Elucidation of the molecular pathogenesis of genetic disorders caused by defects in DNA damage response using deep proteomic analysis

• Project/Area Number: 18H03372
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 63020:Radiation influence-related
• Research Institution: Nagoya University
• Principal Investigator: Oka Yasuyoshi 名古屋大学, 環境医学研究所, 講師 (60762383)
• Co-Investigator(Kenkyū-buntansha): 荻 朋男 名古屋大学, 環境医学研究所, 教授 (80508317)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥17,550,000 (Direct Cost: ¥13,500,000、Indirect Cost: ¥4,050,000); Fiscal Year 2020: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000); Fiscal Year 2019: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000); Fiscal Year 2018: ¥8,320,000 (Direct Cost: ¥6,400,000、Indirect Cost: ¥1,920,000)
• Keywords: DNA損傷応答システム / ゲノム不安定性 / 遺伝性疾患 / プロテオーム解析 / 疾患ゲノム解析 / マルチオミクス解析

Outline of Final Research Achievements

DNA damage response is prerequisite for the maintenance of genomic stability. Mutations in genes encoding many components of DNA damage response can result in a number of genetic disorders. Recent extensive studies using NGS analysis identify pathogenic mutations in patients with genomic instability. Because the average healthy person has dozens of genetic variants predicted to severely disrupt protein-coding genes, known as loss-of-function variants, and WES is not able to detect chromosomal translocations, large chromosomal deletions and non-canonical splicing mutations, it is difficult to narrow down and identify pathogenic mutations from patients with extremely rare genetic diseases using only NGS technologies. Using deep proteome analysis, we found the novel disease-causing mutation in the RNASEH2B gene from the patient with microcephaly, cerebral atrophy, and basal ganglia calcification, who was undiagnosed using a WES analysis.

Academic Significance and Societal Importance of the Research Achievements

本研究では、全エキソーム解析のみでは疾患発症因子の同定に至らなかった症例について、プロテオーム解析を実施することで、原因因子を特定することが可能となった。全エキソーム解析に加えて、全ゲノム解析、RNAシーケンス解析、本研究で実施したプロテオーム解析を組み合わせた、マルチオミクス解析を実施することにより、診断率の向上ならびに未診断遺伝性疾患の病態解明へと繋がることが期待される。

Research Products

• [Journal Article] A novel missense variant in CUL3 shows altered binding ability to BTB-adaptor proteins leading to diverse phenotypes of CUL3-related disorders (2021)
  • Author(s): Kato Kohji、Miya Fuyuki、Oka Yasuyoshi、Mizuno Seiji、Saitoh Shinji
  • Journal Title: Journal of Human Genetics Volume: 66 Issue: 5 Pages: 491-498
  • DOI: 10.1038/s10038-020-00868-9
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] The sodium-glucose cotransporter-2 inhibitor Tofogliflozin prevents the progression of nonalcoholic steatohepatitis-associated liver tumors in a novel murine model. (2021)
  • Author(s): Yoshioka N, Tanaka M, Ochi K, Watanabe A, Ono K, Sawada M, Ogi T, Itoh M, Ito A, Shiraki Y, Enomoto A, Ishigami M, Fujishiro M, Ogawa Y, Suganami T.
  • Journal Title: Biomed Pharmacother Volume: 140 Pages: 111738-111738
  • DOI: 10.1016/j.biopha.2021.111738
  • Peer Reviewed / Open Access
• [Journal Article] Dealing with transcription-blocking DNA damage: Repair mechanisms, RNA polymerase II processing and human disorders (2021)
  • Author(s): Jia Nan、Guo Chaowan、Nakazawa Yuka、van den Heuvel Diana、Luijsterburg Martijn S.、Ogi Tomoo
  • Journal Title: DNA Repair Volume: 106 Pages: 103192-103192
  • DOI: 10.1016/j.dnarep.2021.103192
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] ELOF1 is a transcription-coupled DNA repair factor that directs RNA polymerase II ubiquitylation (2021)
  • Author(s): van der Weegen Yana、(著者19人)、Ogi Tomoo、Wolthuis Rob M. F.、Luijsterburg Martijn S.
