Novel sex development gene CXorf6 : determination of clinical spectrum in mutation positive patients and clarification of underlying factors

• Project/Area Number: 19390290
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Pediatrics
• Research Institution: National Research Institute for Child Health and Development
• Principal Investigator: OGATA Tsutomu National Research Institute for Child Health and Development, 小児思春期発育研究部, 部長 (40169173)
• Co-Investigator(Kenkyū-buntansha): FUKAMI Maki 国立成育医療センター(研究所), 小児思春期発育研究部, 室長 (40265872) ; WADA Yuka 国立成育医療センター(研究所), 小児思春期発育研究部, 共同研究員 (80399485)
• Project Period (FY): 2007 – 2009
• Project Status: Completed (Fiscal Year 2009)
• Budget Amount: ¥18,720,000 (Direct Cost: ¥14,400,000、Indirect Cost: ¥4,320,000); Fiscal Year 2009: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2008: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2007: ¥9,880,000 (Direct Cost: ¥7,600,000、Indirect Cost: ¥2,280,000)
• Keywords: 性分化 / 遺伝子変異 / 遺伝子機能 / 臨床像 / ノックアウトマウス / CXorf6 / MAMLD1 / 尿道下裂 / Notchシグナル / ノックダウン / Metabolic syndrome / 性分化異常症 / Metabglic syndrome / 卵巣機能不全 / 精子形成障害 / テストステロン産生

Research Abstract

We have obtained the following findings during the research period : (1) Functional studies revealed that CXorf6 has a transactivation function for the canonical Notch target HES3, and is regulated bySF-1 that functions as a master gene for sex development ; (2) Knockdown experiments showed that CXorf6 has a regulatory function for the testicular steroidogenic enzymes ; (3) Mutation analysis identified further CXorf6 mutations in patients with hypospadias ; and (4) Knockout mouse experiments indicated that CXorf6 is involved in metabolic syndrome.

