Clarification of molecular basis of pubertal disorders and disorders of sex development

• Project/Area Number: 26293224
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Endocrinology
• Research Institution: National Center for Child Health and Development
• Principal Investigator: Fukami 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, その他 (40265872)
• Co-Investigator(Kenkyū-buntansha): 小島 祥敬 福島県立医科大学, 医学部, 教授 (60305539)
• Research Collaborator: IGARASHI Maki 国立成育医療研究センター, 分子内分泌研究部, 研究員 (10623035)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥16,640,000 (Direct Cost: ¥12,800,000、Indirect Cost: ¥3,840,000); Fiscal Year 2016: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2015: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000); Fiscal Year 2014: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000)
• Keywords: 遺伝子 / 内分泌 / 疾患 / 性分化 / ゲノム / 生殖 / 内分泌学 / 生殖内分泌

Outline of Final Research Achievements

The aim of this study was to clarify novel causes of pubertal disorders and disorders of sex development (DSD), through systematic molecular analyzes of clinical samples. To this end, we employed various molecular technologies including next-generation sequencing (NGS), array-based comparative genomic hybridization (array CGH), microsatellite analysis, and pyrosequencing.
The results of this study include the following. (i) We clarified the contribution of each known causative gene to the etiology of gonadotropin deficiency and non-syndromic hypospadias. (ii) We determined the role of the backdoor pathway in the androgen production of eumenorrheic women. (iii) We identified a novel missence substitution of NR5A1 that induces testicular development in genetic females. (iv) We identified a protein truncating mutation of NR0B1 that underlies precocious puberty.

