Comprehensive mutation and susceptibility analyses and its clinical application in disorders of sex development and reproductive dysfunction

2008 Fiscal Year Final Research Report

• Project/Area Number: 16086215
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• 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): KATSUMATA Noriyuki 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 (10260340) ; 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) ; SATO Naoko 国立成育医療センター研究所, 小児思春期発育研究部, 研究員 (10383069)
• Project Period (FY): 2004 – 2008
• Keywords: 性分化異常症 / 単一遺伝子疾患 / 多因子疾患 / ヒト遺伝疾患 / 内分泌撹乱物質

Research Abstract

単一遺伝子疾患としての性分化異常症:新規尿道下裂責任遺伝子MAMLD1の同定と機能解析、胎児期・乳児期特異的男性ホルモン産生経路backdoor pathway の同定、第14 染色体父性ダイソミーと母性ダイソミー表現型を招く(エピ)遺伝的機序の解明、AD4BP/SF1 遺伝子上昇の同定と機能解析、ゴナドトロピン分泌不全症の遺伝的機序の解明を行った。多因子疾患としての性分化異常症:内分泌撹乱化学物質感受性ハプロタイプの同定、外陰部異常症発症感受性多型の同定を行った。

Research Products

• [Journal Article] CHD7 mutations in patients initially diagnosed with Kallmann syndrome - the clinical overlap with CHARGE syndrome (2009)
  • Author(s): Ogata T(計10 名中4 番目), Sato N(計10名中5 番目), Claahsen-van der Grinten HL, van der Donk K, Seminara S, Bergman JE, Brunner HG, Crowley WF Jr, Hoefsloot LH
  • Journal Title: Clinical Genetics 75 (1) Pages: 65-71
• [Journal Article] Premature ovarian failure and androgen receptor gene CAG repeat lengths weighted by X chromosome inactivation patterns (2009)
  • Author(s): Ogata T(計9 名中最終)
  • Journal Title: Fertility and Sterility 91 (2) Pages: 649-652
• [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
• [Journal Article] Molecular mechanisms leading to the phenotypic development in paternal and maternal uniparental disomy for chromosome 14 (2008)
  • Author(s): Ogata T, Kagami M
  • Journal Title: Clinical Pediatric Endocrinology 17 (4) Pages: 103-111
• [Journal Article] Molecular mechanisms regulating phenotypic outcome in paternal and maternal uniparental disomy for chromosome 14 (2008)
  • Author(s): Ogata T, Kagami M, Ferguson-Smith AC
  • Journal Title: Epigenetics 3 (4) Pages: 181-187
• [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] Genomic imprinting at the mammaliad Dlk1-Dio3 domain (2008)
  • Author(s): da Rocha ST, Edwards CA, Ito M, Ogata T, Ferguson-Smith AC
  • Journal Title: Trends in Genetics 24 (6) Pages: 306-16
• [Journal Article] Monozygotic female twins discordant for Silver-Russell syndrome and hypomethylation of the H19-DMR (2008)
  • Author(s): Yamazawa K, Kagami M, Fukami M, Ogata T
  • Journal Title: Journal of Human Genetics 53 (10) Pages: 950-955
• [Journal Article] Placentomegaly in paternal uniparental disomy for human chromosome 14 (2008)
  • Author(s): Kagami M, Yamazawa K, Matsubara K, Matsuo N, Ogata T
  • Journal Title: Placenta 29 (8) Pages: 760-761
• [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 (10) Pages: 3697-702
• [Journal Article] Molecular andclinical findings and their correlations in Silver-Russell syndrome: implications for the critical role of IGF2 as the growth determinant and the differential imprinting regulation of the IGF2-H19 domain in bodies and placentas (2008)
  • Author(s): Ogata T(計15 名中最終)
  • Journal Title: Journal of Molecular Medicine 86 (10) Pages: 1171-1181
• [Journal Article] Epimutation (hypomethylation) affecting the chromosome 14q32.2 imprinted region in a girl with upd(14)mat-like phenotype (2008)
  • Author(s): Ogata T(計5 名中2 番目)
  • Journal Title: European Journal of Human Genetics 16 (8) Pages: 1019-1023
• [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(筆頭), Ogata T(計10 名中最終)
  • Journal Title: Journal of Biological Chemistry 283 (9) Pages: 5525-5532
• [Journal Article] Essential role of Rtl1 in the feto-maternal interface of mouse placenta (2008)
