Identification and functional elucidation of genetic abnormalities in patients with disorders of sex development using next-generation approaches

• Project/Area Number: 26860837
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• 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, その他部局等, 研究員 (10623035)
• Project Period (FY): 2014-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2015: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2014: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: 性分化疾患 / 次世代シークエンス / アレイCGH / 性分化疾患（DSD） / 次世代シークエンス（NGS） / ｱﾚｲCGH / SOX9 / NR5A1 / NR0B1

Outline of Final Research Achievements

We performed systematic molecular analysis of 173 patients with disorders of sex development (DSD). Remarkable findings include: (1)Identification of a splice site mutation of MAMLD1 in a patient with hypospadias. (2)Identification of genetic alterations in SOX9 and its flanking region in 3 patients with 46,XY DSD without campomelic dysplasia. (3)Identification of causative gene mutations in 8 patients with hypospadias. (4)Identification of copy number gain of SOX3 in DSD-negative females. (5)Identification of copy number variations at azoospermia-related region in patients with hypospadias. (6)Identification of identical NR5A1 mutations in two 46,XX individuals with testicular tissues. The findings from (1) to (5) were published in scientific journals, and (6) was submitted.

Research Products

• [Int'l Joint Research] アバディーン大学(英国)
• [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
• [Journal Article] Lack of Skeletal Dysplasia in Patients with Missense Mutations and Upstream Deletion of SOX9. (2015)
  • Author(s): Katoh-Fukui Y, Igarashi M, Nagasaki K, Horikawa R, Nagai T, Tsuchiya T, Suzuki E, Miyado M, Hata K, Nakabayashi K, Hayashi K, Matsubara Y, Baba T, Morohashi K, Igarashi A, Ogata T, Takada S, and Fukami M
  • Journal Title: Molecular Genetics & Genomic Medicine Volume: 3 Issue: 6 Pages: 550-557
  • DOI: 10.1002/mgg3.165
  • Peer Reviewed / Open Access / Int'l Joint Research
• [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 Issue: 3 Pages: 1-1
  • DOI: 10.1159/000377653
  • Peer Reviewed / 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 Issue: 3 Pages: 1-1
  • DOI: 10.1159/000380842
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Fertility preservation in a family with a novel <i>NR5A1</i> mutation (2015)
  • Author(s): Yagi H, Takagi M, Kon M, Igarashi M, Fukami M, Hasegawa Y.
  • Journal Title: Endocrine Journal Volume: 62 Issue: 3 Pages: 289-295
  • DOI: 10.1507/endocrj.EJ14-0340
  • NAID: 130005060861
  • ISSN: 0918-8959, 1348-4540
  • 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) Issue: 3 Pages: 499-506
  • DOI: 10.1093/humrep/deu364
  • Peer Reviewed / Open Access / 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) Issue: 10 Pages: 549-553
