Establishment of the targeted NGS panel and the associated immune factors-test system for SRNS

• Project/Area Number: 16K10066
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pediatrics
• Research Institution: Kansai Medical University (2017-2018); Kobe University (2016)
• Principal Investigator: SHONO Akemi 関西医科大学, 医学部, 研究員 (10535066)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2018: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 遺伝性腎疾患 / ステロイド抵抗性ネフローゼ症候群 / 次世代シークエンサー / 疾患パネル解析 / ネフローゼ症候群 / ステロイド抵抗性 / 免疫因子 / ポドサイト / SRNS / 遺伝学 / 遺伝子

Outline of Final Research Achievements

This research design was approved by the Institutional Review Board of Kobe University School of Medicine, and the participants-derived samples and data from all affiliated institutes in Japan were collected by obtaining their written informed consents.
Genetic analysis using the targeted next generation sequencing panel (43-49 genes for SRNS/FSGS) was conducted on the affected individuals with congenital and infantile nephrotic syndrome, and steroid resistant nephrotic syndrome. The candidate mutations and their genetic segregation were confirmed by the Sanger sequencing. The causative genes were identified in an approximately 30% of the recruited familial or sporadic cases (67 out of 219 cases) to date. NPHS2 mutations were not identified in this study so far, resulting in reflection of the racial differences in the incidence compared to the Europe and the United states as reported.

Academic Significance and Societal Importance of the Research Achievements

欧州・米国・韓国においては、すでにいくつかSRNS/FSGS疾患パネルを用いた遺伝子解析と腎生検による病理学的組織所見や予後、長期フォローアップデータを統計学的にまとめた報告が出てきており、それを基にした治療方針の決定などが成されてきている。しかし、本邦では解析症例数の少なさと包括的データベースの構築が追いついておらず、患者背景や疾患発症機序に基づく検査診断体制の整備が立ち後れているのが現状である。本研究により、遺伝情報と免疫応答による複合的病態理解が進めば、副作用の少ない疾患特異的治療の開発につながり、患者QOLの向上が期待できる。

