ヒト疾患解析にもとづく性差構築機序の解明

2014 Fiscal Year Annual Research Report

• Project Area: Molecular mechanisms for establishment of sex differences.
• Project/Area Number: 22132004
• Research Institution: Hamamatsu University School of Medicine
• Principal Investigator: 緒方 勤 浜松医科大学, 医学部, 教授 (40169173)
• Co-Investigator(Kenkyū-buntansha): 筒井 和義 早稲田大学, 教育・総合科学学術院, 教授 (20163842) ; 深見 真紀 独立行政法人国立成育医療研究センター, その他部局等, その他 (40265872)
• Project Period (FY): 2010-04-01 – 2015-03-31
• Keywords: 性差 / ヒト疾患 / ゲノム / エピゲノム / 遺伝子機能

Outline of Annual Research Achievements

本年度における主たる成果は以下の通りである。
1.裂手裂足症と性分化疾患の関連性の同定：われわれは、尿道下裂を呈する患者を含む裂手裂足症患者を有する51家系中27家系において、全く同一の日本人創始者効果によるBHLHA9を含む重複を見いだした。そして、BHLHAが、肢芽と外性器で発現していることを見出した。これは、BHLHA9が四肢末端と外性器の形成に関与することを示唆する世界初のデータである。また、裂手裂足症とゴナドトロピン分泌不全を伴う3例において機能低下を伴うFGFR1変異を見いだした。
2.Backdoor pathwayの解析：Backdoor pathwayは、testosteroneを経由しないdihydrotestosterone (DHT) 産生経路として、女児性分化疾患発症への関与が注目されている。われわれは、世界で初めて胎児診断されたPOR欠損症患者の縦断的ステロイド分析および正常男児・女児の臍帯血を用いたステロイド分析により、Backdoor pathwayが主に胎児副腎で営まれていること、中間代謝産物は多いもののDHTまでの産生は乏しいことを世界で初めて見出した。
3.Kagami-Ogata症候群における詳細な臨床像の決定：われわれが長期にわたって研究してきた第14染色体父性ダイソミーおよびその類縁疾患が、European Network for Human Congenital Imprinting DisorderによりKagami-Ogata syndromeと命名され、さらに、国際的疾患登録データベースであるOMIMにおいて#608149という番号が割り振られた。この成果は、2015年2月14日、午前10時のNHK全国ニュースで放送され、また、2015年3月4日の産経新聞朝刊と2015年3月6日の静岡新聞朝刊で報道された。

