Genome-wide analyses of gene regulation mechanism during development of external genitalia and their clinical application

• Project/Area Number: 24390372
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Urology
• Research Institution: Nagoya City University
• Principal Investigator: Hayashi Yutaro 名古屋市立大学, 医学(系)研究科(研究院), 准教授 (40238134)
• Co-Investigator(Kenkyū-buntansha): KAMISAWA Hideyuki 名古屋市立大学, 大学院医学研究科, 研究員 (00551277) ; KOHRI Kenjiro 名古屋市立大学, 学長 (30122047) ; MIZUNO Kentaro 名古屋市立大学, 大学院医学研究科, 講師 (70448710) ; 小島 祥敬 福島県立医科大学, 医学部, 教授 (60305539)
• Project Period (FY): 2012-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥18,590,000 (Direct Cost: ¥14,300,000、Indirect Cost: ¥4,290,000); Fiscal Year 2015: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000); Fiscal Year 2014: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000); Fiscal Year 2013: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2012: ¥9,750,000 (Direct Cost: ¥7,500,000、Indirect Cost: ¥2,250,000)
• Keywords: ゲノム解析研究 / 性分化疾患 / 精巣 / 性分化 / ゲノムワイド解析 / 尿道下裂 / プロモーター領域

Outline of Final Research Achievements

The importance of tissue-specific promoter region is now attracting attention in the field of developmental biology. In the present study, we aimed to elucidate the developmental mechanisms of external genitalia comprehensively through genome-wide analyses of gene mutations in the patients with hypospadias, as the typical developmental disorder of external genitalia. First, we investigated the genomic structures in the patients with 46,XY testicular DSD (Disorders of sex development). As a result, we detected copy number variation at the upstream 566kb genomic region of SOX3 gene at Xq27.1. We estimated this regions as specific promoter region of SOX3 gene during testicular development.

Research Products

• [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] Truncating mutation in NFIA causes brain malformation and urinary tract defects (2015)
  • Author(s): Negishi Y, Miya F, Hattori A, Mizuno K, Hori I, Ando N, Okamoto N, Kato M, Tsunoda T, Yamasaki M, Kanemura Y, Kosaki K. Saitoh S
  • Journal Title: Human Genome Variation Volume: 2 Pages: 15007-15010
  • Peer Reviewed / Open Access
• [Journal Article] Clear cell sarcoma of the kidney distinguished from synovial sarcoma of the kidney by genetic analysis (2015)
  • Author(s): Hirose M, Mizuno K, Kamisawa H, Nishio H, Moritoki Y, Kohri K, Hayashi Y.
  • Journal Title: BMC Research Notes Volume: 8 Issue: 1 Pages: 129-133
  • DOI: 10.1186/s13104-015-1100-5
  • Peer Reviewed / Open Access
• [Journal Article] Laparoscopic modified bypass pyeloplasty: a simple procedure for straightforward ureteral spatulation and intracorporeal suturing (2015)
  • Author(s): Haga N, Sato Y, Ogawa S, Yabe M, Akaihata H, Hata J, Ishibashi K, Mizuno K, Hayashi Y, Kojima Y
  • Journal Title: International Urology and Nephrology Volume: 47 Issue: 12 Pages: 1933-1938
  • DOI: 10.1007/s11255-015-1123-9
  • Peer Reviewed
• [Journal Article] Proinflammatory and Metabolic Changes Facilitate Renal Crystal Deposition in an Obese Mouse Model of Metabolic Syndrome. (2015)
  • Author(s): Taguchi K, Okada A, Hamamoto S, Iwatsuki S, Naiki T, Ando R, Mizuno K, Tozawa K, Kohri K, Yasui T.