  • Journal Title: Nature Cell Biology Volume: 23 Issue: 6 Pages: 595-607
  • DOI: 10.1038/s41556-021-00688-9
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Predominant cellular mitochondrial dysfunction in the TOP3A gene-caused Bloom syndrome-like disorder (2021)
  • Author(s): Jiang Wenjun、Jia Nan、Guo Chaowan、Wen Juan、Wu Lingqian、Ogi Tomoo、Zhang Huiwen
  • Journal Title: Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease Volume: 1867 Issue: 6 Pages: 166106-166106
  • DOI: 10.1016/j.bbadis.2021.166106
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Transcription-Coupled DNA Repair: From Mechanism to Human Disorder (2021)
  • Author(s): van den Heuvel Diana、van der Weegen Yana、Boer Daphne E.C.、Ogi Tomoo、Luijsterburg Martijn S.
  • Journal Title: Trends in Cell Biology Volume: 31 Issue: 5 Pages: 359-371
  • DOI: 10.1016/j.tcb.2021.02.007
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Extensive multiple organ involvement in VEXAS syndrome (2021)
  • Author(s): Takahashi Noriyuki、Takeichi Takuya、Nishida Tetsuya、Takahashi Yasuhiro、Sato Juichi、Yamamura Masahiro、Ogi Tomoo、Akiyama Masashi
  • Journal Title: Arthritis & Rheumatology Volume: - Issue: 10 Pages: 1896-1897
  • DOI: 10.1002/art.41775
  • NAID: 120007126470
  • Peer Reviewed
• [Journal Article] Hereditary Mucoepithelial Dysplasia and Autosomal-Dominant IFAP Syndrome Is a Clinical Spectrum Due to SREBF1 Variants (2020)
  • Author(s): Murase Chiaki、Takeichi Takuya、Nomura Toshifumi、Ogi Tomoo、Akiyama Masashi
  • Journal Title: Journal of Investigative Dermatology Volume: in press Issue: 6 Pages: 1596-1598
  • DOI: 10.1016/j.jid.2020.09.035
  • NAID: 120007175360
  • Peer Reviewed
• [Journal Article] Expanding the phenotype of biallelic loss‐of‐function variants in the <scp> <i>NSUN2</i> </scp> gene: Description of four individuals with juvenile cataract, chronic nephritis, or brain anomaly as novel complications (2020)
  • Author(s): Kato Kohji、Mizuno Seiji、Morton Jenny、Toyama Miho、Hara Yuichiro、Wasmer Evangeline、Lehmann Alan、Ogi Tomoo
  • Journal Title: American Journal of Medical Genetics Part A Volume: 185 Issue: 1 Pages: 282-285
  • DOI: 10.1002/ajmg.a.61927
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Digenic mutations in ALDH2 and ADH5 impair formaldehyde clearance and cause a multisystem disorder, AMeD syndrome (2020)
  • Author(s): Oka Y, Hamada M, Nakazawa Y, ..., Tanaka M, Suganami T, Nakada S, Mitsutake N, Hara Y, Kato K, ..., Kaneko H, Matsumoto N, Matsuda F, Matsuo K, Takahashi Y, Mashimo T, Kojima S, Ogi T
  • Journal Title: Science Advances Volume: 6 Issue: 51 Pages: 7197-7197
  • DOI: 10.1126/sciadv.abd7197
  • Peer Reviewed / Open Access
• [Journal Article] Topoisomerase I-driven repair of UV-induced damage in NER-deficient cells (2020)
  • Author(s): Saha Liton Kumar、Wakasugi Mitsuo、Akter Salma、Prasad Rajendra、Wilson Samuel H.、Shimizu Naoto、Sasanuma Hiroyuki、Huang Shar-yin Naomi、Agama Keli、Pommier Yves、Matsunaga Tsukasa、Hirota Kouji、Iwai Shigenori、Nakazawa Yuka、Ogi Tomoo、Takeda Shunichi
  • Journal Title: Proceedings of the National Academy of Sciences Volume: 117 Issue: 25 Pages: 14412-14420
  • DOI: 10.1073/pnas.1920165117
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Ubiquitination of DNA Damage-Stalled RNAPII Promotes Transcription-Coupled Repair (2020)
  • Author(s): Nakazawa Y, Hara Y, Oka Y, Komine O, van den Heuvel D, Guo C, Daigaku Y, Isono M, He Y, Shimada M, Kato K, Jia N, Hashimoto S, Kotani Y, Miyoshi Y, Tanaka M, Sobue A, Mitsutake N, Suganami T, Masuda A, Ohno K, Nakada S, Mashimo T, Yamanaka K, Luijsterburg MS, Ogi T
  • Journal Title: Cell Volume: 19 Issue: 6 Pages: 1228-1244
  • DOI: 10.1016/j.cell.2020.02.010
  • NAID: 120006871293
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Severe achondroplasia due to two de novo variants in the transmembrane domain of FGFR3 on the same allele: A case report. (2020)
  • Author(s): Nagata T, Matsushita M, Mishima K, Kamiya Y, Kato K, Toyama M, Ogi T, Ishiguro N, Kitoh H.