Research Progress Status

26年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

26年度が最終年度であるため、記入しない。

Research Products

• [Journal Article] Hemodynamic assessment in a child with renovascular hypertension using time-resolved three-dimensional cine phase-contrast MRI (2015)
  • Author(s): Ishikawa T*, Takehara Y, Yamashita S, Iwashima S, Sugiyama M, Wakayama T, Johnson K, Wieben O, Sakahara H, Ogata T
  • Journal Title: J Magn Reson Imaging Volume: 41(1) Pages: 165-168
  • DOI: 10.1002/jmri.24522
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] A 45,X/46,XY DSD (Disorder of Sexual Development) case with an extremely uneven distribution of 46,XY cells between lymphocytes and gonads. (2015)
  • Author(s): Nomura R, Miyai K, Okada M, Kajiwara M, Ono M, Ogata T, Onishi I, Sato M, Sekine M, Akashi T, Mizutani S, Kashimada K
  • Journal Title: Clin Pediatr Endocrinol Volume: 24(1) Pages: 11-14
  • DOI: 10.1297/cpe.24.11
  • Peer Reviewed
• [Journal Article] Silver-Russell syndrome without body asymmetry in three patients with duplications of maternally derived chromosome 11p15 involving CDKN1C (2015)
  • Author(s): Nakashima S, Kato F, Kosho T, Nagasaki K, Kikuchi T, Kagami M, Fukami M, Ogata T
  • Journal Title: J Hum Genet Volume: 60(2) Pages: 91-95
  • DOI: 10.1038/jhg.2014.100
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Detecting copy number variations in whole exome sequencing data using exome hidden markov model - an expectation of “exome-first” approach. (2015)
  • Author(s): Miyatake S, Koshimizu E, Fujita A, Fukai R, Imagawa E, Ohba C, Kuki I, Makita Y, Ogata T, Nakashima M, Tsurusaki Y, Miyake N, Saitsu H, Matsumoto N
  • Journal Title: J Hum Genet Volume: 1 Pages: 124
  • DOI: 10.1038/jhg.2014.124
  • Peer Reviewed
• [Journal Article] Copy-number variations in Y chromosomal azoospermia factor regions identified by multiplex ligation-dependent probe amplification (2015)
  • Author(s): Saito K, Miyado M, Kobori Y, Tanaka Y, Ishikawa H, Yoshida A, Katsumi M, Saito H, Kubota T, Okada H, Ogata T, Fukami M
  • Journal Title: J Hum Genet Volume: 60(3) Pages: 127-31
  • DOI: 10.1038/jhg.2014.115
  • Peer Reviewed
• [Journal Article] Comprehensive clinical studies in 34 patients with molecularly defined UPD(14)pat and related conditions (Kagami-Ogata syndrome) (2015)
  • Author(s): Kagami M, Kurosawa K, Miyazaki O, Ishino F, Matsuoka K, Ogata T
  • Journal Title: Eur J Hum Genet Volume: 2 Pages: 1-8
  • DOI: 10.1038/ejhg.2015.13
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Novel splice site mutation in MAMLD1 in a patient with hypospadias. (2015)
  • Author(s): 10.1038/ejhg.2015.13
  • Journal Title: Sex Dev Volume: 3 Pages: 1
  • DOI: 10.1159/000380842
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Molecular basis of non-syndromic hypospadias: Systematic mutation screening and genome-wide copy-number analysis of 62 patients. (2015)
  • Author(s): Kon M, Suzu ki E, Dung VC, Hasegawa Y, Mitsui T, Muroya K, Ueoka K, Igarashi N, Nagasaki K, Oto Y, Hamajima T, Yoshino K, Igarashi M, Kato-Fukui Y, Nakabayashi K, Hayashi K, Hata K, Matsubara Y, Moriya K, Ogata T, Nonomura K, Fukami M
  • Journal Title: Hum Reprod Volume: 30(3) Pages: 499-506
  • DOI: 10.1093/humrep/deu364
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Impact of a novel homozygous mutation in nicotinamide nucleotide transhydrogenase on mitochondrial DNA integrity in a case of familial glucocorticoid deficiency. (2015)
  • Author(s): Fujisawa Y, Napoli E, Wong S, Song G, Yamaguchi R, Matsui T, Nagasaki K, Ogata T, Giulivi C
  • Journal Title: BBA clinical Volume: 3 Pages: 70-78