  • DOI: 10.1038/jhg.2014.70
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [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) Issue: 4 Pages: 1130-1136
  • DOI: 10.1016/j.fertnstert.2014.06.017
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Rapid generation of mouse models with defined point mutations by the CRISPR/Cas9 system (2014)
  • Author(s): Inui M, Miyado M, Igarashi M, Tamano M, Kubo A, Yamashita S, Asahara H, Fukami M, Takada S.
  • Journal Title: Scientific Reports Volume: 4 Issue: 1 Pages: 5396-5396
  • DOI: 10.1038/srep05396
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] SRY陰性46,XX精巣性性分化疾患患者2例に共通するNR5A1ミスセンス変異の同定 (2015)
  • Author(s): 五十嵐 麻希 、鹿島田 健一 、箱田 明子 、高澤 啓 、菅野 潤子、宮戸 真美 、 加藤 朋子、乾 雅史 、関戸 良平 、高田 修治 、緒方 勤 、深見 真紀
  • Organizer: 日本人類遺伝学会第60回大会
  • Place of Presentation: 東京
  • Year and Date: 2015-10-14
• [Presentation] SOX9伸長変異（p.Q496fsX578）はタンパク不安定性を介してacampomelic campomelic dysplasiaを招く (2015)
  • Author(s): 山口理惠, 楢村哲生, 加藤芙弥子, 門奈央子, 五十嵐麻希, 深見真紀, 緒方勤
  • Organizer: 日本人類遺伝学会第60回大会
  • Place of Presentation: 東京
  • Year and Date: 2015-10-14
• [Presentation] SRY陰性46,XX精巣性性分化疾患患者2例に共通するNR5A1ミスセンス変異の同定 (2015)
  • Author(s): 五十嵐 麻希 、鹿島田 健一 、箱田 明子 、高澤 啓 、菅野 潤子、宮戸 真美 、 加藤 朋子、乾 雅史 、関戸 良平 、高田 修治 、緒方 勤 、深見 真紀
  • Organizer: 第49回日本小児内分泌学会学術集会
  • Place of Presentation: 東京
  • Year and Date: 2015-10-08
• [Presentation] Vanishing Testis SyndromeにおけるDSD関連遺伝子の網羅的変異解析 (2015)
  • Author(s): 福井由宇子, 五十嵐麻希, 長崎啓祐, 位田忍, 堀川玲子, 鈴木江莉奈, 宮戸真美, 中村明枝, 緒方勤, 深見真紀
  • Organizer: 第49回日本小児内分泌学会学術集会
  • Place of Presentation: 東京
  • Year and Date: 2015-10-08
• [Presentation] SOX9伸長変異（p.Q496fsX578）はタンパク不安定性を介してacampomelic campomelic dysplasiaを招く (2015)
  • Author(s): 山口理惠, 楢村哲生, 加藤芙弥子, 門奈央子, 五十嵐麻希, 深見真紀, 緒方勤
  • Organizer: 第49回日本小児内分泌学会学術集会
  • Place of Presentation: 東京
  • Year and Date: 2015-10-08
• [Presentation] ヒト性分化疾患の網羅的遺伝子変異解析 (2015)
  • Author(s): 五十嵐 麻希、今 雅史、泉 陽子、福井 由宇子、鈴木 江莉奈、和田 友香、宮戸 真美、緒方 勤、深見 真紀
  • Organizer: 第88回 日本内分泌学会各術総会
  • Place of Presentation: 東京
  • Year and Date: 2015-04-23 – 2015-04-25
• [Presentation] ヒト性分化疾患の網羅的遺伝子変異解析. (2015)
  • Author(s): 五十嵐 麻希、今 雅史、泉 陽子、福井 由宇子、鈴木 江莉奈、和田 友香、宮戸 真美、緒方 勤、深見 真紀
  • Organizer: 日本内分泌学会学術総会
  • Place of Presentation: 東京
  • Year and Date: 2015-04-23
• [Presentation] Systematic mutation analysis of patients with disorders of sex development. (2015)
  • Author(s): Igarashi M, Izumi Y, Kon M, Kato-Fukui Y, Suzuki E, Wada Y, Miyado M, Ogata T, Fukami M
  • Organizer: Seventh international symposium in the biology of vertebrate sex determination
  • Place of Presentation: ﾊﾜｲ
  • Year and Date: 2015-04-13 – 2015-04-17
• [Presentation] Systematic mutation analysis of patients with disorders of sex development. (2015)
  • Author(s): Maki Igarashi, Yoko Izumi, Masafumi Kon, Yuko Kato-Fukui, Erina Suzuki, Yuka Wada, Mami Miyado, Tsutomu Ogata, Maki Fukami