  • Author(s): Ogata T(計14 名中11 番目)
  • Journal Title: Nature Genetics 40 (2) Pages: 243-248
• [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): Ogata T(計24 名中最終)
  • Journal Title: Nature Genetics 40 (2) Pages: 237-242
• [Journal Article] Placental hypoplasia in maternal uniparental disomy for chromosome 7 (2008)
  • Author(s): Ogata T(計5 名中最終)
  • Journal Title: Americam Journal of Medical Gneteics A 146 (4) Pages: 514-516
• [Journal Article] Abnormal urethra formation as a model for hypospadias of the split-hand-foot malformation (SHFM) (2008)
  • Author(s): Ogata T(計12 名中3 番目)
  • Journal Title: European Journal of Human Genetics 16 (1) Pages: 36-44
• [Journal Article] Haplotype analysis of the estrogen receptor α gene in male genital and reproductive abnormalities (2007)
  • Author(s): Ogata T(計11 名中最終)
  • Journal Title: Human Reproduction 22(5) Pages: 1279-1284
• [Journal Article] Hypogonadotropic hypogonadism in an adult female with heterozygous hypomorphic mutation of SOX2 (2007)
  • Author(s): Sato N(筆頭), Ogata T(計7 名中最終)
  • Journal Title: European Journal of Endocrinology 156 (2) Pages: 167-171
• [Journal Article] CXorf6 is a causative gene for hypospadias (2006)
  • Author(s): Fukami M(筆頭), Ogata T(計12 名中最終)
  • Journal Title: Nature Genetics 38 (12) Pages: 1369-1371
• [Journal Article] Mutation and polymorphism analyses of INSL3 and LGR8/GREAT in 62 Japanese patients with cryptorchidism (2006)
  • Author(s): gata T(計 7 名中最終)
  • Journal Title: Hormone Research 67 (2) Pages: 73-76
• [Journal Article] Kallmann syndrome phenotype in a female patient with CHARGE syndrome and CHD7 mutation (2006)
  • Author(s): Ogata T(計6 名中筆頭)
  • Journal Title: Endocrine Journal 53 (6) Pages: 741-743
• [Journal Article] Urine steroid hormone profile analysis in cytochrome P450 oxidoreductase deficiency: implication for the backdoor pathway to dihydrotestosterone (2006)
  • Author(s): Fukami M(計10 名中9 番目)、 Ogata T(計10 名中最終)
  • Journal Title: Journal of Clinical Endocrinology and Metabolism 91 (7) Pages: 2643-2649
• [Journal Article] Somatic and germline mutations of the fibroblast growth factor receptor 1 gene in a mother and the son: implication for apparently mutation negative Kallmann syndrome (2006)
  • Author(s): Sato N, Ohyama K, Fukami M, Okada M, Ogata T
  • Journal Title: Journal of Clinical Endocrinology and Metabolism 91 (4) Pages: 1415-1418
• [Journal Article] Cytochrome P450 oxidoreductase deficiency in three patients initially regarded as having 21-hydroxylase deficiency and/or aromatase deficiency (2006)
  • Author(s): Fukami M, Hasegawa T, Horikawa R, Ohashi T, Nishimura G, Homma K, Ogata T
  • Journal Title: Pediatric Research 59 (2) Pages: 276-280
• [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: Fertility and Sterility 85 (3) Pages: 787-790
• [Journal Article] Association of common LH variant with hyperfunctional promoter in a Japanese infertile woman (2005)
  • Author(s): Ogata T(計5 名中2 番目)
  • Journal Title: Endocrine Journal 52 (6) Pages: 781-784
• [Journal Article] Association of severe micropenis with Gly146Ala polymorphism in the gene for steroidogenic factor-1 (2005)
  • Author(s): Wada Y, Okada M, Hasegawa T, Ogata T
  • Journal Title: Endocrine Journal 52(4) Pages: 445-448
• [Journal Article] Segmental and full paternal isodisomy for chromosome 14 in three patients: localization of the critical region and implication for the clinical features. (2005)
  • Author(s): Ogata T(計9 名中最終)
  • Journal Title: American Journal of Medical Genetics A 138 (2) Pages: 127-132
• [Journal Article] Gonadotropin therapy in Kallmann syndrome caused by heterozygous mutations of the gene for fibroblast growth factor receptor 1: report of three families (2005)