  • DOI: 10.1016/j.bbacli.2014.12.003
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] SOX3 overdosage permits normal sex development in females with random X inactivation (2015)
  • Author(s): Igarashi M, Mikami H, Katsumi M, Miyado M, Izumi Y, Ogata T, Fukami M
  • Journal Title: Sex Dev Volume: 3 Pages: 1
  • DOI: 10.1159/000377653
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Microhomology-Mediated Microduplication in the Y Chromosomal Azoospermia Factor a (AZFa) Region in a Male with Mild Asthenozoospermia. (2015)
  • Author(s): Katsumi M, Ishikawa H, Tanaka Y, Saito K, Kobori Y, Okada H, Saito H, Nakabayashi K, Matsubara Y, Ogata T, Fukami M, Miyado M
  • Journal Title: Cytogenet Genome Res Volume: 3 Pages: 1
  • DOI: 10.1159/000377649
  • Peer Reviewed
• [Journal Article] Lack of genomic rearrangements involving the aromatase gene CYP19A1 in breast cancer. (2014)
  • Author(s): Fukami M*, Suzuki J, Nakabayashi K, Tsunashima R, Ogata T, Shozu M, Noguchi S
  • Journal Title: Breast Cancer Volume: 21 (3) Pages: 382-385
  • DOI: 10.1007/s12282-013-0471-5
  • Peer Reviewed
• [Journal Article] Aromatase excess syndrome in a family with upstream deletion of CYP19A1. (2014)
  • Author(s): Shihara D, Miyado M, Nakabayashi K, Shozu M, Nagasaki K, Ogata T, Fukami M
  • Journal Title: Clin Endocrinol Volume: 81(2) Pages: 314-316
  • DOI: 10.1111/cen.12329
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] IMAGe syndrome: clinical and genetic implications based on Iinvestigations in three Japanese patients. (2014)
  • Author(s): Kato F, Hamajima T, Hasegawa T, Amano N, Horikawa R, Nishimura G, Nakashima S, Fuke T, Sano S, Fukami M, Ogata T
  • Journal Title: Clin Endocrinol Volume: 80 (5) Pages: 706-713
  • DOI: 10.1111/cen.12379
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Genome-wide parent-of-origin DNA methylation analysis reveals the intricacies of the human imprintome and suggests a germline methylation independent establishment of imprinting (2014)
  • Author(s): Court F, Tayama C, Romanelli V, Martin-Trujillo A, Iglesias-Platas I, Okamura K, Sugahara N, Simon C, Moore H, Harness J, Keirstead H, Vicente Sanchez-Mut J, Kaneki E, Lapunzina P, Soejima H, Wake N, Esteller M, Ogata T, Hata K, Nakabayashi K, Monk D
  • Journal Title: Genome Res Volume: 24 (4) Pages: 554-569
  • DOI: 10.1101/gr.164913.113
  • Peer Reviewed
• [Journal Article] Identification and functional characterization of two novel NPR2 mutations in Japanese patients with short stature (2014)
  • Author(s): Amano N, Mukai T, Ito Y, Narumi S, Tanaka T, Yokoya S, Ogata T, Hasegawa T
  • Journal Title: J Clin Endocrinol Metab Volume: 99 (4) Pages: E713-718
  • DOI: 10.1210/jc.2013-3525
  • Peer Reviewed / Open Access
• [Journal Article] TBX1 mutation identified by exome sequencing in a Japanese family with 22q11.2 deletion syndrome-like craniofacial features and hypocalcemia. (2014)
  • Author(s): Ogata T*, Niihori T, Tanaka N, Kawai M, Nagashima T, Funayama R, Nakayama K, Nakashim S, Kato F, Fukami M, Aoki Y, Matsubara Y
  • Journal Title: PLoS One Volume: 9(3) Pages: e91598
  • DOI: 10.1371/journal.pone.0091598
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] A missense single-nucleotide polymorphism in the sialic acid acetyl esterase gene is associated with anti–PIT-1 antibody syndrome. (2014)
  • Author(s): Yamamoto M, Iguchi G, Bando H, Fukuoka H, Suda K, Takahashi M, Nishizawa H, Matsumoto R, Tojo K, Mokubo A, Ogata T, Takahashi Y
  • Journal Title: Endocr J Volume: 61 (6) Pages: 641-644
  • DOI: org/10.1507/endocrj
  • Peer Reviewed / Open Access
• [Journal Article] Mutation Spectrum and Phenotypic Variation in Nine Patients with SOX2 abnormalities (2014)