Research Products

• [Journal Article] Clinical spectrum of male patients with OFD1 mutations. (2019)
  • Author(s): Sakakibara N, Morisada N, Nozu K, Nagatani K, Ohta T, Shimizu J, Wada T, Shima Y, Yamamura T, Minamikawa S, Fujimura J, Horinouchi T, Nagano C, Shono A, Ye MJ, Nozu Y, Nakanishi K, Iijima K.
  • Journal Title: J Hum Genet. Volume: 64 Issue: 1 Pages: 3-9
  • DOI: 10.1038/s10038-018-0532-x
  • NAID: 120006888530
  • Peer Reviewed
• [Journal Article] Strong Association of the HLA-DR/DQ Locus with Childhood Steroid-Sensitive Nephrotic Syndrome in the Japanese Population. (2018)
  • Author(s): Jia X, Horinouchi T, Hitomi Y, Shono A, Khor SS, Omae Y, Kojima K, Kawai Y, Nagasaki M, Kaku Y, Okamoto T, Ohwada Y, Ohta K, Okuda Y, Fujimaru R, Hatae K, Kumagai N, Sawanobori E, Nakazato H, Ohtsuka Y, Nakanishi K, Shima Y, Tanaka R, Ashida A, Kamei K, Ishikura K, Nozu K, Tokunaga K, Iijima K
  • Journal Title: J Am Soc Nephrol. Volume: 29 Issue: 8 Pages: 2189-2199
  • DOI: 10.1681/asn.2017080859
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Long-term clinicopathologic observation in a case of steroid-resistant nephrotic syndrome caused by a novel Crumbs homolog 2 mutation. (2018)
  • Author(s): Watanabe S, Aizawa T, Tsukaguchi H, Tsugawa K, Tsuruga K, Shono A, Nozu K, Iijima K, Joh K, Tanaka H.
  • Journal Title: Nephrology (Carlton) Volume: - Issue: 7 Pages: 697-702
  • DOI: 10.1111/nep.13244
  • Peer Reviewed
• [Journal Article] Natural History and Genotype?Phenotype Correlation in Female X-Linked Alport Syndrome (2017)
  • Author(s): Yamamura Tomohiko、Nozu Kandai、Fu Xue Jun、Nozu Yoshimi、Ye Ming Juan、Shono Akemi、Yamanouchi Satoko、Minamikawa Shogo、Morisada Naoya、Nakanishi Koichi、Shima Yuko、Yoshikawa Norishige、Ninchoji Takeshi、Morioka Ichiro、Kaito Hiroshi、Iijima Kazumoto
  • Journal Title: Kidney Int Rep. Volume: 2 Issue: 5 Pages: 850-855
  • DOI: 10.1016/j.ekir.2017.04.011
  • NAID: 120006373817
  • Peer Reviewed / Open Access
• [Journal Article] ETV6-ABL1 fusion combined with monosomy 7 in childhood B-precursor acute lymphoblastic leukemia. Int J Hematol. (2017)
  • Author(s): Uemura S, Nishimura N, Hasegawa D, Shono A, Sakaguchi K, Matsumoto H, Nakamachi Y, Saegusa J, Yokoi T, Tahara T, Tamura A, Yamamoto N, Saito A, Kozaki A, Kishimoto K, Ishida T, Nino N, Takafuji S, Mori T, Iijima K, Kosaka Y.
  • Journal Title: Int J Hematol. Volume: 印刷中 Issue: 5 Pages: 604-609
  • DOI: 10.1007/s12185-017-2371-5
  • Peer Reviewed
• [Journal Article] Involvement of WNT Signaling in the Regulation of Gestational Age-Dependent Umbilical Cord-Derived Mesenchymal Stem Cell Proliferation. (2017)
  • Author(s): 7: Iwatani S, Shono A, Yoshida M, Yamana K, Thwin KKM, Kuroda J, Kurokawa D, Koda T, Nishida K, Ikuta T, Fujioka K, Mizobuchi M, Taniguchi-Ikeda M, Morioka I, Iijima K, Nishimura N.
  • Journal Title: Stem Cells Int. Volume: - Pages: 1-16
  • DOI: 10.1155/2017/8749751
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Gestational Age-Dependent Increase of Survival Motor Neuron Protein in Umbilical Cord-Derived Mesenchymal Stem Cells. (2017)
  • Author(s): Iwatani S, Harahap NIF, Nurputra DK, Tairaku S, Shono A, Kurokawa D, Yamana K, Thwin KKM, Yoshida M, Mizobuchi M, Koda T, Fujioka K, Taniguchi-Ikeda M, Yamada H, Morioka I, Iijima K, Nishio H, Nishimura N.
  • Journal Title: Front Pediatr. Volume: - Pages: 194-194
  • DOI: 10.3389/fped.2017.00194
