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2007 Fiscal Year Final Research Report Summary

Clarification of molecular bases involved in 46, XX disorders development in patients with cytochrome P450 oxidoreductase deficiency

Research Project

Project/Area Number 18591178
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Pediatrics
Research InstitutionNational Research Institute for Child Health and Development

Principal Investigator

FUKAMI Maki  National Research Institute for Child Health and Development, National Research Institute for Child Health and Development, Deptarment of Perinatal Pathophysiololgy, Laboratory Chief (40265872)

Co-Investigator(Kenkyū-buntansha) HASEGAWA Tomonobu  Keio University, 医学部・小児科, Associate Professor (20189533)
Project Period (FY) 2006 – 2007
KeywordsCytochrome P450 Oxidoreductase / Steroidogenesis / 46, XX DSD / Endocrinology / Urine steroid hormone analysis
Research Abstract

1. Genotype-phenotype correlation of cytochrome P450 oxidoreductase(POR) deficiency(PORD) Clinical and molecular studies were performed on 33 Japanese cases with PORD. A total of 12 mutations were identified, with R457H accounting for 〜70% of mutant alleles. Clinical features of 33 cases included abnormal skeletal development and adrenal dysfunction in patients of both sexes, undermasculinization during fetal and pubertal periods in male patients(46, XY disorders of sex development; 46, XY DSD), and virilization during fetal life and poor pubertal development in female patients(46, XX DSD) Genotype-phenotype correlation analysis revealed that skeletal abnormalities clearly depended on mutation types, and adrenal dysfunction and 46, XY DSD were partially correlated to the genotypes. By contrast, 46, XX DSD were present in almost all cases irrespectively to mutation types.
2. Urine Steroid hormone analysis To obtain evidence for the presence of an alternative pathway for androgen synthesi … More s(the "backdoor" pathway) in PORD, urine steroid profile analysis was performed by gas chromatography/mass spectrometry. In the PORD patients, the urine steroid ratios reflecting CYP17A1 and CYP21A2 activities were decreased throughout the examined age. Furthermore, etiocholanolone and 11-hydroxyandrosterone, that should originate almost exclusively in the conventional "frontdoor" pathway, were grossly normal or somewhat decreased since early infancy, whereas androsterone, that can derive not only via the conventional "frontdoor" pathway but also from 5α- pregnane-3α, 17α-diol-20-one in the "backdoor" pathway, was increased during the early infancy and remained grossly normal thereafter. Thus, the androsterone/etiocholanolone ratio was increased during the early infancy and remained grossly normal thereafter. The increased androsterone excretion as compared with the etiocholanolone and 11-hydroxyandrosterone excretions in the early infancy would suggest the presence of the "backdoor" pathway.
3. Conclusion The present study suggests that 46, XX DSD in POR would be ascribed to defective androgen conversion in the placenta due to aromatase deficiency, and androgen overproduction via the "backdoor pathway". Less

  • Research Products

    (16 results)

All 2008 2007 2006

All Journal Article (10 results) (of which Peer Reviewed: 3 results) Presentation (6 results)

  • [Journal Article] Mastermind-like domain-containing 1 (MAMLD1 or CXorf6) transactivates the Hes3 promoter, augments testosterone production, and contains the SF1 target sequence.2008

    • Author(s)
      Fukami M, Ogata T., et. al.
    • Journal Title

      J Biol Chem. 283(9)

      Pages: 5525-5532.

    • Description
      「研究成果報告書概要(和文)」より
    • Peer Reviewed
  • [Journal Article] Mastermind-like domain-containing 1(MAMLD1 or CXorf6) transactivates the Hes3 promoter, augments testosterone production, and contains the SF1 target sequence.2008

    • Author(s)
      Fukami M, Wada Y, Okada M, Kato F, Katsumata N, Baba T, Morohashi K, Laporte J, Kitagawa M, Ogata T.
    • Journal Title

      J Biol Chem29 283(9)

      Pages: 5525-32

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Urine steroid hormone profile analysis in cytochrome P450 oxidoreductase deficiency: implication for the backdoor pathway to dihydrotestosterone.2006

    • Author(s)
      Homma K, Hasegawa T, Fukami M, et. al.
    • Journal Title

      J Clin Endocrinol Metab 91(7)

      Pages: 2643-2649

    • Description
      「研究成果報告書概要(和文)」より
    • Peer Reviewed
  • [Journal Article] Association of cryptorchidism with Gly146Ala polymorphism in the gene for steroidogenic factor-1.2006

