Comprehensive investigation of etiology and pathophysiology of disorders of sex development(DSD)

• Project/Area Number: 17390294
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Pediatrics
• Research Institution: Asahikawa Medical College
• Principal Investigator: FUJIEDA Kenji Asahikawa Medical College, 医学部, 教授 (60173407)
• Co-Investigator(Kenkyū-buntansha): MUKAI Tokuo 旭川医科大学, 医学部, 助教 (50374799) ; NAKAMURA Eiki 旭川医科大学, 大学病院, 医員 (20396352)
• Co-Investigator(Renkei-kenkyūsha): SUZUKI Shigeru 旭川医科大学, 大学病院, 医員 (80516394)
• Project Period (FY): 2005 – 2008
• Project Status: Completed (Fiscal Year 2008)
• Budget Amount: ¥17,100,000 (Direct Cost: ¥15,000,000、Indirect Cost: ¥2,100,000); Fiscal Year 2008: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2007: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2006: ¥4,000,000 (Direct Cost: ¥4,000,000); Fiscal Year 2005: ¥4,000,000 (Direct Cost: ¥4,000,000)
• Keywords: 性分化異常症(DSD) / yeast two-hybrid screening / 先天性リポイド過形成症 / 先天性副腎低形成症 / StAR、DAX-1 / AHC / 相互作用因子 / 性分化異常症 / yeast two-hybridscreening / リポイド渦形成症 / 副腎低形成症 / StAR / DAX-1 / リポイド過形成症 / Kallmann症候群 / hypogonadotropic hypogonadism / KAL1 / GPR54 / yeast two-hybridシステム / XY女性 / WT1 / アンドロゲン受容体 / SOX9

Research Abstract

ヒト性分化異常症(disorders of sex development ; DSD)の病因・病態の解明を目的に以下の研究を行った。
(1) 候補遺伝子アプローチにより46, XY DSDを対象に遺伝子解析を行った。その結果、WT1遺伝子に既知の変異を、SOX9、AR、Ad4BP/SF-1にそれぞれ新規遺伝子変異を同定した。このうちAd4BP/SF-1変異は副腎不全を伴わない精巣形成不全患者において同定された。
(2) DSDのなかで最も頻度が高いステロイドホルモン産生異常症についての成因探索を目的に、先天性リポイド過形成症の病因であるStAR蛋白と、X連鎖性先天性副腎低形成症の原因であるDAX-1/AHCについてヒト副腎cDNAライブラリーを作成し、それぞれの相互作用因子についてのスクリーニングをyeast two-hybridシステムを用いて行った。その結果、候補因子をそれぞれ3種、30種同定した。現在各候補因子についてその病因的意義を検討している。

Research Products

• [Journal Article] Ogata T : Cytochrome P450 oxidoreductase deficiency : Identification and characterization of biallelic mutations and genotype-phenotype correlations in 35 Japanese patients (2009)
  • Author(s): Fukami M, Nishimura G, Homma K, Nagai T, Hanaki K, Uematsu A, Ishii T, Numakura C, Sawada H, Nakacho M, Kowase T, Motomura K, Haruna H, Nakamura M, Ohishi A, Adachi M, Tajima T, Hasegawa Y, Hasegawa T, Horikawa R, Fujieda K
  • Journal Title: J Clin Endocrinol Metab (in press)
  • Peer Reviewed
• [Journal Article] A novel heterozygous mutation of steroidogenic factor-1(SF-1/Ad4BP)gene(NR5A1)in a 46 (2009)
  • Author(s): Tajima T, Fujiwara F, Fujieda K
  • Journal Title: XY disorders of sex development(DSD)patient without adrenal failure. Endocr J (in press)
  • Peer Reviewed
• [Journal Article] Cytochrome P450 Oxidoreductase Deficiency : Identificationand Characterization of Biallelic Mutations and Genotype-Phenotype Correlations in 35 Japanese Patients (2009)
  • Author(s): Fukami M, Nishimura G, Homma K, Nagai T, Hanaki K, Uematsu A, Ishii T, Numakura C, Sawada H, Nakacho M, Kowase T, Motomura K, Haruna H, Nakamura M, Ohishi A, Adachi M, Tajima T, Hasegawa Y, Hasegawa T, Horikawa R, Fujieda K. Ogata T
  • Journal Title: J Clin Endocrinol Metab (In press)