  • Author(s): Suzuki J, Azuma N, Dateki S, Soneda S, Muroya K, Yamamoto Y, Saito R, Sano S, Nagai T, Wada H, Endo A, Urakami T, Ogata T, Fukami M
  • Journal Title: J Hum Genet Volume: 59 (6) Pages: 353-356
  • DOI: 10.1038/jhg.2014.34
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Uniparental disomy of chromosome 8 leading to homozygosity of a CYP11B1 mutation in a patient with congenital adrenal hyperplasia: Implication for a rare etiology of an autosomal recessive disorder. (2014)
  • Author(s): Matsubara K, Kataoka N, Ogita S, Sano S, Ogata T, Fukami M*, Katsumata N
  • Journal Title: Endocr J Volume: 61 (6) Pages: 629-633
  • DOI: org/10.1507/endocrj
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Early vitamin K deficiency bleeding in a neonate associated with maternal Crohn's disease (2014)
  • Author(s): Ohishi A, Nakashima S, Ogata T, Iijima S
  • Journal Title: J Perinatol Volume: 34(8) Pages: 636-639
  • DOI: 10.1038/jp.2014.64
  • Peer Reviewed
• [Journal Article] De novo frameshift mutation in fibroblast growth factor 8 in a male patient with gonadotropin deficiency. (2014)
  • Author(s): Suzuki E, Yatsuga S, Igarashi M, Miyado M, Nakabayashi K, Hayashi K, Hata K, Umezawa A, Yamada G, Ogata T, Fukami M
  • Journal Title: Horm Res Paediatr Volume: 81 (2) Pages: 139-144
  • DOI: 10.1159/000355380
  • Peer Reviewed / Open Access
• [Journal Article] Rationale and study design of the Japan environment and children’s study (JECS) (2014)
  • Author(s): Kawamoto T, Nitta H, Murata K, Toda E, Tsukamoto N, Hasegawa M, Yamagata Z, Kayama F, Kshi R, Ohya Y, Saito H, Sago H, Okuyama M, Ogata T, Yokoya S, Koresawa Y, Shibata Y, Nakayama S, Michikawa T, Takeuchi A, Saitoh H
  • Journal Title: BMC Public Health Volume: 14 Pages: 25
  • DOI: 10.1186/1471-2458-14-25
  • Peer Reviewed / Open Access
• [Journal Article] A novel de novo point mutation of OCT-binding site in the IGF2/H19-imprinting control region in a patient with Beckwith-Wiedemann syndrome (2014)
  • Author(s): Higashimoto K, Jozaki K, Kosho T, Matsubara K, Sato T, Yamada D, Yatsuki H, Maeda T, Ohtsuka Y, Nishioka K, Joh K, Koseki H, Ogata T, SoejimaH
  • Journal Title: Clin Genet Volume: 86 (6) Pages: 539-544
  • DOI: 10.1111/cge.12318
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Comprehensive and quantitative multilocus methylation analysis reveals the susceptibility of specific imprinted differentially methylated regions (DMRs) to aberrant methylation in Beckwith-Wiedemann syndrome with epimutations (2014)
  • Author(s): Maeda T, Higashimoto K, Jozaki K, Hitomi H, Nakabayashi K, Makita Y, Tonoki H, Okamoto N, Takada F, Ohashi H, Migita M, Kosaki R, Matsubara K, Ogata T, Matsuo M, Hamasaki Y, Ohtsuka Y, Nishioka K, Joh K, Mukai T, Hata K, Soejima H
  • Journal Title: Genet Med Volume: 16(12) Pages: 903-912
  • DOI: 10.1038/gim.2014.46
  • Peer Reviewed / Open Access
• [Journal Article] Genome-wide copy number analysis and systematic mutation screening in 58 patients with hypogonadotropic hypogonadism (2014)
  • Author(s): Izumi Y, Suzuki E, Kanzaki S, Yatsuga S, Kinjo S, Igarashi M, Maruyama T, Sano S, Horikawa R, Sato N, Nakabayashi K, Hata K, Umezawa A, Ogata T, Yoshimura Y, Fukami M
  • Journal Title: Fertil Steril Volume: 102(4) Pages: 1130-1136
  • DOI: 10.1016/j.fertnstert.2014.06.017
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Clinical and molecular studies in four patients with SRY-positive 46,XX testicular disorders of sex development: implications for variable sex development and genomic rearrangements. (2014)
