Molecular pathogenesis of human genetic disorders associated with deficiency in the DNA repair and damage response system

• Project/Area Number: 17H00783
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Risk sciences of radiation and chemicals
• Research Institution: Nagoya University
• Principal Investigator: OGI Tomoo 名古屋大学, 環境医学研究所, 教授 (80508317)
• Co-Investigator(Kenkyū-buntansha): 光武 範吏 長崎大学, 原爆後障害医療研究所, 教授 (50404215) ; 真下 知士 大阪大学, 医学系研究科, 准教授 (80397554)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥42,770,000 (Direct Cost: ¥32,900,000、Indirect Cost: ¥9,870,000); Fiscal Year 2019: ¥10,660,000 (Direct Cost: ¥8,200,000、Indirect Cost: ¥2,460,000); Fiscal Year 2018: ¥15,210,000 (Direct Cost: ¥11,700,000、Indirect Cost: ¥3,510,000); Fiscal Year 2017: ¥16,900,000 (Direct Cost: ¥13,000,000、Indirect Cost: ¥3,900,000)
• Keywords: ゲノム不安定性疾患 / DNA修復 / DNA損傷応答 / 次世代オミクス解析 / 転写共役修復 (TC-NER) / 修復

Outline of Final Research Achievements

We have investigated on human genetic disorders associated with genome instability. Patients with these syndromes have developed various clinical manifestations due to malfunctions of DNA repair and damage response system. We have collected undiagnosed cases and tried to elucidate the genetic cause of diseases using the Multi-omics approach that involves next-generation sequencing, high-accurate mass spectrometry, and precise DNA repair assays. Once we identified pathogenic variants, we have performed in vitro and in vivo analyses as well as animal studies so that we could get new insights into the molecular pathogenesis of the diseases. Recently, we have reported a detailed molecular mechanism of the initiation of transcription-coupled repair, which is compromised in Cockayne syndrome.

Academic Significance and Societal Importance of the Research Achievements

ゲノム不安定性疾患群とは、DNA修復・損傷応答システムの先天異常により発症する疾患の総称であり、多数の疾患が含まれ、また各々の病態が類似することから臨床診断に難渋することも多い。オミクス解析により、ゲノム不安定性疾患の発症メカニズムを遺伝子・分子レベルで詳細に理解することは、難病患者の確定診断技術の開発や疾患緩和薬/治療薬開発へ寄与するとともに、ゲノムの安定維持機構の作動原理の理解を通して、がんや老化といった人類が直面している医学上の未解決課題に挑戦する上で欠かすことのできない基礎科学知識の蓄積に貢献することが可能である。