  • Peer Reviewed
• [Journal Article] A novel heterozygous mutation of steroidogenic factor-1(SF-1/Ad4BP) gene (NR5A1) in a 46, XY disorders of sex development (DSD) patient without adrenal failure (2009)
  • Author(s): Tajima T, Fujiwara F, Flljieda K
  • Journal Title: Endocr J (In press)
  • Peer Reviewed
• [Journal Article] Four Japanese patients with adrenal hypoplasia congenita and hypogonadotropic hypogonadism caused by DAX-1 gene mutations : mutant DAX-1 failed to repress steroidogenic acute regulatory protein(StAR)and luteinizing hormone beta-subunit gene promoter activity (2008)
  • Author(s): Okuhara K, Abe S, Kondo T, Fujita K, Koda N, Mochizuki H, Fujieda K, Tajima T
  • Journal Title: Endocr J 55 Pages: 97-103
  • Peer Reviewed
• [Journal Article] 先天性副腎低形成 (2008)
  • Author(s): 藤枝憲二
  • Journal Title: 日本内科学会誌 97 Pages: 736-742
  • NAID: 10021253855
• [Journal Article] 性分化異常症の管理に関する合意見解、日本小児内分泌学会性分化委員会報告 (2008)
  • Author(s): 緒方勤、堀川玲子、長谷川奉延、位田忍、向井徳男、安達昌功、有坂治、藤枝憲二
  • Journal Title: 日本小児科学会雑誌 112 Pages: 565-578
• [Journal Article] Four Japanese patients with adrenal hypoplasia congenitaand hypogonadotropic hypogonadism caused by DAX-1 gene mutations : mutant DAX-1 failed to repress steroidogenicacute regulatory protein (StAR) and luteinizing hormonebeta-subunit gene promoter activity (2008)
  • Author(s): Okuhara K, Abe S, Kondo T, Fujita K, Koda N, Mochizuki H, Fujieda K, Talima T
  • Journal Title: Endocr J 55 Pages: 97-103
  • Peer Reviewed
• [Journal Article] 性分化異常症の管理に関する合意見解 (2008)
  • Author(s): 緒方勤、堀川玲子、長谷川奉延、位田忍、向井徳男、安達昌功、有坂治、藤枝憲二
  • Journal Title: 日本小児科学会雑誌 112 Pages: 565-578
  • NAID: 10024132484
  • Peer Reviewed
• [Journal Article] Four Japanese patients with adrenal hypoplasia congenita and hypogonadotropic hypogonadism caused by DAX-1 gene mutations: mutant DAX-1 failed to repress steroidogenic acute regulatory protein(StAR)and luteinizing hormone beta-subunit gene promoter activity. (2008)
  • Author(s): Okuhara K, Abe S, Kondo T, Fujita K, Koda N, Mochizuki H, Fujieda K, Tajima T
  • Journal Title: Endocr J. 55 Pages: 97-103
  • Peer Reviewed
• [Journal Article] DAX-1異常症 (2007)
  • Author(s): 藤枝憲二
  • Journal Title: 最新医学 62 Pages: 1241-1247
  • NAID: 120001814718
• [Journal Article] 性分化異常症の診断と治療-特に先天性副腎過形成症を中心に (2007)
  • Author(s): 藤枝憲二
  • Journal Title: 日本小児泌尿器科学会雑誌 16 Pages: 125-129
• [Journal Article] LWPES/ESPE Consensus Group(Fujieda K, et.al.) : Consensus statement on management of intersex disorders (2006)
  • Author(s): Hughes IA, Houk C, Ahmed SF, Lee PA
  • Journal Title: Arch Dis Child 91 Pages: 554-563
  • Peer Reviewed
• [Journal Article] SCC異常症 (2006)
  • Author(s): 藤枝憲二、勝又規行
  • Journal Title: ホルモンと臨床 54 Pages: 61-64
  • NAID: 10019247912
• [Journal Article] 先天性副腎過形成症 (2006)
  • Author(s): 藤枝憲二
  • Journal Title: 新領域別症候群シリーズ、内分泌症候群(第2版)、別冊日本臨床 No.1 Pages: 673-676
• [Journal Article] リポイド過形成症 (2006)
  • Author(s): 藤枝憲二
  • Journal Title: 新領域別症候群シリーズ、内分泌症候群(第2版)、別冊日本臨床 No.1 Pages: 692-695
