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STRUCTURE-FUNCTION ANALYSIS OF DAX-1 USING Molecular analysis

Research Project

Project/Area Number 09470176
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Pediatrics
Research InstitutionHokkaido University

Principal Investigator

FUJIEDA kenji  Hokkaido University Hospital, Lecturer, 医学部・附属病院, 講師 (60173407)

Co-Investigator(Kenkyū-buntansha) MOROHASHI Kenichirou  National Institute of Basic Biology, Professor, 基礎生物学研究所・形質統御実験施設, 教授 (30183114)
SAITOH Shinji  Hokkadio University Hospital, Assistant, 医学部・附属病院, 助手 (00281824)
Project Period (FY) 1997 – 1999
Project Status Completed (Fiscal Year 1999)
Budget Amount *help
¥12,200,000 (Direct Cost: ¥12,200,000)
Fiscal Year 1999: ¥3,800,000 (Direct Cost: ¥3,800,000)
Fiscal Year 1998: ¥5,800,000 (Direct Cost: ¥5,800,000)
Fiscal Year 1997: ¥2,600,000 (Direct Cost: ¥2,600,000)
KeywordsDAX-1 / Molecular enetics / Congenital adrenal hypoplasia / Gene exression / Gene regulation / Gonadotropin / ゴナドトロピン / 性腺機能低下症
Research Abstract

The DAX-1 provides one of the rare known examples of mammalian transcriptional repressors whose the loss of function is associated with a congenital disorder, Adrenal hypoplasia congenita (AHC). However, the information about the structure-function of the DAX-1 or its function at the molecular level is so limited. Therefore, we performed first in this project the mutation analysis of the DAX-1 gene in the 20 suspected patients with X-linked AHC from 16 families. We identified three frameshift mutation (151 delAG, 935delC, 1376delTinsG), three nonsense mutations (Y91X. Y271X, Q395X), five missense mutations (V269D, L278R. W291C, L466R) and two deletion mutations. We showed that these missense mutations reduced their ability to silence StAR promotor activity, suggesting nonfunctional. All missense mutations reported are located only in the C-terminal presumptive ligand-binding domain. Thus, it was suggested that the C-terminal half of the DAX-1 protein may be important than the N-termina … More l half for DAX-1 function. The 3-D structure of the ligand binding domain we constructed also supported these findings. Clinical analysis showed that there was no correlation between the age at presentation and the type of the mutation. Furthermore, we identified five adolescent and adult patients with hypogonadotropic hypogonadism. Nevertheless, they retained normal Leydig cell functions, but they had impaired Sertoli cell function. This suggests that DAX-1 plays some role in gonadotropin secretion and also spermatogenesis. We could demonstrate that the wild type DAX-1 suppresses the LH β promoter activity, but the mutant DAX-1 displayed the loss of function for gonadotropin secretion.
We also analyzed the mechanism of action of DAX-1. This project suggested also DAX-1 suppress the human StAR gene promoter function, that it can act in part through cis element binding SF-1, and associates with the coactivaor RIP140, which modulates DAX-1 action. However, these analysis indicated that the full picture of the wide phenotypic variability in the patients with AHC may not be explained solely by the loss of the repressor function of the DAX-1 itself. Less

Report

(4 results)
  • 1999 Annual Research Report   Final Research Report Summary
  • 1998 Annual Research Report
  • 1997 Annual Research Report
  • Research Products

    (22 results)

All Other

All Publications (22 results)

