Molecular mechanism leading to impaired sexual differentiation and reproductive failure in patients with MAMLD mutations

• Project/Area Number: 20390265
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Endocrinology
• Research Institution: National Research Institute for Child Health and Development
• Principal Investigator: FUKAMI Maki National Research Institute for Child Health and Development, 臨床内分泌研究室, 室長 (40265872)
• Co-Investigator(Kenkyū-buntansha): WADA Yuka 独立行政法人 国立成育医療研究センター, 分子内分泌研究部, 研究員 (80399485) ; OGATA Tsutomu 独立行政法人 国立成育医療研究センター, 分子内分泌研究部, 部長 (40169173)
• Project Period (FY): 2008 – 2010
• Project Status: Completed (Fiscal Year 2010)
• Budget Amount: ¥18,590,000 (Direct Cost: ¥14,300,000、Indirect Cost: ¥4,290,000); Fiscal Year 2010: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2009: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2008: ¥7,930,000 (Direct Cost: ¥6,100,000、Indirect Cost: ¥1,830,000)
• Keywords: 生殖内分泌学 / 性分化 / 性ホルモン / ステロイド / MAMLD1 / Notch

Research Abstract

Clinical analysis of mutation-positive patients indicated that loss of function of MAMLD1 leads to various clinical features including abnormal genitalia, testosterone deficiency, impaired spermatogenesis and infertility. In vitro assays suggested that Mamld1 enhances Cyp17a1 expression primarily in Leydig cells and permit to produce a sufficient amount of testosterone for male sex development. Collectively, it is likely that SF1-MAMLD1-CYP17A1 axis plays a critical role in regulation of testosterone production in the testis.

Research Products

• [Journal Article] 最近話題の遺伝子異常による内分泌および類縁疾患.性分化疾患 (2011)
  • Author(s): 深見真紀
  • Journal Title: ホルモンと臨床 58(印刷中) Pages: 7-7
• [Journal Article] Mamld1 knockdown reduces testosterone production and Cyp17al expression in mouse Leydig tumor cells. (2011)
  • Author(s): Nakamura M, Fukami M, Sugawa F, Miyado M, Nonomura K, Ogata T
  • Journal Title: PLoS ONE Volume: 印刷中
  • Peer Reviewed
• [Journal Article] Exonic polymorphisms of MAMLD1 (CXorf6) are associated with hypospadias. (2011)
  • Author(s): Kalfa N, Cassorla F, Abdennabi IO, Audran F, Philibert P, Daures JP, Baskin L, Fukami M, Ogata T, Sultan C
  • Journal Title: J Urol Volume: 印刷中
  • Peer Reviewed
• [Journal Article] Aromatase Excess Syndrome : Identification of Cryptic Duplications and Deletions Leading to Gain-of-Function of CYP19A1 and Assessment of. Phenotypic Determinants. (2011)
  • Author(s): Fukami M, Shozu M, Soneda S, Kato F, Inagaki A, Takagi H, Hanaki K, Kanzaki S, Ohyama K, Sano T, Nishigaki T, Yokoya S, Binder G, Horikawa R, Ogata T
  • Journal Title: J Clin Endocrinol Metab Volume: 印刷中
  • Peer Reviewed
• [Journal Article] Hypothalamic dysfunction in a female with isolated hypogonadotropic hypogonadism and compound heterozygous TACR3 mutations and clinical manifestation in her heterozygous mother (2010)
  • Author(s): Fukami M, Maruyama T, Yoshimura Y, Ogata T.
  • Journal Title: Horm Res Paediatr. 73(6) Pages: 477-481
• [Journal Article] Anorectal and urinary anomalies and aberrant retinoic acid metabolism in cytochrome P450 oxidoreductase deficiency. (2010)
  • Author(s): Fukami M, Nagai T, Mochizuki H, Muroya K, Yamada G, Takitani K, Ogata T.