  • Journal Title: Molecular Genetics & Genomic Medicine Volume: 8 Issue: 3 Pages: 1-1
  • DOI: 10.1002/mgg3.1148
  • Peer Reviewed / Open Access
• [Journal Article] A novel NCSTN missense mutation in the signal peptide domain causes hidradenitis suppurativa, which has features characteristic of an autoinflammatory keratinization disease. (2020)
  • Author(s): Takeichi T, Matsumoto T, Nomura T, Takeda M, Niwa H, Kono M, Shimizu H, Ogi T, Akiyama M.
  • Journal Title: Br J Dermatol. Volume: 182 Issue: 2 Pages: 491-493
  • DOI: 10.1111/bjd.18445
  • Peer Reviewed / Open Access
• [Journal Article] Reduced stratum corneum acylceramides in autosomal recessive congenital ichthyosis with a NIPAL4 mutation. (2020)
  • Author(s): Murase Y, Takeichi T, Kawamoto A, Tanahashi K, Okuno Y, Takama H, Shimizu E, Ishikawa J, Ogi T, Akiyama M.
  • Journal Title: Journal of Dermatological Science Volume: 97 Issue: 1 Pages: 50-56
  • DOI: 10.1016/j.jdermsci.2019.12.001
  • NAID: 120006849002
  • Peer Reviewed / Open Access
• [Journal Article] Hailey-Hailey disease with oesophageal involvement due to a previously unreported ATP2C1 mutation (2019)
  • Author(s): Kono M, Kodera M, Inasaka Y, Hasegawa I, Muro Y, Nakazawa Y, Ogi T, Akiyama M.
  • Journal Title: European Journal of Dermatology Volume: 印刷中
  • Peer Reviewed
• [Journal Article] Bi-allelic TARS Mutations Are Associated with Brittle Hair Phenotype. (2019)
  • Author(s): Theil AF, Botta E, Raams A, Smith DEC, Mendes MI, Caligiuri G, Giachetti S, Bione S, Carriero R, Liberi G, Zardoni L, Swagemakers SMA, Salomons GS, Sarasin A, Lehmann A, van der Spek PJ, Ogi T, Hoeijmakers JHJ, Vermeulen W, Orioli D.
  • Journal Title: American Journal of Human Genetics Volume: 105 Issue: 2 Pages: 434-440
  • DOI: 10.1016/j.ajhg.2019.06.017
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The JAK/STAT3 and NF-kappa B signaling pathways regulate cancer stem cell properties in anaplastic thyroid cancer cells (2019)
  • Author(s): K. Shiraiwa, M. Mitsutake, Y. Nakazawa, T. Ogi, K. Suzuki, V. Saenko, K. Umezawa, S. Yamashita, K. Tsukamoto
  • Journal Title: Thyroid Volume: in press Issue: 5 Pages: 674-682
  • DOI: 10.1089/thy.2018.0212
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] A Japanese Case of Galli-Galli Disease due to a Previously Unreported POGLUT1 Mutation (2019)
  • Author(s): Kono M、Sawada M、Nakazawa Y、Ogi T、Muro Y、Akiyama M
  • Journal Title: Acta Dermato Venereologica Volume: 99 Issue: 4 Pages: 458-459
  • DOI: 10.2340/00015555-3119
  • Peer Reviewed / Open Access
• [Journal Article] Functional Comparison of XPF Missense Mutations Associated to Multiple DNA Repair Disorders (2019)
  • Author(s): Marin M, Ramirez MJ, Carmona MA, Jia N, Ogi T, Bogliolo M, Surralles J.