Research Products

• [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] Xp22.31 Microdeletion due to Microhomology-Mediated Break-Induced Replication in a Boy with Contiguous Gene Deletion Syndrome. (2017)
  • Author(s): Nagai K, Shima H, Kamimura M, Kanno J, Suzuki E, Ishiguro A, Narumi S, Kure S, Fujiwara I, Fukami M
  • Journal Title: Cytogenet Genome Res. Volume: 151 Issue: 1 Pages: 1-4
  • DOI: 10.1159/000458469
  • Peer Reviewed / Int'l Joint Research / 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] NR0B1 Frameshift Mutation in a Boy with Idiopathic Central Precocious Puberty. (2016)
  • Author(s): Shima H, Fukami M et al.
  • Journal Title: Sex Dev. Volume: 10 Pages: 205-209
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Endocrinopathies in a Boy with Cryptic Copy-number Variations on 4q, 7q, and Xp (2016)
  • Author(s): Okuno M, Ogata T, Nakabayashi K, Urakami T, Fukami M, Nagasaki K.
  • Journal Title: Hum Genome Variat Volume: 未定
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Copy-Number Variations of the Azoospermia Factor Region or 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: Sex Dev Volume: 未定
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Multiple Androgen Biosynthesis Pathways Are Operating in Women with Polycystic Ovary Syndrome. (2016)
  • Author(s): Saito K, Matsuzaki T, Iwasa T, Miyado M, Saito H, Hasegawa T, Homma K, Inoue E, Kubota T, Irahara M, Ogata T, Fukami M
  • Journal Title: J Steroid Biochem Mol Biol Volume: 158 Pages: 31-37
  • DOI: 10.1016/j.jsbmb.2016.02.010
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Loss-of-Function SOX10 Mutation in a Patient with Kallmann Syndrome, Hearing Loss, and Iris Hypopigmentation. (2015)
  • Author(s): Suzuki E, Izumi Y, Chiba Y, Horikawa R, Matsubara Y, Tanaka M, Ogata T, Fukami M, Naiki Y.
  • Journal Title: Hormone Research in Paediatrics Volume: 84 Issue: 3 Pages: 212-216
  • DOI: 10.1159/000436965
  • Peer Reviewed / Int'l Joint Research / 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] 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] Hypogonadotropic hypogonadism in a female patient previously diagnosed as having Waardenburg syndrome due to a SOX10 mutation. (2015)
  • 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: 未定
  • Peer Reviewed / Acknowledgement Compliant
• [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) Issue: 3 Pages: 127-31
  • DOI: 10.1038/jhg.2014.115
  • Peer Reviewed
• [Journal Article] Novel Splice Site Mutation in MAMLD1 in a Patient with Hypospadias (2015)
  • Author(s): Igarashi M, Wada Y, Kojima Y, Miyado M, Nakamura M, Muroya K, Mizuno K, Hayashi Y, Nonomura K, Kohri K, Ogata T, Fukami M
  • Journal Title: Sex Dev Volume: 未定
  • 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: 未定
  • 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 Issue: 4 Pages: 1-1
  • DOI: 10.1159/000377649
  • Peer Reviewed
• [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
• [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
  • Year and Date: 2016-11-18
  • Int'l Joint Research
• [Presentation] NR0B1 Frameshift Mutation in a Boy with Precocious Puberty and Normal Adrenal Function. (2016)
  • Author(s): Shima H, Yatsuga S, Nakamura A, Sano S, Sasaki T, Katsumata N, Suzuki E, Ogata T, Narumi S, Fukami M.
  • Organizer: The 9th Biennial Scientific Meeting of the Asia Pacific Paediatric Endocrine Society
  • Place of Presentation: 東京
  • Year and Date: 2016-11-18
  • Int'l Joint Research
• [Presentation] X chromosomal deletion due to microhomology-mediated break-induced replication in a boy with Xp22.3 contiguous gene deletion syndrome: Implications for novel genomic defects leading to Kallmann Syndrome. (2016)
  • Author(s): Nagai K, Shima H, Kamimura M, Kanno J, Fujiwara I, Suzuki E, Narumi S, Ishiguro A, Fukami M.
  • Organizer: The 9th Biennial Scientific Meeting of the Asia Pacific Paediatric Endocrine Society
  • Place of Presentation: 東京
  • Year and Date: 2016-11-18
  • Int'l Joint Research
• [Presentation] 性分化疾患 (2015)
  • Author(s): 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: 2015-10-09
  • Invited
• [Presentation] 難聴と虹彩色素脱出を伴うKallmann症候群患者におけるSOX10機能喪失変異の同定 (2015)
  • Author(s): 鈴木江莉奈、泉陽子、千葉悠太、堀川玲子、内木康博、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] 性分化疾患の遺伝子診断と遺伝カウンセリング (2015)
  • Author(s): 深見真紀
  • Organizer: 第68回福井臨床遺伝研究会
  • Place of Presentation: 福井
  • Year and Date: 2015-07-27
  • Invited
• [Presentation] 性分化疾患の遺伝子診断 (2015)
  • Author(s): 深見真紀
  • Organizer: 第88回日本内分泌学会学術総会
  • Place of Presentation: 東京
  • Year and Date: 2015-04-25
  • Invited
• [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回日本内分泌学会学術総会
  • Place of Presentation: 東京
  • Year and Date: 2015-04-25
• [Presentation] FGFR1 変異が同定された裂手裂足症に低ゴナドトロピン性性腺機能低下症を伴う3例 (2015)
  • Author(s): 大高幸之助、矢ケ崎英晃、三好達也、長谷川行洋、長谷川奉延、三好秀明、渥美達也、瀬尾美鈴、佐藤直子、深見真紀、緒方勤
  • Organizer: 第88回日本内分泌学会学術総会
  • Place of Presentation: 東京
  • Year and Date: 2015-04-24
• [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: Hawai
  • Year and Date: 2015-04-15
  • Int'l Joint Research
• [Presentation] 先天性疾患の遺伝子診断 (2014)
  • Author(s): 深見真紀
  • Organizer: 日本人類遺伝学会
  • Place of Presentation: 船堀
  • Year and Date: 2014-11-22
  • Invited
• [Remarks] 研究開発法人国立成育医療研究センター
  • URL: https://www.ncchd.go.jp/
• [Remarks] 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
  • URL: http://nrichd.ncchd.go.jp/endocrinology/
• [Remarks] 国立研究開発法人国立成育医療研究センター
  • URL: http://www.ncchd.go.jp/
• [Remarks] 国立成育医療研究センター
  • URL: http://www.ncchd.go.jp/
• [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/