• [Journal Article] 20, 22デスモラーゼ欠損症 (2006)
  • Author(s): 藤枝憲二
  • Journal Title: 新領域別症候群シリーズ、内分泌症候群(第2版)、別冊日本臨床 No.1 Pages: 696-698
• [Journal Article] 副腎性器症候群 (2006)
  • Author(s): 藤枝憲二
  • Journal Title: 新領域別症候群シリーズ、内分泌症候群(第2版)、別冊日本臨床 No.2 Pages: 643-646
• [Journal Article] ステロイドサルファターゼ欠損症 (2006)
  • Author(s): 鈴木滋、藤枝憲二
  • Journal Title: 新領域別症候群シリーズ、内分泌症候群(第2版)、別冊日本臨床 No.3 Pages: 494-496
• [Journal Article] Molecular analysis of the CLCNKB gene in Japanese patients with classic Bartter syndrome. (2006)
  • Author(s): Tajima, T, Nawate M, Takahashi Y, Mizoguchi Y, Sugihara S, Yoshimoto M., Murakami M, Adachi M, Tachibana K., Mochizuki H, Fujieda K
  • Journal Title: Endocr J. 53・5 Pages: 647-652
  • NAID: 10020613203
• [Journal Article] Global inequalities in paediatric endocrine practice : statement of minimal acceptable care. Statement from the International Societies for Paediatric Endocrinology. (2006)
  • Author(s): Savage MO, Cassorla FG, Gluckman PD, Gruters-Kieslich A, Raghupathy P, Silink M, Czernichow P, Chiarelli F, Rogol AD, Crock PA, Cowell CT, Fujieda K, Arnhold IJ
  • Journal Title: Horm Res. 65・3 Pages: 111-113
• [Journal Article] Consensus statement on management of intersex disorders. (2006)
  • Author(s): Hughes IA, Houk C, Ahmed SF, Lee PA, LWPES/ESPE Consensus Group (Fujieda K, et al.
  • Journal Title: Arch Dis Child. 91 Pages: 554-563
• [Journal Article] Molecular basis of adrenal insufficiency (2005)
  • Author(s): Fujieda K, Tajima T
  • Journal Title: Pediatr Res 57
  • Peer Reviewed
• [Journal Article] Inappropriate tall stature and renal ectopy in a male patient with X-linked congenital adrenal hypoplasia due to a novel missense mutation in the DAX-1 gene (2005)
  • Author(s): Franzese A, Brunetti-Pierri N, Spadaro R, Mukai T, Valerio G
  • Journal Title: Am J Med Genet 135 Pages: 72-74
  • Peer Reviewed
• [Journal Article] 先天性副腎皮質ステロイド合成異常症の分子基盤 (2005)
  • Author(s): 藤枝憲二、田島敏広、向井徳男
  • Journal Title: 医学の歩み 213 Pages: 401-407
• [Journal Article] 先天性副腎過形成症 (2005)
  • Author(s): 藤枝憲二、向井徳男
  • Journal Title: 周産期医学 35 Pages: 1245-1248
• [Journal Article] 副腎ステロイド合成酵素異常症の診断基準・病型分類・重症度 (2005)
  • Author(s): 藤枝憲二
  • Journal Title: 内科 95 Pages: 1835-1839
• [Journal Article] Global Inequalities in Paediatric Endocrine Practice : Statement of Minimal Acceptable Care. Statement from the International Societies for Paediatric Endocrinology. (2005)
  • Author(s): Savage MO, Fujieda K, Arnhold IJ, et al.
  • Journal Title: Horm Res 65・3 Pages: 111-113
• [Journal Article] Molecular basis of adrenal insufficiency. (2005)
  • Author(s): Fujieda K, Tajima T
  • Journal Title: Pediatr Res 57
• [Journal Article] Results of long-term follow-up after treatment of central precocious puberty with leuprorelin acetate : evaluation of effectiveness of treatment and recovery of gonadal function. The TAP-144-SR Japanese Study Group on Central Precocious Puberty. (2005)
  • Author(s): Tanaka T, Fujieda K, Kugu K, et al.
