-944

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Annual Research Report 2004 Final Research Report Summary
  • [Journal Article] Clinical and molecular analysis of patients with renal hypouricemia in Japan -influence of URAT1 gene on urinary urate excretion-2004

    • Author(s)
      Ichida K et al.
    • Journal Title

      J Am Soc Nephrol 15-1

      Pages: 164-173

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Function and localization of urate transporter 1 in mouse kidney.2004

    • Author(s)
      Hosoyamada M et al.
    • Journal Title

      J Am Soc Nephrol 15-2

      Pages: 261-268

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] A high prevalence of renal hypouricemia caused by inactive SLC22A12 in Japanese.2004

    • Author(s)
      Iwai N et al.
    • Journal Title

      Kidney Int 66-3

      Pages: 935-944

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Urate transport via human PAH transporter hOAT1 and its gene structure.2003

    • Author(s)
      Ichida K et al.
    • Journal Title

      Kidney Int 63・1

      Pages: 143-155

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Urate transport via human PAH transporter hOAT1 and its gene structure.2003

    • Author(s)
      Ichida K et al.
    • Journal Title

      Kidney Int 63-1

      Pages: 143-155

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Molecular identification of a renal urate anion exchanger that regulates blood urate levels.2002

    • Author(s)
      Enomoto A et al.
    • Journal Title

      Nature 417・6887

      Pages: 447-452

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Familial juvenile gouty nephropathy : exclusion of 16p12 from the candidate locus.2002

    • Author(s)
      Ohno I et al.
    • Journal Title

      Nephron 92・3

      Pages: 573-575

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Molecular identification of a renal urate anion exchanger that regulates blood urate levels.2002

    • Author(s)
      Enomoto A et al.
    • Journal Title

      Nature 417-6887

      Pages: 447-452

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Familial juvenile gouty nephropathy : exclusion of 16p12 from the candidate locus.2002

    • Author(s)
      Ohno I et al.
    • Journal Title

      Nephron 92-3

      Pages: 573-575

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Publications] Ichida K.: "Clinical and molecular analysis of patients with renal hypouricemia in Japan-influence of URAT1 gene on urinary urate excretion."J Am Soc Nephrol. 15. 164-173 (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Hosoyama M.: "Function and localization of urate transporter 1 in mouse kidney."J Am Soc Nephrol. 15. 261-268 (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Gok F.: "Mutational analysis of the xanthine dehydrogenase gene in a Turkish family with autosomal recessive classical xanthinuria."Nephrol Dial Transplant. 18. 2278-2283 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Enomoto A.: "Molecular identification of a renal urate anion exchanger that regulates blood urate levels"Nature. 417. 447-452 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Kimura H.: "Human organic anion transporters and human organic cation transporters mediate renal transport of prostaglandins"J Pharmacol Exp Ther. 301. 293-298 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Ohno I.: "Familial juvenile gouty nephropathy : exclusion of 16p12 from the candidate locus"Nephron. 92. 573-575 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Ichida K.: "Urate transport via human PAH transporter hOAT1 and its gene structure"Kidney Int. 63. 143-155 (2003)

    • Related Report
      2002 Annual Research Report

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Published: 2002-04-01   Modified: 2016-04-21  

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