    • Author(s)
      Wada Y, Fukami M, et. al.
    • Journal Title

      Fertil Steril 85(3)

      Pages: 787-790

    • Description
      「研究成果報告書概要(和文)」より
    • Peer Reviewed
  • [Journal Article] P450 oxidoreductase (POR) 遺伝子異常症.2006

    • Author(s)
      緒方勤、本間桂子、深見真紀
    • Journal Title

      ホルモンと臨床 54

      Pages: 523-530

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Cytochrome P450 oxidoreductase (POR) 異常症患者13家系17例における分子遺伝学的および臨床的解析.2006

    • Author(s)
      深見真紀、緒方勤
    • Journal Title

      ホルモンと臨床増刊号 54

      Pages: 167-172

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Urine steroid hormone profile analysis in cytochrome P450 oxidoreductase deficiency : implication for the backdoor pathway to dihydrotestosterone.2006

    • Author(s)
      Homma K, Hasegawa T, Nagai T, Adachi M, Horikawa R, Fujiwara I, Tajima T, Takeda R, Fukami M, Ogata T.
    • Journal Title

      J Clin Endocrinol Metab 91(7)

      Pages: 2643-9

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Association of cryptorchidism with Gly146Ala polymorphism in the gene for steroidogenic factor-1.2006

    • Author(s)
      Wada Y, Okada M, Fukami M, Sasagawa I, Ogata T.
    • Journal Title

      Fertil Steril 85(3)

      Pages: 787-790

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] POR deficiency. (in Japanese)2006

    • Author(s)
      Ogata T, Homma K, Fukami M.
    • Journal Title

      Clinical Endocrinology 54

      Pages: 523-530

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Molecular and clinical analysis on 17 patients with POR deficiency. (in Japanese)2006

    • Author(s)
      Fukami M, Ogata T.
    • Journal Title

      Clinical Endocrinology 54

      Pages: 167-175

    • Description
      「研究成果報告書概要(欧文)」より
  • [Presentation] Genotype-Phenotype correlations in 29 patients with POR deficiency: Implications for the presence of the "backdoor pathway"2008

    • Author(s)
      Fukami M, et. al.
    • Organizer
      17th Clinical Endocrinology Update
    • Place of Presentation
      Tokyo, Japan
    • Year and Date
      2008-03-10
    • Description
      「研究成果報告書概要(欧文)」より
  • [Presentation] POR異常症:29例における遺伝子型-表現型解析と臨床スペクトラムの検討2007

    • Author(s)
      深見真紀, 他
    • Organizer
      第41回日本小児内分泌学会
    • Place of Presentation
      横浜
    • Year and Date
      2007-11-07
    • Description
      「研究成果報告書概要(和文)」より
  • [Presentation] Genotype-Phenotype correlations in 29 patients with POR deficiency.2007

    • Author(s)
      Fukami M, et. al.
    • Organizer
      49th annual meeting of Japanese society of pediatric endocrinology
    • Place of Presentation
      Yokohama, Japan
    • Year and Date
      2007-11-07
    • Description
      「研究成果報告書概要(欧文)」より
  • [Presentation] The Novel Hypospadias Gene CXorf6 Transactivates the Promoter of a Non-Canonical Notch Target Gene Hes3 and Contains the Target Sequence for SF-12007

    • Author(s)
      Fukami M, et. al.
    • Organizer
      Endocrine society's 89^<th> annual meeting
    • Place of Presentation
      Toronto (Canada)
    • Year and Date
      2007-06-02
    • Description
      「研究成果報告書概要(和文)」より
  • [Presentation] The Novel Hypospadias Gene CXorf6 Transactivates the Promoter of a Non-Canonical Notch Target Gene Hes3 and Contains the Target Sequence for SF-12007

    • Author(s)
      Fukami M, et. al.
    • Organizer
      Endocrine society's 89th annual meeting.
    • Place of Presentation
      Toronto, Canada
    • Year and Date
      2007-06-02
    • Description
      「研究成果報告書概要(欧文)」より
  • [Presentation] POR異常症における表現型の決定因子:遺伝子型と胎児期特異的男性ホルモン産生経路(backdoor pathway)2007

    • Author(s)
      深見真紀, 他
    • Organizer
      第17回臨床内分泌代謝Updateクリニカルアワー
    • Place of Presentation
      東京
    • Year and Date
      2007-03-10
    • Description
      「研究成果報告書概要(和文)」より

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Published: 2010-02-04  

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