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Cloning of the Causative Gene for Type II Cystinuria

Research Project

Project/Area Number 13470330
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Urology
Research InstitutionChiba University

Principal Investigator

ITO Haruo  Chiba University, Graduate School of Medicine, Professor, 大学院・医学研究院, 教授 (20009583)

Project Period (FY) 2001 – 2003
Project Status Completed (Fiscal Year 2003)
Budget Amount *help
¥7,300,000 (Direct Cost: ¥7,300,000)
Fiscal Year 2003: ¥1,700,000 (Direct Cost: ¥1,700,000)
Fiscal Year 2002: ¥2,200,000 (Direct Cost: ¥2,200,000)
Fiscal Year 2001: ¥3,400,000 (Direct Cost: ¥3,400,000)
KeywordsCystinuria / Cystinuria gene / R BAT gene / BAT1 gene / Urinary excretion of cystine / Stone recurrence / Order-made medicine / Gene therapy / rBAT遺伝子 / BAT2
Research Abstract

In 1992, the rBAT gene was identified as a causative gene for cystinuria. We discovered 5 new mutations of the rBAT gene in type I cystinuria in 43 patients. In 1999, we identified BAT1 as a causative gene in non-type I cystinuria. The BAT1 protein is an approximately 40-kDa protein that encodes 487 amino acids. In humans, BAT1 mRNA was shown to be present in the renal proximal tubular lumen.
Functional studies suggest that the 2 molecules encoded by the rBAT and BAT1 genes are dimeric membrane proteins on renal tubular luminal membranes that function as cystine transporters. An analysis of the BAT1 gene in 41 patients detected 7 mutations. In 2 patients, there were no mutations of either gene. A high frequency of a P482L (PRO 482 to LEU) missense mutation in the BAT1 gene was detected in 31 of 35 patients (about 90%).
This mutation in the intracytoplasmic C terminus of the BAT protein, specifically 6 amino acids before the stop codon, causes a decrease in cystine absorption. Rather than a change in the structure of the protein itself, there is inhibition or regulatory factor binding. This leads to sorting abnormalities to luminal cell membranes. The P482L mutation has not been reported in genetic analysis in Westerners. This is a "hot spot" mutation for cystinuria in Japanese patients. Correlation of clinical findings with these gene mutations shows that patients with type I cystinuria have a lower incidence of stone recurrence and lower urinary excretion of cystine than those with non-type I cystinuria. Therefore, genetic diagnosis to predict discase severity can be clinically useful not only in preventing stone recurrence in known cases, but also in preventing the onset of disease in asymptomatic carriers.

Report

(4 results)
  • 2003 Annual Research Report   Final Research Report Summary
  • 2002 Annual Research Report
  • 2001 Annual Research Report
  • Research Products

    (28 results)

All Other

All Publications (28 results)

  • [Publications] 伊藤晴夫: "栄養学的にみた尿路結石症"ホルモンと臨床. 49-1. 23-30 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] 伊藤晴夫: "腎結石の病態解明に向けての新展開"泌尿器科外科. 14. 399-404 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Mizoguchi K: "Human cystinuria-related transporter : Localization and functional characterization"Kindly International. 59. 1821-1833 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Masanari Ishihara: "Cystine Transport Activity of Heterozygous rBAT Mutants Expressed in Xenopus Oocytes"Nephron. 91. 276-280 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] 伊藤晴夫: "シスチン尿症"小児内科. 34. 824-826 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] 伊藤晴夫: "シスチン尿症の最近の知見 原因遺伝子の同定から臨床応用へ"日医雑誌. 130. 293-297 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] 伊藤晴夫: "尿路結石症診療ガイドライン"金原出版(株). 87 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] 伊藤晴夫: "今日の治療指針"(株)医学書院. 1 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] 伊藤晴夫: "尿路結石症 泌尿器科ナースの疾患別ケアハンドブック"メデイカ出版. 28 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] 伊藤晴夫: "予防から最新治療まで 尿路結石症を治す"(株)法研. 190 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Haruo Ito: "Nutrition and Urolithiasis"Clinical endocrinology. 49. 23-30 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Haruo Ito: "Elucidation of the cause of kidney stone formation"Japanese Journal of Urological Surgery. 14. 399-404 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Mizoguchi K: "Human cystinuria-related transporter : Localization and functional characterization"Kindly International. 59. 1821-1833 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Masanari Ishihara: "Cystine Transport Activity of Heterozygous rBAT Mutants Expressed in Xenopus Oocytes"Nephron. 91. 276-280 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Haruo Ito: "Japanese Journal of Pediatric Medicine"Cystinuria. 34(Supplement). 824-826 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Haruo Ito: "Recent advance of cystinuria research"The Journal of the Japan Medical Association. 130. 293-297 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Haruo Ito: "Guideline for urolithiasis practice (editorial member), Japanese Journal of Endourology and Japanese Association of Urolithiasis Research"The Japanese Urological Association. 87 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Haruo Ito: "Today's therapy 45, Kidney. ureter. bladder stone"744 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Haruo Ito: "Urolithiasis ; Handbook for urological nurses"196-223 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Haruo Ito: "Urolithiasis ; From prevention to latest therapy."Houkenn Shuppann. 190 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] 伊藤晴夫, 茂田安弘, 植田健: "シスチン尿症の最近の知見 原因遺伝子の同定からの臨床応用へ"日医雑誌. 130巻第2号. 293-297 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] 伊藤晴夫: "尿路結石症を治す"(株)法研. 190 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Y.Naya, et al.: "Association of dietary fatty acids with urinary oxalate excretion in calcium oxalate stone-formers in their fourth decade"BJU International. 89. 842-846 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Masanari Ishihara, et al.: "Cystine Transport Activity of Heterozygous rBAT Mutants Expressed in Xenopus Oocytes"Nephron. 91. 276-280 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] TAKAOMI KODAMA, et al.: "Detection and identification of oxalate-degrading bacteria in human feces"International Journal of Urology. 9. 392-397 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] 伊藤 晴夫: "シスチン尿症"小児内科. 34巻増刷号. 824-826 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] 伊藤 晴夫外: "尿路結石症診療ガイドライン 日本泌尿器科学会/日本Endourology・ESWL学会/日本尿路結石症学会編"金原出版株式会社. 87 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Ken'ichi Mizoguchi et al.: "Human cystinuria-related transporter:Localization and functional characterization"Kidney International. Vol.59. 1821-1833 (2001)

    • Related Report
      2001 Annual Research Report

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Published: 2001-04-01   Modified: 2016-04-21  

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