Analysis of a new genetic disorder caused by the deficiency in radiation-induced DNA double-strand break repair

• Project/Area Number: 15H05333
• Research Category: Grant-in-Aid for Young Scientists (A)
• Allocation Type: Single-year Grants
• Research Field: Risk sciences of radiation and chemicals
• Research Institution: Nagasaki University
• Principal Investigator: NAKAZAWA Yuka 長崎大学, 原爆後障害医療研究所, 助教 (00533902)
• Research Collaborator: JEGGO Penny
• Project Period (FY): 2015-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥24,310,000 (Direct Cost: ¥18,700,000、Indirect Cost: ¥5,610,000); Fiscal Year 2016: ¥11,700,000 (Direct Cost: ¥9,000,000、Indirect Cost: ¥2,700,000); Fiscal Year 2015: ¥12,610,000 (Direct Cost: ¥9,700,000、Indirect Cost: ¥2,910,000)
• Keywords: 修復 / DNA修復 / NHEJ / 遺伝性疾患

Outline of Final Research Achievements

We analyzed an uncharacterised Cockayne syndrome like patient with normal NER (nucleotide excision repair) activity. We performed next-generation exome sequencing and identified pathogenic mutations in the XRCC4 gene, which encodes a non-homologous end joining (NHEJ) protein required for the ligation process. Our XRCC4 syndrome patient retained normal immune response, although LIG4 syndrome patients usually display immunodeficiency. Fibroblast cell lines derived from the XRCC4 and LIG4 patients showed significant radiation sensitivity. We performed plasmid-based V(D)J recombination assays for the XRCC4 patient cell lines. We are currently establishing model mice to further study molecular pathogeneses of XRCC4 syndrome.