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Cryptic exon activation in SLC12A3 in Gitelman syndrome. (2017)
  • Author(s): Nozu K, Nozu Y, Nakanishi K, Konomoto T, Horinouchi T, Shono A, Morisada N, Minamikawa S, Yamamura T, Fujimura J, Nakanishi K, Ninchoji T, Kaito H, Morioka I, Taniguchi-Ikeda M, Vorechovsky I, Iijima K
  • Journal Title: J Hum Genet. Volume: 62 Issue: 2 Pages: 335-337
  • DOI: 10.1038/jhg.2016.129
  • NAID: 40021065185
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Female X-linked Alport syndrome with somatic mosaicism (2016)
  • Author(s): Yokota K, Nozu K, Minamikawa S, Yamamura T, Nakanishi K, Kaneda H, Hamada R, Nozu Y, Shono A, Ninchoji T, Morisada N, Ishimori S, Fujimura J, Horinouchi T, Kaito H, Nakanishi K, Morioka I, Taniguchi-Ikeda M, Iijima K.
  • Journal Title: Clin Exp Nephrol. Volume: 印刷中 Issue: 5 Pages: 877-883
  • DOI: 10.1007/s10157-016-1352-y
  • Peer Reviewed / Open Access
• [Journal Article] Genetic, Clinical, and Pathologic Backgrounds of Patients with Autosomal Dominant Alport Syndrome. (2016)
  • Author(s): Kamiyoshi N, Nozu K, Fu XJ, Morisada N, Nozu Y, Ye MJ, Imafuku A, Miura K, Yamamura T, Minamikawa S, Shono A, Ninchoji T, Morioka I, Nakanishi K, Yoshikawa N, Kaito H, Iijima K
  • Journal Title: Clin J Am Soc Nephrol. Volume: 11 Issue: 8 Pages: 1441-1449
  • DOI: 10.2215/cjn.01000116
  • Peer Reviewed
• [Journal Article] Identification of mutations in FN1 leading to glomerulopathy with fibronectin deposits. (2016)
  • Author(s): Ohtsubo H, Okada T, Nozu K, Takaoka Y, Shono A, Asanuma K, Zhang L, Nakanishi K, Taniguchi-Ikeda M, Kaito H, Iijima K, Nakamura SI
  • Journal Title: Pediatr Nephrol. Volume: 58 Issue: 9 Pages: 1459-1467
  • DOI: 10.1007/s00467-016-3368-7
  • Peer Reviewed / Open Access
• [Journal Article] X-linked Alport syndrome associated with a synonymous p.Gly292Gly mutation alters the splicing donor site of the type IV collagen alpha chain 5 gene. (2016)
  • Author(s): Fu XJ, Nozu K, Eguchi A, Nozu Y, Morisada N, Shono A, Taniguchi-Ikeda M, Shima Y, Nakanishi K, Vorechovsky I, Iijima K.
  • Journal Title: Clin Exp Nephrol. Volume: 20(5) Pages: 699-702
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] 次世代シークエンサーを用いた先天性腎尿路奇形(CAKUT)の原因遺伝子解析 (2016)
  • Author(s): 森貞 直哉, 庄野 朱美, 野津 寛大, 叶 明娟, 神田 祥一郎, 井藤 奈央子, 亀井 宏一, 伊藤 秀一, 山本 勝輔, 里村 憲一, 田中 亮二郎, 西尾 久英, 飯島 一誠
  • Journal Title: 発達腎研究会誌 Volume: 24(1) Pages: 13-15
  • Peer Reviewed
• [Presentation] 早産児の臍帯由来間葉系幹細胞の増殖におけるWNTシグナル経路の役割 (2017)
  • Author(s): 岩谷 壮太, 庄野 朱美, 山名 啓司, Khin Kyae Mon Thwin, 黒川 大輔, 西田 浩輔, 西山 将広, 藤岡 一路, 生田 寿彦, 吉田 牧子, 溝渕 雅巳, 森岡 一朗, 飯島 一誠, 西村 範行
  • Organizer: 第16回日本再生医療学会総会
  • Place of Presentation: 仙台国際センター（宮城県仙台市）
  • Year and Date: 2017-03-07
• [Presentation] ブレオマイシン誘発肺障害モデルラットにおける臍帯由来間葉系幹細胞の効果 (2017)
  • Author(s): 山名 啓司, 岩谷 壮太, 黒川 大輔, Kyae Mon Thwin Khin, 西田 浩輔, 西山 将広, 藤岡 一路, 庄野 朱美, 生田 寿彦, 吉田 牧子, 溝渕 雅巳, 森岡 一朗, 飯島 一誠, 西村 範行
  • Organizer: 第16回日本再生医療学会総会
  • Place of Presentation: 仙台国際センター（宮城県仙台市）
  • Year and Date: 2017-03-07
• [Presentation] エクソンスキッピング療法によるアルポート症候群特異的治療法の開発 (2017)
  • Author(s): 庄野朱美, 野津寛大, 小泉誠, 大西朗之, 高石巨澄, 山村智彦, 南川将吾, 飯島一誠
  • Organizer: 第52 回日本小児腎臓病学会学術集会
• [Presentation] NGSターゲット遺伝子シークエンスパネルによるCAKUTおよびNPHの包括的原因遺伝子解析 (2017)
  • Author(s): 森貞直哉, 庄野朱美, 野津寛大, 忍頂寺毅史, 叶明娟, 井藤奈央子, 神田祥一郎, 亀井宏一, 石倉健司, 伊藤秀一, 山本勝輔, 塚口裕康, 里村憲一, 田中亮二郎, 飯島一誠
  • Organizer: 第52 回日本小児腎臓病学会学術集会
• [Presentation] minigeneを用いた遺伝性腎疾患におけるpathogenic splicing variantの同定 (2017)