  • Journal Title: Mol Genet Metab. 100(3) Pages: 269-273
• [Journal Article] 小児内分泌学の進歩2009.性分化異常症発症責任遺伝子MAMLD1の臨床的および分子遺伝学的解析 (2010)
  • Author(s): 深見真紀、和田友香、上松あゆ美、長谷川奉延、緒方勤
  • Journal Title: ホルモンと臨床 57(12) Pages: 1025-1029
• [Journal Article] Anorectal and urinary anomalies and aberrant retinoic acid metabolism in cytochrome P450 xidoreductase deficiency (2010)
  • Author(s): Fukami M, Nagai T, Mochizuki H, Muroya K, Yamada G, Takitani K, Ogata T
  • Journal Title: Mol Genet Metab Volume: 100(3) Pages: 269-273
  • Peer Reviewed
• [Journal Article] 性分化異常症発症責任遺伝子MAMLD1の臨床的および分子遺伝学的解析 (2010)
  • Author(s): 深見真紀、和田友香、上松あゆ美、長谷川奉延、緒方勤
  • Journal Title: ホルモンと臨床 Volume: 57(12) Pages: 1025-1029
• [Journal Article] Hypothalamic dysfunction in a female with isolated hypogonadotropic hypogonadism and compound heterozygous TACR3 mutations and clinical manifestation in her heterozygous mother. (2010)
  • Author(s): Fukami M, Maruyama T, Yoshimura Y, Ogata T
  • Journal Title: Horm Res Paediatr Volume: 73(6) Pages: 477-481
  • Peer Reviewed
• [Journal Article] 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, Ogata T.
  • Journal Title: J Clin Endocrinol Metab. 94(5) Pages: 1723-1731
• [Journal Article] MAMLD1 (CXorf6) : a new gene involved in hypospadias. (2009)
  • Author(s): Ogata T, Laporte J, Ogata T.
  • Journal Title: Horm Res.(current name : Horm Res Paediatr) 71(5) Pages: 245-252
• [Journal Article] 日本人が発見にかかわった遣伝子:尿道下裂(CXorf6) (2009)
  • Author(s): 深見真紀、和田友香、緒方勤
  • Journal Title: 小児科 50(7) Pages: 939-945
• [Journal Article] 性分化異常症発症責任遺伝子MAMLD1の臨床的および分子遺伝学的解析 (2009)
  • Author(s): 深見真紀、和田友香, 他
  • Journal Title: ホルモンと臨床 (印刷中)
• [Journal Article] Cytochrome P450 Oxidoreductase Deficiency : Identification and Characterization of Biallelic Mutations and Genotype-Phenotype Correlations in 35 Japanese Patients (2009)
  • Author(s): 深見真紀, et al
  • Journal Title: Journal of Clinical Endocrinology and Metabolism 94 Pages: 1723-31
  • Peer Reviewed
• [Journal Article] MAMLD1(CXorf6): a new gene involved in hypospadias (2009)
  • Author(s): Ogata T, Laporte J, Fukami M
  • Journal Title: Hormone Research 71 Pages: 245-252
• [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 Chem. 283(9) Pages: 5525-5532
• [Journal Article] MAMLD1 (CXorf6) is a new gene for hypospadias. (2008)
  • Author(s): 緒方勤, 深見真紀, 和田友香
  • Journal Title: Clin Pediatr Endocrinol. 17(4) Pages: 87-93
  • NAID: 10031199580
• [Journal Article] MAMLD1 (CXorf6) : a new gene for hypospadias. (2008)
  • Author(s): 緒方勤, 和田友香, 深見真紀
  • Journal Title: Sex Dev. 2(4-5) Pages: 244-250
• [Journal Article] MAMLD1 : a new gene for hypospadias. (2008)
  • Author(s): 和田友香, 深見真紀, 緒方勤
  • Journal Title: J Japan Soc Reproduct Endocrinol 13 Pages: 37-42
• [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: Journal of Biological Chemistry 283 Pages: 5525-5532
  • Peer Reviewed
• [Journal Article] MAMLD1 (CXorf6) is a new gene for hypospadias (2008)
  • Author(s): Ogata T, Fukami M, Wada Y.