  • Journal Title: Genes Volume: 10 Issue: 1 Pages: 60-60
  • DOI: 10.3390/genes10010060
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Functional and clinical relevance of novel mutations in a large cohort of patients with Cockayne syndrome. (2018)
  • Author(s): Calmels N, Botta E, Jia N, Fawcett H, Nardo T, Nakazawa Y, Lanzafame M, Moriwaki S, Sugita K, Kubota M, Obringer C, Spitz MA, Stefanini M, Laugel V, Orioli D, Ogi T, Lehmann A.
  • Journal Title: Journal of Medical Genetics Volume: 55 Issue: 5 Pages: 329-343
  • DOI: 10.1136/jmedgenet-2017-104877
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Cerebellar ataxia-dominant phenotype in patients with ERCC4 mutations (2018)
  • Author(s): Doi H、Koyano S、Miyatake S、Nakajima S、Nakazawa Y、Kunii M、Tomita-Katsumoto A、Oda K、Yamaguchi Y、Fukai R、Ikeda S、Kato R、Ogata K、Kubota S、Hayashi N、Takahashi K、Tada M、Tanaka K、Nakashima M、Tsurusaki Y et al.
  • Journal Title: Journal of Human Genetics Volume: 63 Issue: 4 Pages: 417-423
  • DOI: 10.1038/s10038-017-0408-5
  • Peer Reviewed / Open Access
• [Presentation] プロテオーム解析を用いたDNA損傷応答機構の破綻により発症する遺伝性疾患の分子病態解明 (2021)
  • Author(s): 岡泰由、荻朋男
  • Organizer: 日本放射線影響学会
  • Invited
• [Presentation] RNA polymerase IIのユビキチン化修飾による転写共役修復開始反応の分子機構とその破綻により発症する哺乳類の神経変性のメカニズム. (2019)
  • Author(s): 荻朋男
  • Organizer: 第42回日本分子生物学会年会
  • Invited
• [Presentation] 転写共役ヌクレオチド除去修復機構に重要なRNAポリメラーゼユビキチン化部位の同定 (2019)
  • Author(s): 中沢由華, 原雄一郎, 岡泰由, 小峯起, Diana van den Heuvel, 郭朝万, 大学保一, 磯野真由, 何予希, 嶋田繭子, 加藤香奈, 賈楠, 橋下悟, 小谷祐子, 三好由夏, 田中都, 祖父江顕, 光武範吏, 菅波孝祥, 増田章男, 大野欽司, 中田慎一郎, 真下知士, 山中宏二, Martijn S. Luijsterburg, 荻朋男
  • Organizer: 第42回日本分子生物学会年会
• [Presentation] ChIP-seqを利用したDNA損傷およびヌクレオチド除去修復のモニタリング. (2019)
  • Author(s): 原雄一郎, 中沢由華, 岡泰由, 小峯起, Diana van den Heuvel, 郭朝万, 大学保一, 磯野真由, 何予希, 嶋田繭子, 加藤香奈, 賈楠, 橋下悟, 小谷祐子, 三好由夏, 田中都, 祖父江顕, 光武範吏, 菅波孝祥, 増田章男, 大野欽司, 中田慎一郎, 真下知士, 山中宏二, Martijn S. Luijsterburg, 荻朋男.
  • Organizer: 第42回日本分子生物学会年会
• [Presentation] VPS35Lの両アレルにおける機能喪失型バリアントは 3C/Ritscher-Schinzel 症候群に類似の先天異 常症候群の原因となる (2019)
  • Author(s): 加藤耕治, 岡泰由, 村松秀城, Vasilev F, 大友孝信, 大石久史, 河野好彦, 中沢由華, 荻朋男, 高橋義行, 齋藤伸治.
  • Organizer: 日本人類遺伝学会第64回大会
• [Presentation] 希少未診断疾患におけるゲノム解析およびデータ評価パイプラインの構築 (2019)
  • Author(s): 中沢由華, 原雄一郎, 遠山美穂, 岡泰由, 荻朋男.