  • Author(s): 3.山村智彦, 野津寛大, 久富隆太郎, 上田博章, 藤丸李可, 藤村順也, 城之内智子, 中西啓太, 南川将吾, 庄野朱美, 忍頂寺毅史, 貝藤裕史, 中西浩一, 飯島一誠
  • Organizer: 第52 回日本小児腎臓病学会学術集会
• [Presentation] 次世代シークエンサーによる稀少ネフロン癆関連シリオパチーの原因遺伝子解析 (2016)
  • Author(s): 森貞直哉，野津寛大，庄野朱美，忍頂寺毅史，田中亮二郎，飯島一誠
  • Organizer: 第39回日本小児遺伝学会学術集会
  • Place of Presentation: 慶應義塾大学三田北館ホールと会議室（東京都港区）
  • Year and Date: 2016-12-09
• [Presentation] Biallelic NUP107 mutations in early childhood-onset steroid resistant nephrotic syndrome. (2016)
  • Author(s): Miyake N, Tsukaguchi H, Koshimizu E, Shono A, Matsumoto N.
  • Organizer: American Society of Human Genetics 2016 Annual Meeting
  • Place of Presentation: Vancouver (Canada)
  • Year and Date: 2016-10-16
  • Int'l Joint Research
• [Presentation] Rare nephronophthisis related ciliopathy identified by next generation sequencing in ten non-consanguineous families. (2016)
  • Author(s): Morisada N, Shono A, Nozu K, Ninchoji T, Nagatani K, Ohta T, Shimizu J, Yoshikawa T, Saida K, Ishimori S, Yasui M, Nagano C, Kamei K, Ishikura K, Ito S, Tanaka R, Iijima K.
  • Organizer: American Society of Human Genetics 2016 Annual Meeting
  • Place of Presentation: Vancouver (Canada)
  • Year and Date: 2016-10-16
  • Int'l Joint Research
• [Presentation] 遺伝子から見たネフローゼ 遺伝子異常から見た特発性ネフローゼ症候群発症機序-ステロイド感受性ネフローゼも含めて- (2016)
  • Author(s): 庄野朱美
  • Organizer: 第51回日本小児腎臓病学会学術集会
  • Place of Presentation: ウインクあいち（愛知県名古屋市）
  • Year and Date: 2016-07-07
  • Invited
• [Presentation] 小児早期発症ステロイド抵抗性ネフローゼ症候群におけるNUP107変異の同定 (2016)
  • Author(s): 塚口裕康, 三宅紀子, 輿水江里子, 庄野朱美, 野津寛大, 秋岡祐子, 服部元史, 香美祥二,飯島一誠, 松本直通
  • Organizer: 第59回日本腎臓学会学術総会
  • Place of Presentation: パシフィコ横浜（神奈川横浜市）
  • Year and Date: 2016-06-17
• [Presentation] 両アレル性NUP107変異は早期小児期発症ステロイド抵抗性ネフローゼ症候群を引き起こす (2016)
  • Author(s): 三宅紀子, 塚口裕康, 輿水江里子, 庄野朱美, 野津寛大, 秋岡祐子, 服部元史, 飯島一誠, 松本直通
  • Organizer: 第119回日本小児科学会学術集会
  • Place of Presentation: ロイトン札幌/さっぽろ芸術文化の館（北海道札幌市）
  • Year and Date: 2016-05-13
• [Presentation] Biallelic NUP107 Mutations Cause Early Childhood-Onset Steroid Resistant Nephrotic Syndrome. (2016)
  • Author(s): Miyake N, Tsukaguchi H, Koshimizu E, Shono A, Matsunaga S, Shiina M, Mimura Y, Imamura S, Hirose T, Okudela K, Cheong HI, Ohashi K, Imamoto N, Ryo A, Ogata K, Iijima K, Matsumoto N.
  • Organizer: The 13th International Congress of Human Genetics 2016
  • Place of Presentation: 国立京都国際会館（京都府京都市）
  • Year and Date: 2016-04-03
  • Int'l Joint Research
• [Presentation] The comprehensive genetic analysis of congenital anomalies of the kidney and urinary tract (CAKUT) in Japan. (2016)
  • Author(s): Morisada N, Shono A, Taniguchi-Ikeda M, Nozu K, Kamei K, Ishikura K, Ito S, Tanaka R, Nishio H, Iijima K.
  • Organizer: The 13th International Congress of Human Genetics 2016
  • Place of Presentation: 国立京都国際会館（京都府京都市）
  • Year and Date: 2016-04-03
  • Int'l Joint Research
• [Remarks] 神戸大学大学院医学研究科内科系講座小児科学分野
  • URL: http://www.med.kobe-u.ac.jp/pediat/
• [Remarks] 国立大学法人 神戸大学
  • URL: http://www.kobe-u.ac.jp/
• [Remarks] 神戸大学 医学研究科・医学部
  • URL: http://www.med.kobe-u.ac.jp/
• [Patent(Industrial Property Rights)] アルポート症候群治療薬 (2017)
  • Inventor(s): 飯島、野津、庄野、小泉、大西、高石、足立
  • Industrial Property Rights Holder: 飯島、野津、庄野、小泉、大西、高石、足立
  • Industrial Property Rights Type: 特許
  • Filing Date: 2017
• [Patent(Industrial Property Rights)] アルポート症候群治療薬 (2017)
  • Inventor(s): 飯島、野津、庄野、小泉、大西、高石、足立
  • Industrial Property Rights Holder: 飯島、野津、庄野、小泉、大西、高石、足立
  • Industrial Property Rights Type: 特許
  • Filing Date: 2017
  • Overseas