  • Organizer: Seventh international symposium in the biology of vertebrate sex determination
  • Place of Presentation: ハワイ島
  • Year and Date: 2015-04-13
  • Int'l Joint Research
• [Presentation] 低ゴナドトロピン性性腺機能低下症58例の網羅的遺伝子解析 (2015)
  • Author(s): 鈴木江莉奈, 泉陽子, 神崎晋, 八ツ賀秀一, 金城さおり, 五十嵐麻希, 中林一彦, 梅沢明弘, 秦健一郎, 緒方勤, 深見真紀
  • Organizer: 第19回日本生殖内分泌学会学術集会
  • Place of Presentation: 大阪
  • Year and Date: 2015-01-10
• [Presentation] ヒト性分化異常症の網羅的遺伝子変異解析 (2014)
  • Author(s): 五十嵐 麻希、今 雅史、泉 陽子、福井 由宇子、鈴木 江莉奈、和田 友香、宮戸 真美、緒方 勤、深見 真紀
  • Organizer: 第37回日本分子生物学会年会
  • Place of Presentation: 神奈川
  • Year and Date: 2014-11-25 – 2014-11-27
• [Presentation] SRY(+)46,XX精巣性性分化疾患4症例における性分化決定因子と転座発症機序の解析 (2014)
  • Author(s): 中島信一, 大石彰, 高田史男, 河村秀樹, 小野裕之, 五十嵐麻希, 深見真紀, 緒方勤
  • Organizer: 第48回日本小児内分泌学会学術集会
  • Place of Presentation: 静岡
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] SOX9 frameshift mutation in a patient with acampomelic campomelic dysplasia:the second case (2014)
  • Author(s): 37.山口理惠, 楢村哲生, 加藤芙弥子, 永田絵子, 中島信一, 馬場崇, 諸橋憲一郎, 五十嵐麻希, 深見真紀, 緒方勤
  • Organizer: 第48回日本小児内分泌学会学術集会
  • Place of Presentation: 静岡
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] 46,XX精巣性性分化疾患を伴わない母娘例におけるSOX3重複の同定 (2014)
  • Author(s): 五十嵐麻希, 三上仁, 勝見桃理, 泉陽子, 緒方勤, 深見真紀
  • Organizer: 第48回日本小児内分泌学会学術集会
  • Place of Presentation: 静岡
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] 非症候性尿道下裂発症における単一遺伝子変異の寄与の解明 (2014)
  • Author(s): 今雅史, 室谷浩二, 長谷川行洋, 長崎啓祐, Dung Vu Chi, 上岡克彦, 大戸佑二, 五十嵐登, 三井貴彦, 鈴木江莉奈, 五十嵐麻希, 福井由宇子, 守屋仁彦, 野々村克也, 緒方勤, 深見真紀
  • Organizer: 第48回日本小児内分泌学会学術集会
  • Place of Presentation: 静岡
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] Identification of a missense MAP3K1 mutation in a patient with hypospadias. (2014)
  • Author(s): Igarashi M, Horikawa R, Nakabayashi K, Hata K, Ogata T, Fukami M.
  • Organizer: 53th annual ESPE meeting
  • Place of Presentation: Dublin
  • Year and Date: 2014-09-18 – 2014-09-20
• [Presentation] Mutation analysis of KDM3A (lysine-specific demethylase 3A) in patients with hypospadias. (2014)
  • Author(s): Kon M, Igarashi M, Izumi Y, Kato-Fukui Y, Mizuno K, Hayashi Y, Kohri K, Kojima Y, Nonomura K, Ogata T, Fukami M.
  • Organizer: 53rd Annual ESPE Meeting
  • Place of Presentation: Dublin
  • Year and Date: 2014-09-18 – 2014-09-20
• [Presentation] 妊孕性が確認できた新規SF1遺伝子異常症の父子例 (2014)
  • Author(s): 八木弘子, 高木優樹, 長谷川行洋, 五十嵐麻希, 今雅史, 深見真紀
  • Organizer: 第87回日本内分泌学会学術総会
  • Place of Presentation: 福岡
  • Year and Date: 2014-04-24 – 2014-04-26
• [Presentation] SRY陽性46,XX DSD(disorders of sex development)4症例の遺伝学的解析 (2014)
  • Author(s): 中島信一, 大石彰, 高田史男, 永田絵子, 加藤芙弥子, 山口理惠, 五十嵐麻希, 深見真紀, 中西俊樹, 緒方勤
  • Organizer: 第87回日本内分泌学会学術総会
  • Place of Presentation: 福岡
  • Year and Date: 2014-04-24 – 2014-04-26
• [Book] 日常診療における性分化の診かた。性分化疾患と遺伝子異常。 (2014)
  • Author(s): 五十嵐 麻希、深見 真紀
  • Total Pages: 5
  • Publisher: 小児内科
• [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