  • Journal Title: J Clin Endocrinol Metab 90・3 Pages: 1371-1376
• [Presentation] Congenital lipoid adrenal hyperplasia with bilateral ovarian endometrioma (2008)
  • Author(s): Sugawara T, Kudo M, Fujieda K, Sakuragi N
  • Organizer: 41st Annual Meeting of the Society for the Study of Reproduction
  • Place of Presentation: Kailua-Kona, USA
• [Presentation] NR5A1遺伝子異常(Ad4/BP)による精巣形成不全の1例 (2007)
  • Author(s): 田島敏広、石津桂、藤枝憲二
  • Organizer: 第15回日本ステロイドホルモン学会学術集会
  • Place of Presentation: 仙台
  • Year and Date: 2007-11-24
• [Presentation] NR5A1遺伝子異常(Ad4/BP)による精巣形成不全の1例 (2007)
  • Author(s): 田島敏広、石津 桂、藤枝憲二
  • Organizer: 第15回日本ステロイドホルモン学会学術集会
  • Place of Presentation: 仙台市
  • Year and Date: 2007-11-24
• [Presentation] 性分化異常症の診断と治療-特に先天性副腎過形成症を中心に- (2007)
  • Author(s): 藤枝憲二
  • Organizer: 第16回日本小児泌尿器科学会総会
  • Place of Presentation: 神戸
  • Year and Date: 2007-07-14
• [Presentation] P450 oxidoreductase(POR)欠損症の遺伝子診断 (2007)
  • Author(s): 田島敏広、藤枝憲二
  • Organizer: 第17回臨床内分泌Update
  • Place of Presentation: 東京
  • Year and Date: 2007-03-10
• [Presentation] Disorders of steroidogenesis, other than 21-hydroxylase (2007)
  • Author(s): Fujieda K
  • Organizer: ENDO 2007 Meet-the-Professor Session
  • Place of Presentation: Toronto, Canada
• [Presentation] Steroidogenic acute regulatory protein-binding protein is associated with apoptosis and controls steroidogenesis (2007)
  • Author(s): Sugawara T, Hoshi N, Fujieda K
  • Organizer: ENDO 2007
  • Place of Presentation: Toronto, Canada
• [Presentation] Congenital adrenal disorders : From newborn screening to molecular mechanism (2006)
  • Author(s): Fujieda K
  • Organizer: LWPES Trans-Pacific Lecture, Pediatric Academic Societies' 2006 Annual Meeting
  • Place of Presentation: San Francisco, USA
• [Presentation] Disorders of steroidogenesis, other than 21-hydroxylase (2006)
  • Author(s): Fujieda K
  • Organizer: ENDO 2006 Meet-the-Professor Session
  • Place of Presentation: Boston, USA
• [Presentation] Association of spermatogenesis with Ser164Arg and Arg417Trp polymorphism in the gene of steroidogenic acute regulatory protein-binding protein (2006)
  • Author(s): Sugawara T, Makita Y, Fujieda K
  • Organizer: ENDO 2006
  • Place of Presentation: Boston, USA
• [Presentation] International newborn screening(NBS)collaborative study on 21-hydroxylase deficiency congenital adrenal hyperplasia(CAH) (2006)
  • Author(s): Fujieda K, Pang S
  • Organizer: Workshop 5, 6th Meeting of the International Society for Neonatal Screening
  • Place of Presentation: Awaji, Japan
• [Presentation] New disease in CAH screening (2006)
  • Author(s): Tajima T, Fujieda K
  • Organizer: Workshop 5, 6th Meeting of the International Society for Neonatal Screening
  • Place of Presentation: Awaji, Japan
• [Presentation] National survey of the treatment for congenital adrenal hyperplasia detected by mass-screening (2006)
  • Author(s): Adachi M, Fujieda K
  • Organizer: Workshop 5, 6th Meeting of the International Society for Neonatal Screening