Research Products

• [Int'l Joint Research] Sussex Univ. GDSC(英国)
• [Int'l Joint Research] LUMC(オランダ)
• [Int'l Joint Research] CNR(イタリア)
• [Int'l Joint Research] Sussex Univ. GDSC(英国)
• [Int'l Joint Research] LUMC(オランダ)
• [Int'l Joint Research] CNR(イタリア)
• [Int'l Joint Research] Sussex Univ. GDSC(英国)
• [Int'l Joint Research] LUMC(オランダ)
• [Int'l Joint Research] CNR(イタリア)
• [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] Biallelic VPS35L pathogenic variants cause 3C/Ritscher-Schinzel-like syndrome through dysfunction of retriever complex. (2020)
  • Author(s): Kato K, Okuno Y, Vasilev FF, Otomo T, Oishi H, Muramatsu H, Kawano Y, Oka Y, Nakazawa Y, Ogi T, Takahashi Y, Saitoh S.
  • Journal Title: Journal of Medical genetics Volume: 57 Issue: 4 Pages: 245-253
  • DOI: 10.1136/jmedgenet-2019-106213
  • 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] 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
• [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] Novel function of HATs and HDACs in homologous recombination through acetylation of human RAD52 at double-strand break sites (2018)
  • Author(s): Yasuda Takeshi、Kagawa Wataru、Tajima Katsushi
  • Journal Title: PLOS Genetics Volume: 14 Issue: 3 Pages: 1007277-1007277
  • DOI: 10.1371/journal.pgen.1007277
  • NAID: 120006459820
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] ALC1/CHD1L, a chromatin-remodeling enzyme, is required for efficient base excision repair. (2017)
  • Author(s): Tsuda M, Cho K, Ooka M, Shimizu N, Watanabe R, Yasui A, Nakazawa Y, Ogi T, Harada H, Agama K, Nakamura J, Asada R, Fujiike H, Sakuma T, Yamamoto T, Murai J, Hiraoka M, Koike K, Pommier Y, Takeda S, Hirota K.
  • Journal Title: PLos One Volume: 12 Issue: 11 Pages: e0188320-e0188320
  • DOI: 10.1371/journal.pone.0188320
  • NAID: 120006800808
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Common TFIIH recruitment mechanism in global genome and transcription-coupled repair subpathways. (2017)
  • Author(s): Okuda M, Nakazawa Y, Guo C, Ogi T, Nishimura Y.
  • Journal Title: Nucleic Acids Research Volume: 45 Issue: 22 Pages: 13043-13055
  • DOI: 10.1093/nar/gkx970
  • Peer Reviewed / Open Access
• [Journal Article] Transplantation of bioengineered rat lungs recellularized with endothelial and adipose-derived stromal cells (2017)
  • Author(s): Doi Ryoichiro, Tsuchiya Tomoshi, Mitsutake Norisato, Nishimura Satoshi, Matsuu-Matsuyama Mutsumi, Nakazawa Yuka, Ogi Tomoo, Akita Sadanori, Yukawa Hiroshi, Baba Yoshinobu, Yamasaki Naoya, Matsumoto Keitaro, Miyazaki Takuro, Kamohara Ryotaro, Hatachi Go, Sengyoku Hideyori et al.
  • Journal Title: Scientific Reports Volume: 7 Issue: 1 Pages: 1-15
  • DOI: 10.1038/s41598-017-09115-2
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Calcification in dermal fibroblasts from a patient with GGCX syndrome accompanied by upregulation of osteogenic molecules. (2017)
  • Author(s): Okubo Y, Masuyama R, Iwanaga A, Koike Y, Kuwatsuka Y, Ogi T, Yamamoto Y, Endo Y, Tamura H, Utani A.
  • Journal Title: PLoS One. Volume: 12 Issue: 5 Pages: 99-99
  • DOI: 10.1371/journal.pone.0177375
  • NAID: 120007185935
  • Peer Reviewed / Open Access
• [Journal Article] PCNA ubiquitylation ensures timely completion of unperturbed DNA replication in fission yeast. (2017)
  • Author(s): Daigaku Y, Etheridge TJ, Nakazawa Y, Nakayama M, Watson AT, Miyabe I, Ogi T, Osborne MA, Carr AM.
  • Journal Title: PLoS Genetics Volume: 13 Issue: 5 Pages: e1006789-e1006789
  • DOI: 10.1371/journal.pgen.1006789
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Analysis of clinical symptoms and ABCC6 mutations in 76 Japanese patients with pseudoxanthoma elasticum. (2017)
