Elucidation of pathogenic mechanisms of disorders of sex development using systematic molecular analysis

• Project/Area Number: 16K09979
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pediatrics
• Research Institution: National Center for Child Health and Development
• Principal Investigator: Igarashi Maki 国立研究開発法人国立成育医療研究センター, 分子内分泌研究部, 共同研究員 (10623035)
• Co-Investigator(Kenkyū-buntansha): 高田 修治 国立研究開発法人国立成育医療研究センター, システム発生・再生医学研究部, 部長 (20382856) ; 深見 真紀 国立研究開発法人国立成育医療研究センター, 分子内分泌研究部, 部長 (40265872)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2016: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 性分化疾患 / 遺伝子解析 / MAP3K1 / NR5A1 / AR / ナンセンス随伴性スプライス変更 / 遺伝子変異 / GATA4 / PROKR2 / エクソーム解析 / 機能亢進変異 / スプライス異常 / 次世代シークエンス / アレイCGH / 性分化疾患（DSD） / ゲノム解析 / 次世代シークエンサ－ / ゲノム編集

Outline of Final Research Achievements

We performed systematic molecular analysis in patients with disorders of sex development(DSD). Remarkable findings as follows: 1)Identical NR5A1 mutation was found in 2 of 8 patients with testicular/ovotesticular DSD. As the results of functional analyses, we showed for the first time in the world that, this specific mutations in NR5A1 was likely to causes for testicular development in genetic female. 2) GATA4 gene analysis was performed in 119 patients with 46,XY DSD. As the results of functional analyses, we found that a mutation identified in one case might be involved in the onset. This study demonstrate that GATA4 mutations are rare in patients with 46,XY DSD. 3) In addition to the above, principal investigator contributed to the preparation of eight scientific papers.

Academic Significance and Societal Importance of the Research Achievements

本研究成果は、性分化疾患患者の発症原因究明という点で社会的意義がある。性分化疾患患者は、出生直後に外性器の形状から、思春期以降は思春期発来の遅延によって発見されることが多く、患者にとってその原因を知ることは重要である。また、治療方針の決定にも発症原因遺伝子の情報が有用である。
本研究成果は、ヒトの性分化機構の解明という点で学術的意義がある。性分化患者の遺伝子解析を通じて、ヒトの性分化にどういう遺伝子が関与しているのかが見えてくる。これにより、生命の成り立ちをより深く理解することができる。