  • Place of Presentation: Workshop 5, 6th Meeting of the International Society for Neonatal Screening
• [Presentation] The genetic mutations of adrenal insufficiency (2006)
  • Author(s): Fujieda K, Tajima T, Mukai T
  • Organizer: Symposium IV, Adrenal, 4th Biennial Scientific Meeting Asia Pacific Paediatric Endocrine Society 2006
  • Place of Presentation: Pattaya, Thailand
• [Presentation] 性分化異常症の診断と治療-特に先天性副腎過形成症を中心に、シンポジウム5「小児泌尿器科 : 半陰陽の診断と治療 (2006)
  • Author(s): 藤枝憲二
  • Organizer: 第94回日本泌尿器科学総会
  • Place of Presentation: 福岡
• [Presentation] 先天性副腎疾患Update (2006)
  • Author(s): 藤枝憲二
  • Organizer: 第9回日本内分泌学会学術総会教育講演
  • Place of Presentation: 神戸
• [Presentation] ヒト副腎・生殖腺の発生分化機能の異常による性分化異常症 (2005)
  • Author(s): 藤枝憲二
  • Organizer: 第10回日本生殖内分泌学会シンポジウム「性分異常の基礎と臨床」
  • Place of Presentation: 東京
  • Year and Date: 2005-11-03
• [Presentation] 新生児マススクリーニングでみつかる副腎疾患 (2005)
  • Author(s): 田島敏広、藤枝憲二
  • Organizer: 第33回新生児マススクリーニング学会
  • Place of Presentation: 久留米
  • Year and Date: 2005-10-07
• [Presentation] Transcription factors and adrenal development (2005)
  • Author(s): Fujieda K, Mukai T, Okuhara K, Tajima T
  • Organizer: ESPE/LWPES 7th Joint Meeting
  • Place of Presentation: Lyon, France
• [Presentation] Two novel mutations in SOX9 gene in the patients with campomelic dysplasia (2005)
  • Author(s): Mukai T, Okamoto T, Suzuki S, Matsuo K, Ueda O, Ito Y, Fujieda K
  • Organizer: ESPE/LWPES 7th Joint Meeting
  • Place of Presentation: Lyon, France
• [Presentation] Two Japanese patients caused by P450 oxidoreductase(POR)deficiency (2005)
  • Author(s): Tajima T, Tsubaki J, Okuhara K, Ogawa E, Fujieda K
  • Organizer: ESPE/LWPES 7th Joint Meeting
  • Place of Presentation: Lyon, France
• [Presentation] P450と内分泌疾患-先天性副腎皮質過形成症を中心に (2005)
  • Author(s): 田島敏広、藤枝憲二
  • Organizer: 第15回臨床内分泌代謝Update
  • Place of Presentation: 札幌
• [Presentation] 先天性副腎過形成症の遺伝子診断と出生前診断・治療 (2005)
  • Author(s): 田島敏広、藤枝憲二
  • Organizer: 第108回日本小児科学会総会
  • Place of Presentation: 東京
• [Presentation] シンポジウム「性成熟異常症の最近の進歩」AHC(DAX-1)異常症 (2005)
  • Author(s): 向井徳男、藤枝憲二
  • Organizer: 第78回日本内分泌学会学術総会
  • Place of Presentation: 東京
• [Presentation] アンドロゲン受容体遺伝子に新規部分欠失を同定したアンドロゲン不応症の同胞例 (2005)
  • Author(s): 向井徳男、鈴木滋、松尾公美浩、上田修、安達かおり、藤枝憲二
  • Organizer: 第39回日本小児内分泌学会学術集会
  • Place of Presentation: 東京
• [Book] 先天性副腎過形成症、小児疾患診療のための病態生理 (2008)
  • Author(s): 藤枝憲二
  • Publisher: 東京医学社、小児内科
• [Book] 内分泌臨床分野での進歩性成熟異常症最近の進歩、Annual Review糖尿病・代謝・内分泌2007 (2007)
  • Author(s): 藤枝憲二
  • Publisher: 金原出版
• [Book] Annual Review糖尿病・代謝・内分泌2007 (2007)
  • Author(s): 藤枝憲二
  • Publisher: 金原出版
• [Book] 先天性副腎過形成症、先端医療シリーズ小児科の新しい流れ (2005)
  • Author(s): 藤枝憲二、向井徳男、田島敏広(柳澤正義、衛藤義勝、五十嵐隆)
  • Publisher: 先端医療技術研究所
• [Remarks]
  • URL: http://www.pediatric-world.com/asahikawa/ge1/kenkyu.html
• [Remarks]
  • URL: http://www.pediatric-world.com/asahikawa/gel/kenkyu.html
• [Remarks]
  • URL: http://www.pediatric-world.com/asahikawa/gel/kg_2007.html