  • Journal Title: Clinical Pediatric Endocrinology 17 Pages: 87-93
  • NAID: 10031199580
  • Peer Reviewed
• [Journal Article] MAMLD1 : a new gene for hypospadias (2008)
  • Author(s): Wada Y, Fukami M, Ogata T
  • Journal Title: Journal of Japan Society of Reproductive Endocrinology 13 Pages: 37-42
• [Journal Article] MAMLD1 (CXorf6) : a new gene for hypospadias (2008)
  • Author(s): Ogata T, Wada Y, Fukami M
  • Journal Title: Sexual Development 2 Pages: 244-50
• [Journal Article] OTX2 Mutation in a Patient with Anophthalmia, Short Stature, and Partial GH Deficiency : Functional Studies Using the IRBP, HESX1, and POU1F1 Promoters (2008)
  • Author(s): Dateki S, Fukami M, Sato N, Muroya K, Adachi M, Ogata T.
  • Journal Title: Journal of Clinical Endocrinology and Metabolism 93 Pages: 3697-702
  • Peer Reviewed
• [Journal Article] Mamld1 knockdown reduces testosterone production and Cyp17a1 expression in mouse Leydig tumor cells.
  • Author(s): Nakamura M, Fukami M, Sugawa F, Miyado M, Nonomura K, Ogata T
  • Journal Title: PLoS ONE in press
• [Journal Article] Aromatase Excess Syndrome : Identification of Cryptic Duplications and Deletions Leading to Gain-of-Function of CYP19A1 and Assessment of Phenotypic Determinants.
  • Author(s): Fukami M, Shozu M, Soneda S, Kato F, Inagaki A, Takagi H, Hanaki K, Kanzaki S, Ohyama K, Sano T, Nishigaki T, Yokoya S, Binder G, Horikawa R, Ogata T
  • Journal Title: J Clin Endocrinol Metab. in press
• [Presentation] MAMLD1異常症:新規変異の同定と変異陽性患者の表現型 (2010)
  • Author(s): 加藤芙弥子、深見真紀, 他
  • Organizer: 第43回日本小児内分泌学会
  • Place of Presentation: 宇都宮
  • Year and Date: 2010-10-02
• [Presentation] Mamld1発現異常が引き起こすホルモン産生と摂食調節の解析 (2010)
  • Author(s): 宮戸真美、深見真紀, 他
  • Organizer: 第43回日本小児内分泌学会
  • Place of Presentation: 宇都宮
  • Year and Date: 2010-10-01
• [Presentation] 小児内分泌疾患の分子診断 (2010)
  • Author(s): 深見真紀
  • Organizer: 第142回染色体研究会
  • Place of Presentation: 東京
  • Year and Date: 2010-06-11
• [Presentation] Cytochrome P450 oxidoreductase deficiency : identification and characterization of biallelic mutations and genotype-phenotype correlations in 35 Japanese patients. (2010)
  • Author(s): Fukami M, Nishimura G, Homma K, Hasegawa T, Fujieda K, Ogata T
  • Organizer: The 2nd World Conference : Hormonal and Genetic Basis for DSD and Hot Topics in Endocrinology.
  • Place of Presentation: Miami, USA
• [Presentation] MAMLD1 mutations : how do they lead to hypospadias? (2010)
  • Author(s): 深見真紀
  • Organizer: International Symposium on Pediatric Endocrinology.
  • Place of Presentation: Tokyo, Japan
• [Presentation] Mamld1は,マウスライデイッヒ腫瘍細胞において,ステロイド合成酵素遺伝子の発現調節を介し,テストステロン産生に関わっている (2010)
  • Author(s): 中村美智子, 深見真紀, 宮戸真美, 須川史啓, 緒方勤, 野々村克也
  • Organizer: 第19回日本小児泌尿器科学会
  • Place of Presentation: 札幌
• [Presentation] MAMLD1 mutations : how do they lead to hypospadias? (2010)
  • Author(s): Fukami M
  • Organizer: International Symposium on Pediatric Endocrinology.
  • Place of Presentation: Tokyo
• [Presentation] MAMLD1 mutations and impaired testosterone production : phenotypic analysis of mutation-positive patients and knockout mice and in vitro functional assays. (2010)
  • Author(s): Fukami M, Wada Y, Nakamura M, Miyado M, Ogata T.