  • Author(s): Nakashima S, Oishi A, Takada F, Kawamura H, Igarashi M, Fukami M, Ogata T
  • Journal Title: J Hum Genet Volume: 59(10) Pages: 549-553
  • DOI: 10.1038/jhg.2014.70
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Japanese founder duplications/triplications involving BHLHA9 are associated with split-hand/foot malformation with or without long bone deficiency and Gallop-Wolfgang complex (2014)
  • Author(s): Nagata E, Kano H, Fukami M, Ikegawa S, Ogata T et al
  • Journal Title: Orphanet J Rare Dis Volume: 9(1) Pages: 125
  • DOI: 10.1186/s13023-014-0125-5
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Epimutations of the IG-DMR and the MEG3-DMR at the 14q32.2 imprinted region in two patients with Silver-Russell syndrome-compatible phenotype (2014)
  • Author(s): Kagami M, Mizuno S, Matsubars K, Nakabayashi K, Sano S, Fuke T, Fukami M, Ogata T
  • Journal Title: Eur J Hum Genet Volume: 11 Pages: 1-6
  • DOI: 10.1038/ejhg.2014.234.
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Hypogonadotropic hypogonadism in a female patient previously diagnosed as having Waardenburg syndrome due to a SOX10 mutation (2014)
  • Author(s): Izumi Y, Musha I, Suzuki E, Iso M, Jinno T, Horikawa R, Amemiya S, Ogata T, Fukami M, Ohtake A
  • Journal Title: Endocrine Volume: 10 Pages: 1
  • DOI: 10.1007/s12020-014-0434-4
  • Peer Reviewed
• [Journal Article] A missense single-nucleotide polymorphism in the sialic acid acetylesterase (SIAE) gene is associated with anti–PIT-1 antibody syndrome. (2014)
  • Author(s): Yamamoto M, Iguchi G, Bando H, Fukuoka H, Suda K, Takahashi M, Nishizawa H, Matsumoto R, Tojo K, Mokubo A, Ogata T, Takahashi Y
  • Journal Title: Endocr J Volume: 61(6) Pages: 641-644
  • DOI: org/10.1507/endocrj.EJ13-0539
  • Peer Reviewed / Open Access
• [Presentation] 性分化疾患における性同一性障害：性差構築からみる性同一性障害の治療戦略 (2015)
  • Author(s): 緒方勤
  • Organizer: GID（性同一性障害）学会 第17回研究大会
  • Place of Presentation: 大阪
  • Year and Date: 2015-03-21 – 2015-03-22
  • Invited
• [Presentation] Environmental Impacts on Male Sexual Differentiation. (2014)
  • Author(s): Ogata T
  • Organizer: 16th International Congress of Endocrinology & the Endocrine Society’s 96th Annual Meeting & Expo
  • Place of Presentation: シカゴ（米国）
  • Year and Date: 2014-06-21 – 2014-06-24
  • Invited
• [Presentation] 精子形成障害と内分泌撹乱化学物質感受性． (2014)
  • Author(s): 緒方勤
  • Organizer: 第33回アンドロロジー学会
  • Place of Presentation: 軽井沢
  • Year and Date: 2014-06-12 – 2014-06-13
  • Invited
• [Presentation] わかりやすい臨床遺伝学 (2014)
  • Author(s): 緒方勤
  • Organizer: 第9回日本小児耳鼻咽喉科学会
  • Place of Presentation: 浜松
  • Year and Date: 2014-06-06 – 2014-06-07
  • Invited
• [Presentation] インプリンティング疾患発症機序について (2014)
  • Author(s): 緒方勤
  • Organizer: 第56回日本小児神経学会
  • Place of Presentation: 浜松
  • Year and Date: 2014-05-29 – 2014-05-31
  • Invited
• [Presentation] Genetics of DSD (Disorders of sex development) (2014)
  • Author(s): Ogata T
  • Organizer: PAS/ASPR (Pediatric Academic Societies and Asian Society for Pediatric Research) 2014.
  • Place of Presentation: バンクーバー（カナダ）
  • Year and Date: 2014-05-03 – 2014-05-06
  • Invited
• [Presentation] インプリンティング機構と胎児・胎盤の成長 (2014)
  • Author(s): 緒方勤
  • Organizer: 第87回日本内分泌学会
  • Place of Presentation: 福岡
  • Year and Date: 2014-04-24 – 2014-04-26
  • Invited
• [Presentation] 四肢形成不全の分子遺伝学：裂手裂足症およびその関連疾患の発症機序 2014年4月17–18日，那覇． (2014)
  • Author(s): 緒方勤
  • Organizer: 第57回日本手外科学会学術集会
  • Place of Presentation: 那覇
  • Year and Date: 2014-04-17 – 2014-04-18
  • Invited
• [Presentation] 内分泌撹乱環境化学物質と男児外性器異常 (2014)
  • Author(s): 緒方勤
  • Organizer: 第117回日本小児科学会学術集会
  • Place of Presentation: 名古屋
  • Year and Date: 2014-04-11 – 2014-04-13
  • Invited