  • Journal Title: J Urol. Volume: 194 Issue: 6 Pages: 1787-96
  • DOI: 10.1016/j.juro.2015.07.083
  • Peer Reviewed / Open Access
• [Journal Article] Elucidation of distinctive genomic DNA structures in patients with 46, XX testicular disorders of sex development using genome-wide analyses (2014)
  • Author(s): Mizuno K, Kojima Y, Kamisawa H, Moritoki Y, Nishio H, Nakane A, Kurokawa S, Kohri K, Hayashi Y
  • Journal Title: J Urol Volume: (in press) Issue: 2 Pages: 1-7
  • DOI: 10.1016/j.juro.2014.02.044
  • Peer Reviewed / Open Access
• [Journal Article] Distinctive changes in histone H3K4 modification mediated via Kdm5a expression in spermatogonial stem cells of cryptorchid testes (2014)
  • Author(s): Nishio H, Hayashi Y, Moritoki Y, Kamisawa H, Mizuno K, Kojima Y, Kohri K
  • Journal Title: J Urol Volume: 191 Issue: 5S Pages: 1564-72
  • DOI: 10.1016/j.juro.2013.10.071
  • Peer Reviewed
• [Journal Article] Expression profiling of microRNAs in cryptorchid testes : miR-135a contributes to the maintenance of spermatogonial stem cells by regulating FoxO1 (2014)
  • Author(s): Moritoki Y, Hayashi Y, Mizuno K, Kamisawa H, Nishio H, Kurokawa S, Ugawa S, Kojima Y, Kohri K
  • Journal Title: J Urol Volume: 191 Issue: 4 Pages: 1174-80
  • DOI: 10.1016/j.juro.2013.10.137
  • Peer Reviewed / Open Access
• [Journal Article] Extravesical robotically assisted laparoscopic ureteral reimplantation with the ureteral advancement technique for vesicoureteral reflux: initial experiences in Japan (2014)
  • Author(s): Hayashi Y, Mizuno K, Kurokawa S, Nakane A, Kamisawa H, Nishio H, Moritoki Y, Tozawa K, Kohri K, Kojima Y
  • Journal Title: International Journal of Urology Volume: 21 Issue: 10 Pages: 1016-1021
  • DOI: 10.1111/iju.12483
  • Peer Reviewed
• [Journal Article] Can spongioplasty prevent fistula formation and correct penile curvature in TIP urethroplasty for hypospadias? (2013)
  • Author(s): Hayashi Y, Mizuno K, Moritoki Y, Nakane A, Kato T, Kurokawa S, Kamisawa H, Nishio H, Kohri K, Kojima Y.
  • Journal Title: UROLOGY Volume: 81 Issue: 6 Pages: 1330-1335
  • DOI: 10.1016/j.urology.2013.01.005
  • Peer Reviewed
• [Journal Article] Gene expression profile during testicular development in patients with SRY-negative 46, XX testicular disorder of sex development (2013)
  • Author(s): Mizuno K, Kojima Y, Kamisawa H, Moritoki Y, Nishio H, Kohri K, Hayashi Y
  • Journal Title: UROLOGY Volume: 82: 1453 Issue: 6 Pages: 1453-1453
  • DOI: 10.1016/j.urology.2013.08.040
  • Peer Reviewed
• [Journal Article] Cryptic genomic rearrangements in three patients with 46,XY disorders of sex development (2013)
  • Author(s): M. Igarashi, V. C. Dung, E. Suzuki, S. Ida, M. Nakacho, K. Nakabayashi, K. Mizuno, Y. Hayashi, K. Kohri, Y. Kojima, T. Ogata, M. Fukami
  • Journal Title: PLoS. One Volume: 8 Issue: 7 Pages: e68194-e68194
  • DOI: 10.1371/journal.pone.0068194
  • Peer Reviewed
• [Journal Article] Circumcision related to urinary tract infections, sexually transmitted infections, human immunodeficiency virus infections, and penile and cervical cancer. (2013)
  • Author(s): Hayashi Y, Kohri K.
  • Journal Title: International Journal of Urology Volume: 20 Issue: 8 Pages: 769-775
  • DOI: 10.1111/iju.12154
  • NAID: 10031190534
  • Peer Reviewed
• [Journal Article] Association of prolactin-induced protein with preputial development of hypospadias. (2012)
  • Author(s): S. Kurokawa, Y. Kojima, K. Mizuno, H.Kamisawa, K. Tozawa, K. Kohri, Y. Hayashi
  • Journal Title: BJU Int. Volume: 109 Issue: 6 Pages: 926-32
  • DOI: 10.1111/j.1464-410x.2011.10467.x
  • Peer Reviewed
• [Journal Article] Attenuation of spermatogonial stem cell activity in cryptorchid testes. (2012)
  • Author(s): Kamisawa H, Kojima Y, Mizuno K, Imura M, Hayashi Y, Kohri K.