  • Author(s): Sato N, Hasegawa T, Hori N, Fukami M, Yoshimura Y, Ogata T
  • Journal Title: Human Reproduction 20 (8) Pages: 2173-2178
• [Journal Article] Association of cryptorchidism with a specific haplotype of the estrogen receptor α gene: implication for the susceptibility to estrogenic environmental endocrine disruptors (2005)
  • Author(s): Yoshida R, Fukami M, Sasagawa I, Hasegawa T, Kamatani N, Ogata T
  • Journal Title: Journal of Clinical Endocrinology and Metabolism 90(8) Pages: 4716-4721
• [Journal Article] Association of micropenis with Pro185Ala polymorphism of the gene for aryl hydrocarbon receptor repressor involved in dioxin signaling (2005)
  • Author(s): Ogata T(計7 名中最終)
  • Journal Title: Endocrine Journal 52 (1) Pages: 83-88
• [Journal Article] Cytochrome P450 oxidoreductase gene mutations and Antley-Bixler syndrome with abnormal genitalia and/or impaired steroidogenesis: molecular and clinical studies in 10 patients (2005)
  • Author(s): Fukami M(筆頭), Ogata T(計16 名中最終)
  • Journal Title: Journal of Clinical Endocrinology and Metabolism 90 Pages: 414-426
• [Journal Article] Testicular dysgenesis without adrenal insufficiency in a 46,XY patient with a heterozygous inactive mutation of steroidogenic factor-1 (2004)
  • Author(s): Hasegawa T, Fukami M, Sato N, Sasaki G, Fukutani K, Morohashi K, Ogata T
  • Journal Title: Journal of Clinical Endocrinology and Metabolism 89 Pages: 5930-5935
• [Journal Article] Association of male infertility with Pro185Ala polymorphism in the aryl hydrocarbon receptor repressor gene: implication for the susceptibility to dioxins (2004)
  • Author(s): Ogata T(67 名中最終)
  • Journal Title: Fertility and Sterility 82 Pages: 1067-1071
• [Journal Article] Testosterone enanthate therapy is effective and independent of SRD5A2 and AR gene polymorphisms in 53 Japanese boys with micropenis (2004)
  • Author(s): Ogata T(計7 名中最終)
  • Journal Title: Journal of Urology 172 (1) Pages: 319-324
• [Journal Article] Genitourinary phenotype in XX patients with distal 9p monosomy (2004)
  • Author(s): Ogata T(計7 名中最終)
  • Journal Title: Molecular Genetics and Metabolism 82 (2) Pages: 173-179
• [Journal Article] Clinical assessment and mutation analysis of Kallmann syndrome 1 (KAL1) and fibroblast growth factor receptor 1 (FGFR1, or KAL2) in five families and 18 sporadic patients (2004)
  • Author(s): Sato N(筆頭), Ogata T(計19 名中最終)
  • Journal Title: Journal of Clinical Endocrinology and Metabolism 89 (3) Pages: 1079-1088
• [Journal Article] MAMLD1(CXorf6): a new gene involved in hypospadias
  • Author(s): Ogata T, Laporte J, Fukami M
  • Journal Title: Hormone Research (in press)
• [Journal Article] Cytochrome P450 oxidoreductase deficiency: identification and characterization of biallelic mutations and genotype-phenotype correlations in 35 Japanese patients
  • Author(s): Fukami M(筆頭), Ogata T(計21 名中最終)
  • Journal Title: Journal of Clinical Endocrinology and Metabolism (in press)
• [Patent(Industrial Property Rights)] 尿道下裂および他のストロゲン依存性疾患発症のリスクとエストロゲン製剤効果の評価法としてのエストロゲン受容体α 遺伝子のSNP解析法 (2006)
  • Inventor(s): 緒方勤
  • Industrial Property Rights Holder: 国立成育医療センター
  • Industrial Property Number: 2006-116082
  • Filing Date: 2006-04-19
  • Overseas
• [Patent(Industrial Property Rights)] 新規性分化異常症責任遺伝子MHX(Cxor6)によるNotch リポーター遺伝子転写活性化の同定 (2006)
  • Inventor(s): 緒方勤
  • Industrial Property Rights Holder: 国立成育医療センター
  • Filing Date: 2006-04-07
• [Patent(Industrial Property Rights)] エストロゲン受容体α遺伝子におけるハプロタイプブロックの同定および特定ハプロタイプによる男児外陰部異常症発症感受性亢進 (2004)
  • Inventor(s): 緒方勤
  • Industrial Property Rights Holder: 国立成育医療センター
  • Industrial Property Number: 2004-250832
  • Filing Date: 2004-08-30