Research Products

• [Int'l Joint Research] アバディーン大学(英国)
• [Journal Article] A Follow-Up from Infancy to Puberty in a Japanese Male with<b><i> SRY</i></b>-Negative 46,XX Testicular Disorder of Sex Development Carrying a p.Arg92Trp Mutation in <b><i>NR5A1</i></b> (2019)
  • Author(s): Saito-Hakoda Akiko、Kanno Junko、Suzuki Dai、Kawashima Sayaka、Kamimura Miki、Hirano Koji、Sakai Kiyohide、Igarashi Maki、Fukami Maki、Fujiwara Ikuma
  • Journal Title: Sexual Development Volume: 印刷中 Issue: 2 Pages: 60-66
  • DOI: 10.1159/000496777
  • Peer Reviewed
• [Journal Article] Dihydrotestosterone induces minor transcriptional alterations in genital skin fibroblasts of children with and without androgen insensitivity (2019)
  • Author(s): Tanase-Nakao Kanako、Mizuno Kentaro、Hayashi Yutaro、Kojima Yoshiyuki、Hara Mariko、Matsumoto Kenji、Matsubara Yoichi、Igarashi Maki、Miyado Mami、Fukami Maki
  • Journal Title: Endocrine Journal Volume: 66 Issue: 4 Pages: 387-393
  • DOI: 10.1507/endocrj.EJ18-0494
  • NAID: 130007636463
  • ISSN: 0918-8959, 1348-4540
  • Peer Reviewed / Open Access
• [Journal Article] GATA4 mutations are uncommon in patients with 46,XY disorders of sex development without heart anomaly. (2018)
  • Author(s): Igarashi M, Mizuno K, Kon M, Narumi S, Kojima Y, Hayashi Y, Ogata T, Fukami M
  • Journal Title: Asian journal of andrology Volume: 印刷中 Issue: 6 Pages: 0-0
  • DOI: 10.4103/aja.aja_20_18
  • Peer Reviewed / Open Access
• [Journal Article] MIRAGE syndrome is a rare cause of 46,XY DSD born SGA without adrenal insufficiency. (2018)
  • Author(s): Shima H, Hayashi M, Tachibana T, Oshiro M, Amano N, Ishii T, Haruna H, Igarashi M, Kon M, Fukuzawa R, Tanaka Y, Fukami M, Hasegawa T, Narumi S.
  • Journal Title: PLoS One. Volume: 13 Issue: 11 Pages: e0206184-e0206184
  • DOI: 10.1371/journal.pone.0206184
  • Peer Reviewed / Open Access
• [Journal Article] Phenotypic Variation in 46,XX Disorders of Sex Development due to the NR5A1 p.R92W Variant: A Sibling Case Report and Literature Review. (2018)
  • Author(s): Takasawa K, Igarashi M, Ono M, Takemoto A, Takada S, Yamataka A, Ogata T, Morio T, Fukami M, Kashimada K.
  • Journal Title: Sexual Development Volume: 24 Issue: 5-6 Pages: 5-6
  • DOI: 10.1159/000485868
  • Peer Reviewed
• [Journal Article] Gain-of-function mutations in G-protein coupled receptor genes associated with human endocrine disorders. (2018)
  • Author(s): Fukami M, Suzuki E, Igarashi M, Miyado M and Ogata T.
  • Journal Title: Clin Endocrinol (Oxf). Volume: 88 Issue: 3 Pages: 351-359
  • DOI: 10.1111/cen.13496
  • Peer Reviewed / Open Access
• [Journal Article] Paradoxical gain-of-function mutant of the G-protein-coupled receptor PROKR2 promotes early puberty. (2017)
  • Author(s): Fukami M, Suzuki E, Izumi Y, Torii T, Narumi S, Igarashi M, Miyado M, Katsumi M, Fujisawa Y, Nakabayashi K, Hata K, Umezawa A, Matsubara Y, Yamauchi J, Ogata T.
  • Journal Title: Journal of Cellular and Molecular Medicine Volume: - Issue: 10 Pages: 2623-2626
  • DOI: 10.1111/jcmm.13146
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Identical NR5A1 Missense Mutations in Two Unrelated 46,XX Individuals with Testicular Tissues. (2017)
  • Author(s): Igarashi M, Fukami M et al.
  • Journal Title: Hum Mutat. Volume: 38 Issue: 1 Pages: 39-42
  • DOI: 10.1002/humu.23116
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A novel C-terminal truncating NR5A1 mutation in dizygotic twins. (2017)
  • Author(s): Hattori A, Zukeran H, Igarashi M, Toguchi S, Toubaru Y, Inoue T, Katoh-Fukui Y, Fukami M.
  • Journal Title: Hum Genome Var. Volume: 印刷中 Issue: 1 Pages: 17008-17008
  • DOI: 10.1038/hgv.2017.8
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] The p.R92W variant of NR5A1/Nr5a1 induces testicular development of 46,XX gonads in humans, but not in mice: phenotypic comparison of human patients and mutation-induced mice (2016)