  • Journal Title: The Journal of Urology Volume: 187 Issue: 3 Pages: 1047-1052
  • DOI: 10.1016/j.juro.2011.10.170
  • Peer Reviewed
• [Journal Article] Feasible etiology of vanishing testis regarding disturbance of testicular development : histopathologic and immunohistochemical evaluation of testicular nubbins (2012)
  • Author(s): Mizuno K, Kojima Y, Kamisawa H, Kurokawa S, Moritoki Y, Nishio H, Hayashi Y, Kohri K
  • Journal Title: Int J Urol Volume: 19 Issue: 5 Pages: 450-6
  • DOI: 10.1111/j.1442-2042.2011.02951.x
  • NAID: 10030754935
  • Peer Reviewed
• [Presentation] Short- and long-term results of surgical correction for buried penis (2016)
  • Author(s): Hayashi Yutaro, Mizuno Kentaro, Nishio Hidenori, Moritoki Yoshinobu, Kamisawa Hideyuki, Nakane Akihiro, Kurokawa Satoshi, Maruyama Tetsuji, Yasui Takahiro
  • Organizer: The 31th Annual Congress of the European Association of Urology
  • Place of Presentation: ミュンヘン市（ドイツ）
  • Year and Date: 2016-03-11
  • Int'l Joint Research
• [Presentation] Elucidation of regulatory mechanisms during differentiation of spermatogonial stem cell via androgen action (2015)
  • Author(s): Mizuno K, Hayashi Y, Kamisawa H, Moritoki Y, Nishio H, Kurokawa S, Nakane A, Maruyama T, Yasui T
  • Organizer: 26th European Society of Pediatric Urology Congress
  • Place of Presentation: プラハ市（チェコ共和国）
  • Year and Date: 2015-10-14
  • Int'l Joint Research
• [Presentation] 停留精巣を合併したCAKUT症例における遺伝子多型の全エクソーム解析 (2015)
  • Author(s): 水野健太郎、守時良演、林祐太郎、安井孝周
  • Organizer: 第24回 日本小児泌尿器科学会総会
  • Place of Presentation: 御茶ノ水ソラシティカンファレンスセンター（東京都千代田区）
  • Year and Date: 2015-07-01
• [Presentation] Long-term results of the surgical correction for buried penis (2015)
  • Author(s): Hayashi Yutaro, Mizuno Kentaro, Kohri Kenjiro
  • Organizer: The Society for Pediatric Urology 63rd Annual Meeting
  • Place of Presentation: ニューオーリンズ市（アメリカ合衆国）
  • Year and Date: 2015-05-15
  • Int'l Joint Research
• [Presentation] 全エクソーム解析を用いた先天性腎尿路奇形症候群における遺伝子多型の網羅的検索 (2015)
  • Author(s): 水野健太郎、西尾英紀、守時良演、岩月正一郎、神沢英幸、黒川覚史、中根明宏、丸山哲史、梅本幸裕、佐々木昌一、林祐太郎
  • Organizer: 第 103回 日本泌尿器科学会総会
  • Place of Presentation: 石川県立音楽堂、ANAクラウンプラザホテル金沢 他（石川県金沢市）
  • Year and Date: 2015-04-18
• [Presentation] 尿道下裂TIP法における海綿体形成術の経験 (2014)
  • Author(s): 林 祐太郎、水野 健太郎、守時 良演、西尾 英紀
  • Organizer: 第23回日本小児泌尿器科学会総会
  • Place of Presentation: パシフィコ横浜（神奈川県・横浜市）
  • Year and Date: 2014-07-09 – 2014-07-11
• [Presentation] Chordee without Hypospadiasの治療戦略 (2014)
  • Author(s): 林 祐太郎、水野 健太郎、守時 良演、西尾 英紀
  • Organizer: 第23回日本小児泌尿器科学会総会
  • Place of Presentation: パシフィコ横浜（神奈川県・横浜市）
  • Year and Date: 2014-07-09 – 2014-07-11
• [Presentation] 小児泌尿器科医療から“男の一生”を展望する～停留精巣と妊孕性～ (2014)
  • Author(s): 林 祐太郎
  • Organizer: 第33回日本アンドロロジー学会総会
  • Place of Presentation: 軽井沢プリンスホテルウエスト（長野県・軽井沢）
  • Year and Date: 2014-06-12 – 2014-06-13
• [Presentation] 先天性副腎過形成に対する陰核温存型女性外陰形成術 (2014)
  • Author(s): 林 祐太郎、水野 健太郎、守時 良演、郡 健二郎
  • Organizer: 第102回日本泌尿器科学会総会
  • Place of Presentation: 神戸国際会議場（兵庫県・神戸市）