Research Products

• [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: Journal of Clinical Endocrinology & Metabolism 94(5) Pages: 1723-1731
• [Journal Article] Mutation analysis of SOX9 and single copy number variant analysis of the upstream region in eight patients with campomelic dysplasia or acampomelic campomelic dysplasia. (2009)
  • Author(s): Wada Y, Nishimura G, Nagai T, Sawai H, Yoshikata M, Miyagawa S, Hanita T, Sato S, Hasegawa T, Ishikawa S, Ogata T
  • Journal Title: American Journal of Medical Genetics A 149A(12) Pages: 2882-2885
• [Journal Article] MAMLD1 (CXorf6): a new gene involved in hypospadias. (2009)
  • Author(s): Ogata T, Laporte J, Fukami M
  • Journal Title: Hormone Research 71(5) Pages: 245-252
• [Journal Article] MAMLD1(CXorf6): a new gene involved in hypospadias (2009)
  • Author(s): Ogata T, Laporte J, Fukami M
  • Journal Title: Hormone Research 71(5) Pages: 245-252
  • 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, TIshii 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: Journal of Clinical Endocrinology & Metabolism 94(5) Pages: 1723-1731
  • Peer Reviewed
• [Journal Article] Heterozygous OTX2 mutations are associated with variable pituitary phenotype (2009)
  • Author(s): Dateki S, Kosaka K, Hasegawa K, Tanaka H, Azuma N, Yokoya S, Muroya K, Adachi M, Tajima T, Motomura K, Kinoshita E, Moriuchi H, Sato N, Fukami M, Ogata T
  • Journal Title: Journal of Clinical Endocrinology & Metabolism 95(2) Pages: 756-764
  • 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: Journal of Biological Chemistry 283(9) Pages: 5525-5532
• [Journal Article] MAMLD1 (CXorf6): a new gene for hypospadias. (2008)
  • Author(s): Ogata T, Wada Y, Fukami M
  • Journal Title: Sexual Development 2(4-5) Pages: 244-250
• [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(4) Pages: 87-93
  • NAID: 10031199580
• [Journal Article] CXorf6 (MAMR1 : mastermind-related 1) transactivates the Hes3 promoter, augments testosterone production, and contains the target sequence for SF-1 (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(9) Pages: 5525-5532
  • Peer Reviewed
• [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: 93(10) Pages: 3697-702
  • Peer Reviewed
• [Journal Article] Deletions and epimutations affecting the human chromosome 14q32. 2 imprinted region : implications for the phenotypic development in paternal and maternal uniparental disomy for chromosome 14 (2008)
  • Author(s): Kagami M, Sekita Y, Nishimura G, Irie M, Kato F, Okada M, Yamamori S, Kishimoto H, Nakayama M, Tanaka Y, Matsuoka K, Takahashi T, Noguchi M, Tanaka Y, Masumoto K, Utsunomiya T, Kouzan H, Komatsu Y, Ohashi H, Kurosawa K, Kosaki K, Ferguson-Smith AC, Ishino F, Ogata T.
  • Journal Title: Nature Genetics 40(2) Pages: 237-242
  • Peer Reviewed
• [Journal Article] CXorf6(MAMRI:mastermind-related1)trmsactivates the Hes3 promoter, augmentstestosterone production, and contains the target sequence fbr SF-1 (2008)
  • Author(s): Fukami M, Wada Y, Okada M, K:ato F, Katsumata N, Baba T, Morohashi K, Laporte J, Kitagawa M, Ogata T
  • Journal Title: Jburnal of Biological Chemistry 283(9) Pages: 5525-5532
  • Peer Reviewed
• [Journal Article] Hypogonadotropic hypogoBadism in an adult female with heterozygous hypomorphicmutation of SOX2 (2007)
  • Author(s): Sato N, Kamachi Y, Kondoh H, ShimaY, Morohashi K, Honkawa R, Ogata T.
  • Journal Title: European Journal of Endocrinology 156(2) Pages: 167-171
  • Peer Reviewed
• [Journal Article] Isolated hypogonadotropic hypogonadism in a female with tachykinin receptor 3 gene mutations.
  • Author(s): Fukami M, Maruyama T, Yoshimura Y, Ogata T
  • Journal Title: Hormone Research (in press)
• [Journal Article] Anorectal and urinary anomalies and aberrant retinoic acid metabolism in cytochrome P450 oxidoreductase deficiency.
  • Author(s): Fukami M, Nagai T, Mochizuki H, Muroya K, Yamada G, Taketani K, Ogata T
  • Journal Title: Molecular Genetics and Metabolism (in press)
• [Journal Article] Premature ovanan tallure and androgen receptor gene CAG repeat lengths weighted by X chromosome inactivation patterns
  • Author(s): Sugawa F, Wada Y, Okada M, Maruyama T, Uchida H, Arase T, Hamada N, Ishizuka B, Ogata T
  • Journal Title: Fertility and Sterility in press
  • Peer Reviewed
• [Presentation] 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, Dateki S, Sato N, Yoshimura Y, Ogata T
  • Organizer: The 14th International Congress of Endocrinology
  • Place of Presentation: Kyoto
• [Presentation] Impaired expression of Mamld1 disturbs the gene expression of steroidogenic enzyme and feeding regulation. (2010)
  • Author(s): Miyado M, Nakamura M, Fukami M, Miyado K, Ogata T
  • Organizer: The 14th International Congress of Endocrinology
  • Place of Presentation: Kyoto
• [Presentation] Association between MAMLD1 and Steroid Hormone Production. (2010)
  • Author(s): Nakamura M, Miyado M, Sugawa F, Kato F, Fukami M, Ogata T