  • Author(s): Miyado M, Inui M, Igarashi M, Katoh-Fukui Y, Takasawa K, Hakoda A, Kanno J, Kashimada K, Miyado K, Tamano M, Ogata T, Takada S, Fukami M
  • Journal Title: Biol Sex Differ Volume: 7 Issue: 1 Pages: 56-56
  • DOI: 10.1186/s13293-016-0114-6
  • Peer Reviewed / Open Access
• [Journal Article] Copy Number Variations of the Azoospermia Factor Region and SRY Are Not Associated with the Risk of Hypospadias. (2016)
  • Author(s): Kon M, Saito K, Mitsui T, Miyado M, Igarashi M, Moriya K, Nonomura K, Shinohara N, Ogata T, Fukami M.
  • Journal Title: Sexual Development Volume: 10 Issue: 1 Pages: 1-4
  • DOI: 10.1159/000444938
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] MAP3K1遺伝子のナンセンス随伴スプライス変更による46,XY性分化疾患の発症 (2018)
  • Author(s): 五十嵐麻希、金城健一、中尾美奈子、宮戸真美、堀川玲子、 緒方勤、 深見真紀
  • Organizer: 性スペクトラムー連続する表現型としての雌雄 第2 回領域会議
• [Presentation] ナンセンス随伴スプライス変更による 46,XY 性分化疾患の発症 (2018)
  • Author(s): 五十嵐 麻希
  • Organizer: 性スペクトラム-連続する表現型としての雌雄 第一回班会議
• [Presentation] 46,XY性分化疾患兄弟例におけるMAP3K1変異の同定 (2017)
  • Author(s): 五十嵐麻希、金城健一、堀川玲子、緒方勤、深見真紀
  • Organizer: 日本人類遺伝学会
• [Presentation] Nonsense-associated altered splicing leading to a human disorder: Identification of MAP3K1 mutations in two brothers with 46,XY disorders of sex development (2017)
  • Author(s): 五十嵐麻希、金城健一、堀川玲子、緒方勤、深見真紀
  • Organizer: 第40回日本分子生物学会年会
• [Presentation] NR5A1ミスセンス変異p.R92Wは、ヒトとマウスに共通する46,XY精巣形成不全とヒト特異的46,XX精巣形成を招く (2017)
  • Author(s): 宮戸真美, 乾雅史, 五十嵐麻希, 福井由宇子, 玉野萌恵, 宮戸健二, 緒方勤, 高田修治, 深見真紀
  • Organizer: 第21回日本生殖内分泌学会
  • Place of Presentation: 大阪
• [Presentation] Identical NR5A1 Missense Mutations in Two Unrelated 46,XX Individuals with Testicular Tissues. (2016)
  • Author(s): Igarashi M, Takasawa K, Hakoda A, Kanno J, Takada S, Miyado M, Tajima T, Sekido R, Ogata T, Kashimada K, Fukami M.
  • Organizer: The 9th Biennial Scientific Meeting of the Asia Pacific Paediatric Endocrine Society,
  • Place of Presentation: 東京
  • Int'l Joint Research
• [Presentation] Sequence Variations in Genes of the GH-IGF-1 Axis in Children with Idiopathic Short Stature. (2016)
  • Author(s): Hattori A, Katoh-Fukui Y, Matsubara K, Igarashi M, Suzuki E, Nakamura A, Tanaka H, Nagasaki K, Muroya K, Horikawa R, Ida S, Tanaka T, Kamimaki T, Mitani M, Ogata T, Fukami M
  • Organizer: The 9th Biennial Scientific Meeting of the Asia Pacific Paediatric Endocrine Society
  • Place of Presentation: 東京
  • Int'l Joint Research
• [Presentation] Identical NR5A1 Missense Mutations in Two Unrelated 46,XX Individuals with Testicular Tissues. (2016)
  • Author(s): Igarashi M, Takasawa K, Hakoda A, Kanno J, Takada S, Miyado M, Tajima T, Sekido R, Ogata T, Kashimada K, Fukami M
  • Organizer: 第50回日本小児内分泌学会学術集会
  • Place of Presentation: 東京
• [Presentation] 内分泌疾患の原因となる新たなGタンパク共役型受容体機能亢進メカニズムの解明. (2016)
  • Author(s): 鈴木江莉奈, 泉陽子, 鳥居知宏, 五十嵐麻希, 宮戸真美, 勝見桃理, 鳴海覚志, 山内淳司, 藤澤泰子, 緒方勤, 深見真紀
  • Organizer: 第50回日本小児内分泌学会学術集会
  • Place of Presentation: 東京
• [Presentation] NR5A1は、46,XX精巣性性分化疾患の新規発症責任遺伝子である. (2016)
  • Author(s): 五十嵐麻希, 高澤啓, 箱田明子, 菅野潤子, 高田修治, 乾雅史, 宮戸真美, 福井由宇子, 鳴海覚志, 田島敏広, 秦健一郎, 中林一彦, 松原洋一, 緒方勤, 鹿島田健一,深見真紀
  • Organizer: 第39回日本分子生物学会年会
  • Place of Presentation: 神奈川
• [Presentation] NR5A1は、46,XX精巣性性分化疾患の新規発症責任遺伝子である (2016)
  • Author(s): 五十嵐麻希, 高澤啓, 箱田明子, 菅野潤子, 高田修治, 乾雅史, 宮戸真美, 福井由宇子, 田島敏広, 秦健一郎, 中林一彦, 松原洋一, 緒方勤, 鹿島田健一,深見真紀
  • Organizer: 第39回日本小児遺伝学会学術集会
  • Place of Presentation: 東京
• [Remarks] 国立成育医療研究センター 分子内分泌研究部
  • URL: http://nrichd.ncchd.go.jp/endocrinology/index.htm
• [Remarks] 成育医療研究センター プレリリース 「ヒト性分化疾患の原因となる新たな遺伝子変異を発見」
  • URL: https://www.ncchd.go.jp/press/2016/DSDs.html
• [Remarks] 国立成育医療研究センター 研究所 分子内分泌研究部
  • URL: http://nrichd.ncchd.go.jp/endocrinology/index.htm
• [Remarks] リサーチマップ 五十嵐麻希
  • URL: https://researchmap.jp/maki_igarashi
• [Remarks] 国立成育医療研究センター 分子内分泌研究部 研究内容
  • URL: http://nrichd.ncchd.go.jp/endocrinology/ken.htm