  • [Publications] Abe S.et al.: "A novel missense mutation (Leu466Arg) of the DAX-1 gene in a patient with X-linked adrenal hypoplasia congenita"Am.J.Med.Genet.. 84. 87-89 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Fujieda K.et al.: "DAX-1 mutations in adrenal hypoplasia congenita"Molecular Steroidogenesis. 341-344 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Mukai T.et al.: "Expression of Dax-1 in the adrenal gland"Molecular Steroidogenesis. 223-224 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Abe S, et al.: "A novel missense mutation (Leu466R) of the DAX-1 gene in patinets with X-linked adrenal hypolasia congenita"Am J Med Genet. 84. 87-89 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Fujieda K, et al.: "DAX-1 mutatins in adrenal hypoplasia congenita"Molecular Steroidogenesis (Okamoto M, Ishimura Y, Nawata H, eds) , Universal Academy Press. 341-344 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Muaki T, et al.: "Expression of Dax-1 in the adrenal gland"Molecular Steroidogenesis (Okamoto M, Ishimura Y, Nawata H, eds) , Universal Academy Press. 223-224 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Abe, S., et al.: "A novel missense mutation (Leu466Arg) of the DAX-1 gene in a patient with X-linked adrenal hypoplasia congenita"Am. J. Med Genet. 84. 87-89 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] 藤枝憲二: "性の決定・分化の分子機構"Pharma Medica. 18. 185-192 (2000)

    • Related Report
      1999 Annual Research Report
  • [Publications] Fujieda, K., et al.: "DAX-1 mutations in adrenal hypoplasia congenita"Molecular Steroidogenesis. 341-344 (2000)

    • Related Report
      1999 Annual Research Report
  • [Publications] Mukai, T., et al.: "Expression of Dax-1 in the adrenal gland"Molecular Steroidogenesis. 223-224 (2000)

    • Related Report
      1999 Annual Research Report
  • [Publications] Abe S: "A novel missense mutation (L466R)of the DAX-1 gene in a patient with X-linked adrenal livpoplasia congenita" Am J Med Genel. in press

    • Related Report
      1998 Annual Research Report
  • [Publications] 藤枝憲二: "DAX-1遺伝子の構造と機能-X連鎖型先天性副腎低形成症での解析から" ホルモンと臨床. 45. 7-12 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] 阿部修司: "X連鎖型先天性副腎低形成症の18例-DAX-1遺伝子解析" ホルモンと臨床. 32. 165-169 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] 阿部修司: "X連鎖型先天性副腎低形成症の1例-DAX-1遺伝子の下垂体-性腺系に対する影響の検討" ホルモンと臨床. 46. 949-952 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Fujieda K: "Molecular genetics of congeniral adrenal disorders" Proc 9th Fukuoka International Syposium on Perinatal Medicine, 66-75 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Nakae J, Abe S, Tajima T, Shinohara N, Murashita M, et al: "Three novel frameshift and missense mutations and a de novo deletion mutation of the DAX-1 gene in patients with X-linked adrenal hypoplasia congenita." J Clin Endocrinol Metab. 82. 3835-3841 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Fujieda K, Tajima T, Nakae J Sageshima S, et al: "Spontaneous puberty in 46,XX patients with congenital lipoid adrenal hyperplasia" J Clin Invest. 99. 1265-1271 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Nakae J, Tajima T, Sugawara T Hanaki K, Hotsubo T, et al: "Analysis of the steroidogenic acute regulatory protein(StAR)gene in Japanese patients with congenital lipoid adrenal hyperplasia." Hum Molec Genet. 6. 571-576 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Tajima T, Fujieda K, Nakae J, Toyoura T, Shimozawa K et al: "Molecular basis of nonclassical steroid 21-hydroxylase deficiency detected by neonatal screening in Japan." J Clin Endocrinol Metab. 82. 2350-2356 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] 藤枝憲二: "DAX-1" 内分泌・糖尿病科. 5. 456-463 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] 藤枝憲二: "性分化および性成熟の分子生物学" 内分泌・糖尿病科. 4. 162-169 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] 藤枝憲二: "今日の小児治療指針第11版 先天性副腎低形成症" 医学書院, pp195 (1997)

    • Related Report
      1997 Annual Research Report

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Published: 1997-04-01   Modified: 2016-04-21  

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