  • Organizer: 第4回名大医薬系3部局交流シンポジウム
• [Presentation] Biallelic VPS35L pathogenic variants cause 3C/Ritscher-Schinzel-like syndrome through dysfunction of retriever complex (2019)
  • Author(s): Kato K, Oka Y, Muramatsu H, Vasilev F, Otomo T, Oishi H, Kawano Y, Nakazawa Y, Ogi T, Takahashi Y, Saitoh S.
  • Organizer: ASHG 2019 Annual Meeting
  • Int'l Joint Research
• [Presentation] マルチオミクス解析により同定した重症アイカルディ・ゴーティエ症候群の分子病態解析. (2019)
  • Author(s): 岡 泰由, 荻 朋男.
  • Organizer: 第41回日本小児遺伝学会学術集会
• [Presentation] Alterations in RNA polymerase IIo ubiquitination cause Cockayne syndrome-like premature aging phenotype in mice due to TC-NER defect. (2019)
  • Author(s): Ogi T.
  • Organizer: International Symposium on XP and other Nucleotide Excision Repair Disorders
  • Int'l Joint Research / Invited
• [Presentation] Alterations in RNA polymerase IIo ubiquitination cause Cockayne syndrome-like premature aging phenotype in mice due to TC-NER defect. (2019)
  • Author(s): Nakazawa Y, Ogi T.
  • Organizer: International Symposium on XP and other Nucleotide Excision Repair Disorders
  • Int'l Joint Research
• [Presentation] ゲノム不安定性疾患群を中心とした希少難治性疾患の次世代マルチオミクス解析と難病プラットフォーム連携による疾患原因変異の検索. (2019)
  • Author(s): 荻 朋男.
  • Organizer: 難病プラットフォーム公開シンポジウム
  • Invited
• [Presentation] DNA損傷依存的なRNAポリメラーゼのユビキチン化修飾の異常はDNA修復経路の欠損マウスで老化表現型を示す. (2019)
  • Author(s): 荻 朋男.
  • Organizer: 国立遺伝学研究所・研究集会「ゲノムの維持継承を支える分子基盤の包括的理解とその発展」
  • Invited
• [Presentation] Identification of pathogenic mutations in patients with rare diseases using multiomics approaches. (2018)
  • Author(s): Oka Y, Ogi T.
  • Organizer: Japanese Proteomics Society 2018 Conference (JPrOS 2018), 9th Asia-Oceania Human Proteome Organization (AOHUPO), and 66th Annual Conference on Mass Spectrometry
  • Int'l Joint Research
• [Presentation] ゲノム不安定性を示す遺伝性疾患の分子病態. (2018)
  • Author(s): 中沢由華, 荻 朋男.
  • Organizer: 第3回名大医薬系3部局交流シンポジウム～岐阜薬科大学・岐阜大学G-CHAIN・ラクオリア創薬合同シンポジウム～
• [Presentation] RNAポリメラーゼのユビキチン化修飾による転写共役ヌクレオチド除去修復の反応制御とコケイン症候群の病態. (2018)
  • Author(s): 荻 朋男.
  • Organizer: 第41回日本分子生物学会年会
  • Invited
• [Presentation] コケイン症候群の疾患責任遺伝子変異を特定する解析方法について. (2018)
  • Author(s): 荻 朋男, 中沢由華.
  • Organizer: コケイン症候群勉強会
• [Remarks] 名古屋大学環境医学研究所HP
  • URL: http://www.riem.nagoya-u.ac.jp/index.html
• [Remarks] 名古屋大学環境医学研究所 発生遺伝分野HP
  • URL: http://www.riem.nagoya-u.ac.jp/4/genetics/index.html
• [Patent(Industrial Property Rights)] 造血不全、発育遅滞、高発がん性、精神機能障害のモデル動物 (2020)
  • Inventor(s): 荻朋男、岡泰由
  • Industrial Property Rights Holder: 荻朋男、岡泰由
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2020-166756
  • Filing Date: 2020
• [Patent(Industrial Property Rights)] 老化マウスモデル (2019)
  • Inventor(s): 荻朋男
  • Industrial Property Rights Holder: 名古屋大学
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2019-203237
  • Filing Date: 2019