  • Author(s): Iwanaga A, Okubo Y, Yozaki M, Koike Y, Kuwatsuka Y, Tomimura S, Yamamoto Y, Tamura H, Ikeda S, Maemura K, Tsuiki E, Kitaoka T, Endo Y, Mishima H, Yoshiura KI, Ogi T, Tanizaki H, Wataya-Kaneda M, Hattori T, Utani A.
  • Journal Title: Journal of Dermatology Volume: 印刷中 Issue: 6 Pages: 644-650
  • DOI: 10.1111/1346-8138.13727
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] An XPA gene splicing mutation resulting in trace protein expression in an elderly xeroderma pigmentosum group A patient without neurological abnormalities. (2017)
  • Author(s): Takahashi Y, Endo Y, Kusaka A, Nakamaura S, Nakazawa Y, Ogi T, Uryu M, Tsuji M, Furue M, Moriwaki S.
  • Journal Title: British Journal of Dermatology Volume: 印刷中 Issue: 1 Pages: 253-257
  • DOI: 10.1111/bjd.15051
  • Peer Reviewed / Open Access / Int'l Joint Research
• [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] 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] 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] 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] 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] 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] Very mild Japanese Cockayne syndrome (type-IV) cases with a N-terminal truncation mutation in the ERCC6 / CSB gene. (2018)
  • Author(s): Ogi T.
  • Organizer: 国際シンポジウム「早老症と関連疾患」
  • Int'l Joint Research / Invited
• [Presentation] Human genetic disorders associated with TC-NER deficiency. (2017)
  • Author(s): Ogi T.
  • Organizer: 第２回神戸大学バイオシグナル総合研究センター国際シンポジウム
  • Int'l Joint Research / Invited
• [Presentation] Very mild CS type-IV cases with mutation in the CSB gene. (2017)
  • Author(s): Ogi T.
  • Organizer: Cockayne Syndrome Meeting.
  • Int'l Joint Research / Invited
• [Presentation] Human genetics disorders associated with DNA repair deficiency. (2017)
  • Author(s): Ogi T.
  • Organizer: 6th US-Japan DNA Repair Meeting
  • Int'l Joint Research / Invited
• [Presentation] DNA損傷依存的なRNAポリメラーゼの修飾とヒト疾患. (2017)
  • Author(s): 荻 朋男
  • Organizer: 国立遺伝学研究所・研究集会「染色体構築と安定化を担う分子機構」
  • Invited
• [Presentation] ゲノム不安定性を示す遺伝性疾患の次世代マルチオミクス解析. (2017)
  • Author(s): 荻 朋男
  • Organizer: 第7回名古屋大学医学系研究科・生理学研究所合同シンポジウム
  • Invited
• [Presentation] ミニレクチャー「ゲノム不安定性疾患群を中心とした希少疾患の次世代マルチオミクス病態解析」 (2017)
  • Author(s): 荻 朋男
  • Organizer: 第12回東海小児遺伝カンファレンス
  • Invited
• [Presentation] Molecular pathogenesis underlying Cockayne syndrome and UV-sensitive syndrome. (2017)
  • Author(s): Jia N, Guo C, Oka Y, Nakazawa Y, Shimada M, Miyazaki H, Ogi T.
  • Organizer: 第40回日本分子生物学会年会
• [Presentation] Very mild CS type-IV cases with mutations in the CSB gene. (2017)
  • Author(s): Jia N, Guo C, Oka Y, Nakazawa Y, Shimada M, Miyazaki H, Ogi T.
  • Organizer: 第24回DNA複製・組換え・修復ワークショップ
• [Presentation] DNA修復機構欠損性疾患の病態解明研究. (2017)
  • Author(s): 中沢由華、賈楠、嶋田繭子、宮崎仁美、千住千佳子、郭朝万、岡泰由、荻朋男.
  • Organizer: 第２回放射線災害・医科学研究拠点カンファランス
• [Presentation] Whole exome sequencing of 14 schizophrenia multiplex families in Japan. (2017)
  • Author(s): Toyama M, Takasaki Y, Aleksic B, Ogi T, Ozaki N.
  • Organizer: Human Genome Meeting 2018
• [Presentation] マルチオミクス解析による希少遺伝性疾患発症責任因子の同定. (2017)
  • Author(s): 岡泰由、中沢由華、荻朋男.
  • Organizer: 第40回日本分子生物学会年会
• [Presentation] ゲノム不安定性を示す遺伝性疾患群の疾患責任遺伝子変異の探索. (2017)
  • Author(s): 中沢由華、千住千佳子、岡泰由、嶋田繭子、宮崎仁美、郭朝万、賈楠、荻朋男.
  • Organizer: 第40回日本分子生物学会年会
• [Presentation] A Novel Gene Mutation Of Japanese Xeroderma Pigmentosum Complementation Group F Patients. (2017)
  • Author(s): Senju C, Nakazawa Y, Ogi T.
  • Organizer: 第40回日本分子生物学会年会
• [Presentation] Identification of pathogenic mutations in patients with rare diseases using multi-omics analysis. (2017)
  • Author(s): Oka Y, Nakazawa Y, Ogi T.
  • Organizer: 日本プロテオーム学会2017年大会
• [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)] 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