  • Organizer: The 14th International Congress of Endocrinology
  • Place of Presentation: Kyoto
• [Presentation] A Novel Gain of function Mutation in the MAMLD1 gene in patients with Undetermined 46, XY Disorders of Sex Development. (2009)
  • Author(s): Brandao MP, Fukami M, Mendonca BB, Gerdulo M, Domenice S, Arnhold IJP, Ogata T, Costa EMF
  • Organizer: The Endocrine Society's 91st Annual Meeting
• [Presentation] MAMLD1 Homozygous gain-of-function missense mutation causing 46, XX disorder of sex development in a virilized female. (2009)
  • Author(s): Brandao MP, Costa EMF, Fukami M, Santos MG, Pereira NP, Domenice S, Ogata T, Mendonca BB
  • Organizer: The 8th Joint meeting, ESPE-LWPES in association with APEG, APPES, SLEP, JSPE
  • Place of Presentation: New York
• [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 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] 中枢性性腺機能異常症の鑑別診断 (2009)
  • Author(s): 緒方勤
  • Organizer: 第82回日本内分泌学会教育講演
  • Place of Presentation: 前橋
• [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
• [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, 緒方勤
  • Organizer: 第54回日本人類遺伝学会
• [Presentation] 低ゴナドトロピン性性腺機能低下症女性におけるTachykinin受容体3変異の同定と臨床像の解析 (2009)
  • Author(s): 深見真紀, 丸山哲夫, 伊達木澄人, 佐藤直子, 堀川玲子, 緒方勤
  • Organizer: 第43回日本小児内分泌学会
• [Presentation] 低ゴナドトロピン性性腺機能低下症女性におけるTachykinin受容体3変異の同定と臨床像の解析 (2009)
  • Author(s): 深見真紀, 丸山哲夫, 伊達木澄人, 堀川玲子, 吉村泰典, 緒方勤
  • Organizer: 第43回日本生殖内分泌学会
• [Presentation] Gentic causes of hypospadias (2009)
  • Author(s): Ogata T
  • Organizer: The 8th Joint meeting, ESPE-LWPES in association with APEG, APPES, SLEP, JSPE
  • Place of Presentation: New York
• [Presentation] Urine steroid hormone profile analysis in cytochrome P450 oxidoreductase deficiency: implication for the backdoor pathway to dihydrotestosterone. (2008)
  • Author(s): Fukami M, Homma K, Ogata T
  • Organizer: International Symposium for Gonad and Brain Sex Differentiation.
• [Presentation] 性分化異常症の遺伝的機序 (2008)
  • Author(s): 緒方勤
  • Organizer: 第111回日本小児泌科学会学術集会イブニングシンポジウム:性分化異常症診療への新展開
  • Place of Presentation: 東京
• [Presentation] ゴナドトロピン分泌不全症における分子遺伝学的および臨床的解析 (2008)
  • Author(s): 緒方勤
  • Organizer: 第81回内分泌学会学術総会シンポジウム.ゴナドトロピン分泌制御の新知見
  • Place of Presentation: 青森
• [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
• [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42回日本小児内分泌学会学術集会
• [Presentation] 日本人類遺伝学会奨励賞受賞講演: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
• [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, 諸橋憲一郎, 緒方勤
  • Organizer: 第31回日分子生物学会総会
• [Presentation] Disorders of Sex Development : New Gene and New Mechanism (2008)
  • Author(s): Ogata T
  • Organizer: The 47th Meeting of European Society for Paediatric Endocrinology
  • Place of Presentation: Istanbul
• [Presentation] The novel hypospadias gene CXorf6 transactivates the promoter of a non-canonical Notch target gene Hes3 and contains the target sequence for SF-1. (2007)
  • Author(s): Fukami M, Morohashi K, Wada Y, Okada M, Laporte J, Kitagawa M, Ogata T
  • Organizer: The Endocrine Society's 89th Annual Meeting
• [Presentation] POR:まとめと今後の展望 (2007)
  • Author(s): 緒方勤
  • Organizer: 第17回臨床内分泌代謝updateシンポジウム:POR異常症をめぐって
• [Presentation] 性分化異常症の遺伝的機序:新しい展開 (2007)
  • Author(s): 緒方勤
  • Organizer: 第16回日本小児泌尿器科学会総会特別講演
  • Place of Presentation: 神戸
• [Presentation] 新規性分化異常症責任遺伝子の同定 (2007)
  • Author(s): 深見真紀, 緒方勤
  • Organizer: 第17回臨床内分泌代謝update
• [Presentation] 新規性分化異常症責任遺伝子の同定と機能解析 (2007)
  • Author(s): 深見真紀, 和田友香, 長谷川奉延, 山田源, 諸橋憲一郎, 緒方勤
  • Organizer: 第80回内分泌学会学術総会:高得点演題
• [Presentation] CXorf6 (MAMLD1: mastermind-like domain containing 1) transactivates the promoter of Hes3 and contains the target sequence for SF-1 (2007)
  • Author(s): 深見真紀, 和田友香, 岡田美智代, 加藤芙美子, 勝又則行, 馬場崇, 諸橋憲一郎, Jocelyn Laporte, 北川元生, 緒方勤
  • Organizer: 第11回小児分子内分泌研究会
• [Presentation] 新規性分化異常症責任遺伝子の同定と機能解析 (2007)
  • Author(s): 深見真紀, 和田友香, 岡田美智代, 宮林香奈子, 長谷川奉延, 山田源, 諸橋憲一郎, Jocelyn Laporte, 北川元生, 緒方勤
  • Organizer: 第52回日本人類遺伝学会
• [Presentation] 新規性分化異常症責任遺伝子によるNotch標的遺伝子の活性化 (2007)
  • Author(s): 深見真紀, 和田友香, 岡田美智代, 長谷川奉延, 山田源, 諸橋憲一郎, 北川元生, 緒方勤
  • Organizer: 第30回日本分子生物学会年会
• [Presentation] The novel hypospadias gene CXorf6 transactivates the promoter of a non-canonical Notch target gene Hes3 and contaills the target sequence for SF-1 (2007)
  • Author(s): Fukami M, Morohashi K, Wada Y, Okada M, Laporte J, Kitagawa M, Ogata T
  • Organizer: The Endocrine Society's 89th Amual Meeting
  • Place of Presentation: トロント
• [Remarks]
  • URL: http://www.nch.go.jp/endocrinology/index.htm
• [Remarks]
  • URL: http://www.nch.go.jp/endocrinology/index.htm
• [Patent(Industrial Property Rights)] Estrogen receptor alpha gene, genomic DNA, and diagnosis marker (2009)
  • Inventor(s): 緒方勤, 長谷川奉延, 鎌谷直之
  • Filing Date: 2009-10-13
• [Patent(Industrial Property Rights)] Estrogen receptor alpha gene, genomic DNA, and diagnosis marker (2009)
  • Inventor(s): 緒方勤
  • Industrial Property Rights Holder: 成育医療センター
  • Filing Date: 2009-10-13