  • Organizer: The 49th Annual Meeting of European Society for Paediatric Endocrinology
  • Place of Presentation: Prague
• [Presentation] Impaired expression of Mamld1 disturbs the gene expression of steroidogenic enzymes. (2010)
  • Author(s): 宮戸真美, 中村美智子, 深見真紀, 宮戸健二, 緒方勤
  • Organizer: 第33回日本分子生物学会
  • Place of Presentation: 神戸
• [Presentation] ステロイドホルモン産生におけるMamld1の機能解析 (2010)
  • Author(s): 宮戸真美, 中村美智子, 深見真紀, 宮戸健二, 緒方勤
  • Organizer: 第44回日本小児内分泌学会
  • Place of Presentation: 大阪
• [Presentation] A gain of function mutation in the MAMLD1 discloses a new pathway in the etiology of 46, XY disorders of sex development. (2009)
  • Author(s): Brandao MP, Fukami M, Mendonca BB, Santos MG, Domenice S, Arnold IJP, Ogata T, Costa EMF.
  • Organizer: The 8th Joint meeting, ESPE-LWPES in association with APEG, APPES, SLEP, JSPE.
  • Place of Presentation: New York,
• [Presentation] MAMLD1遺伝子におけるスプライス部位変異(IVS4-2A>G)の検討 (2009)
  • Author(s): 和田友香, 深見真紀, 須川史啓, 宮戸真美, 緒方勤
  • Organizer: 第112回日本小児科学会学術集会
  • Place of Presentation: 奈良
• [Presentation] MAMLD1異常症:新規遺伝子変異の同定と変異陽性患者の表現型 (2009)
  • Author(s): 加藤芙弥子, 深見真紀, 和田友香, マイラ ブランダオ, 中村美智子, 上松あゆみ, 長谷川奉延, 宮戸真美, 緒方勤
  • Organizer: 第43回日本小児内分泌学会
  • Place of Presentation: 宇都宮
• [Presentation] Mamld1発現異常が引き起こすホルモン産生と摂食調節の解析 (2009)
  • Author(s): 宮戸真美, 中村美智子, 深見真紀, 宮戸健二, 菊水健史, 小川佳宏, 緒方勤
  • Organizer: 第32回日本分子生物学会
  • Place of Presentation: 横浜
• [Presentation] 性分化異常症責任遺伝子MAMLD1の臨床的および分子遺伝学的解析 (2008)
  • Author(s): 深見真紀
  • Organizer: 第42回日本小児内分泌学会学術総会
  • Place of Presentation: 米子
  • Year and Date: 2008-10-02
• [Presentation] 新規尿道下裂発症責任遺伝子MAMLD1(CXorf6)の同定と機能解析 (2008)
  • Author(s): 深見真紀
  • Organizer: 第53回日本人類遺伝学会
  • Place of Presentation: 横浜
  • Year and Date: 2008-09-29
• [Presentation] 性ステロイド産生障害を招く新規遺伝子疾患 (2008)
  • Author(s): 深見真紀
  • Organizer: 第81回日本内分泌学会学術総会
  • Place of Presentation: 青森
  • Year and Date: 2008-05-17
• [Presentation] 性分化異常症責任遺伝子MAMLD1の臨床的および分子遺伝学的解析 (2008)
  • Author(s): 深見真紀, 和田友香, 須川史啓, 宮戸真美, 上松あゆ美, 長谷川奉延, 緒方勤
  • Organizer: 第53回日本人類遺伝学会
  • Place of Presentation: 横浜
• [Presentation] New aspects of congenital adrenal disease(Meet-the-expert session)
  • Author(s): 深見真紀
  • Organizer: The 8th Joint Meeting of the Lawson Wilkins Pediatric Endocrine Society/European Society for Pediatric Endocrinology
  • Place of Presentation: NY, USA
• [Presentation] Cytochrome P450 oxidoreductase deficiency : identification and characterization of biallelic mutations and genotype-phenotype correlation in 35 Japanese patients
  • Author(s): 深見真紀, et al
  • Organizer: The 2nd World Conference : Hormonal and Genetic Basis for DSD and Hot Topics in Endocrinology
  • Place of Presentation: Miami, USA
• [Remarks] ホームページ等
  • URL: http://111.89.135.117/endocrinology/index.htm
• [Remarks]
  • URL: http://www.nch.go.jp/endocrinology/index.htm