  • Year and Date: 2014-04-24 – 2014-04-27
• [Presentation] 精子幹細胞の分化過程におけるアンドロゲン作用機序の解明 (2014)
  • Author(s): 水野 健太郎、神沢 英幸、守時 良演、黒川 覚史、中根 明宏、梅本 幸裕、佐々木 昌一、林 祐太郎、郡 健二郎
  • Organizer: 第102回日本泌尿器科学会総会
  • Place of Presentation: 神戸国際会議場（兵庫県・神戸市）
  • Year and Date: 2014-04-24 – 2014-04-27
• [Presentation] 小児泌尿器領域の最近の話題 (2013)
  • Author(s): 林祐太郎
  • Organizer: 第65回西日本泌尿器科学会総会
  • Place of Presentation: マリトピア・アバンセ（佐賀）
  • Invited
• [Presentation] 精巣発生における細胞接着制御Rhoシグナル伝達系の機能解析 (2013)
  • Author(s): 水野健太郎、神沢英幸、守時良演、西尾英紀、林祐太郎、郡健二郎
  • Organizer: 第101回日本泌尿器科学会総会
  • Place of Presentation: さっぽろ芸術文化の館（札幌）
• [Presentation] 精子幹細胞分化におけるアンドロゲンの役割 (2013)
  • Author(s): 水野健太郎、神沢英幸、守時良演、西尾英紀、岩月正一郎、梅本幸裕、佐々木昌一、林祐太郎、郡健二郎
  • Organizer: 日本アンドロロジー学会第32回学術大会
  • Place of Presentation: グランキューブ大阪（大阪）
• [Presentation] Elucidation of genomic DNA structures distinctive of patients with 46,XX testicular DSD using genome-wide analyses (2013)
  • Author(s): Mizuno K, Hayashi Y, Kamisawa H, Moritoki Y, Nishio H, Imura M, Shibata Y, Kurokawa S, Nakane A, Kato T, Maruyama T, Kojima Y, Kohri K.
  • Organizer: Society for Pediatric Urology’s 61st Annual Meeting
  • Place of Presentation: San Diego Convention Center( San Diego, USA)
• [Presentation] Functional analysis of Rho signaling cascade concerned with cell adhesion in the process of testicular development. (2013)
  • Author(s): Mizuno K, Hayashi Y, Kamisawa H, Moritoki Y, Nishio H, Imura M, Shibata Y, Kurokawa S, Nakane A, Kato T, Maruyama T, Kojima Y, Kohri K.
  • Organizer: AUA 2013 Annual Meeting
  • Place of Presentation: San Diego Convention Center( San Diego, USA)
• [Presentation] Spermatogonial Stem Cell Activity in Cryptorchid Testes. (2012)
  • Author(s): Kamisawa H, Mizuno K, Kojima Y, Kurokawa S, Moritoki Y, Kubota Y, Kawai N, Tozawa K, Hayashi Y, Kohri K.
  • Organizer: AUA annual meeting
  • Place of Presentation: アトランタ国際会議場(アメリカ)
  • Year and Date: 2012-05-20
• [Presentation] Feasible etiology of vanishing testis regarding disturbance of testicular development ; histopathologic and immunohistochemical evaluation of testicular nubbins. (2012)
  • Author(s): Hayashi Yutaro, Mizuno Kentaro, Kojima Yoshiyuki, Moritoki Yoshinobu, Nishio Hidenori, Kamisawa Hideyuki, Kohri Kenjiro
  • Organizer: AUA annual meeting
  • Place of Presentation: アトランタ国際会議場(アメリカ)
  • Year and Date: 2012-05-20
• [Presentation] Chordee without Hypospadiasの治療戦略。 (2012)
  • Author(s): 林祐太郎、神沢英幸、西尾英紀、守時良演、井村誠、水野健太郎、小島祥敬、郡健二郎
  • Organizer: 第100回日本泌尿器科学会総会
  • Place of Presentation: パシフィコ横浜(神奈川県)
  • Year and Date: 2012-04-22
• [Book] 今日の治療指針 2014 (2014)
  • Author(s): 林 祐太郎
  • Total Pages: 2128
  • Publisher: 医学書院
• [Book] ベッドサイド泌尿器科学 改訂第4版 (2013)
  • Author(s): 林祐太郎、小島祥敬
  • Total Pages: 1080
  • Publisher: 南江堂
• [Book] 今日の治療指針 (2013)
  • Author(s): 林裕太郎
  • Total Pages: 1900
  • Publisher: 医学書院
• [Book] ベッドサイド泌尿器科学 改訂第4版 (2013)
  • Author(s): 林祐太郎、小島祥敬
  • Total Pages: 1080
  • Publisher: 南江堂
• [Book] 今日の治療指針 (2013)
  • Author(s): 林祐太郎
  • Total Pages: 1900
  • Publisher: 医学書院