Research Products

• [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, Miyake N, Saitsu H, Ogi T, Aihara M, Takeuchi H, Matsumoto N, Tanaka F.
  • Journal Title: Journal of Human Genetics Volume: 63 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 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 T, Kagawa W, Ogi T, Kato TA, Suzuki T, Dohmae N, Takizawa K, Nakazawa Y, Genet MD, Saotome M, Hama M, Konishi T, Nakajima NI, Hazawa M, Tomita M, Koike M, Noshiro K, Tomiyama K, Obara C, Gotoh T, Ui A, Fujimori A, Nakayama F, Hanaoka F, Sugasawa K, Okayasu R, Jeggo PA, Tajima K.
  • Journal Title: PLoS Genetics Volume: 14 Pages: e1007277
  • DOI: 10.1371/journal.pgen.1007277
  • 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 Pages: e0188320
  • DOI: 10.1371/journal.pone.0188320
  • 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 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 R, Tsuchiya T, Mitsutake N, Nishimura S, Matsuu-Matsuyama M, Nakazawa Y, Ogi T, Akita S, Yukawa H, Baba Y, Yamasaki N, Matsumoto K, Miyazaki T, Kamohara R, Hatachi G, Sengyoku H, Watanabe H, Obata T, Niklason LE, Nagayasu T.
  • Journal Title: Scientific Reports Volume: 7 Pages: 8447
  • DOI: 10.1038/s41598-017-09115-2
  • Peer Reviewed / Open Access / Int'l Joint Research
• [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 Pages: e1006789
  • DOI: 10.1371/journal.pgen.1006789
  • 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: 177 Pages: 253-257
  • DOI: 10.1111/bjd.15051
  • Peer Reviewed / Open Access
• [Journal Article] A ten-year follow up of a child with mild case of xeroderma pigmentosum complementation group D diagnosed by whole genome sequencing. (2016)
  • Author(s): Ono R, Masaki T, Mayca Pozo F, Nakazawa Y, Swagemakers SM, Nakano E, Sakai W, Takeuchi S, Kanda F, Ogi T, van der Spek PJ, Sugasawa K, Nishigori C
  • Journal Title: Photodermatol Photoimmunol Photomed Volume: 32 Pages: 174-180
  • DOI: 10.1111/phpp.12240.
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Novel compound heterozygous DNA ligase IV mutations in an adolescent with a slowly- progressing radiosensitive-severe combined immunodeficiency. (2015)
  • Author(s): Tamura S, Higuchi K, Tamaki M, Inoue C, Awazawa R, Mitsuki N, Nakazawa Y, Mishima H, Takahashi K, Kondo O, Imai K, Morio T, Ohara O, Ogi T, Furukawa F, Inoue M, Yoshiura K, Kanazawa N.
  • Journal Title: Journal of Clinical Immunology Volume: 160 Pages: 255-260
  • DOI: 0.1016/j.clim.2015.07.004.
  • Peer Reviewed / Open Access
• [Journal Article] XRCC4 deficiency in human subjects causes a marked neurological phenotype but no overt immunodeficiency. (2015)
  • Author(s): Guo C, Nakazawa Y, Woodbine L, Bjorkman A, Shimada M, Fawcett H, Jia N, Ohyama K, Li TS, Nagayama Y, Mitsutake N, Pan-Hammarstrom Q, Gennery AR, Lehmann AR, Jeggo PA, Ogi T.
  • Journal Title: Journal of Allergy and Clinical Immunology Volume: 136 Pages: 1007-1017
  • DOI: 10.1016/j.jaci.2015.06.007.
  • Peer Reviewed / Open Access / Int'l Joint Research
• [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] 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] 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] 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
• [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] A Screening of Cockayne syndrome like patients identified a new class of disease associated with mutations in the XRCC4 gene. (2016)
  • Author(s): 中沢由華
  • Organizer: 10th Quinquennial Conference on Responses to DNA damage: from molecule to disease
  • Place of Presentation: Egmond aan Zee（オランダ）
  • Year and Date: 2016-04-17 – 2016-04-22
  • Int'l Joint Research
• [Presentation] ゲノム不安定性を示す遺伝性疾患の症例収集と病態解析研究. (2015)
  • Author(s): 荻 朋男、中沢由華、唐田清伸、郭 朝万、岡 泰由、賈 楠、嶋田繭子、宮﨑仁美、千住千佳子.
  • Organizer: 第38回日本分子生物学会年会
  • Place of Presentation: 神戸ポートアイランド（兵庫県神戸市）
  • Year and Date: 2015-12-03 – 2015-12-03
• [Presentation] ゲノム不安定性を示す難治性遺伝性疾患群の症例収集とゲノム・分子機能解析による病態解明研究 (2015)
  • Author(s): 中沢 由華、荻 朋男、唐田 清伸、郭 朝万、岡 泰由、 賈 楠、嶋田 繭子、宮崎 仁美、千住 千佳子
  • Organizer: 第38回日本分子生物学会年会
  • Place of Presentation: 神戸ポートアイランド（兵庫県神戸市）
  • Year and Date: 2015-12-02 – 2015-12-02
• [Presentation] XRCC4 deficiency in human subjects causes a marked neurological phenotype but no overt immunodeficiency (2015)
  • Author(s): 郭 朝万、中沢 由華、嶋田 繭子、賈 楠、唐田 清伸、 岡 泰由、宮崎 仁美、千住 千佳子、荻 朋男
  • Organizer: 第38回日本分子生物学会年会
  • Place of Presentation: 神戸ポートアイランド（兵庫県神戸市）
  • Year and Date: 2015-12-02 – 2015-12-02
• [Presentation] 各種コケイン症候群の分子診断. (2015)
  • Author(s): 賈 楠、中沢由華、荻 朋男、唐田清伸、郭 朝万、岡 泰由、 嶋田繭子、 宮崎仁美、 千住千佳子.
  • Organizer: 第38回日本分子生物学会年会
  • Place of Presentation: 神戸ポートアイランド（兵庫県神戸市）
  • Year and Date: 2015-12-02 – 2015-12-02
• [Presentation] ゲノム不安定性を示す難治性遺伝性疾患群の症例収集とゲノム・分子機能解析による病態解明研究 (2015)
  • Author(s): 中沢 由華、荻 朋男、郭 朝万、唐田 清伸、岡 泰由、賈 楠、嶋田 繭子、宮崎 仁美、千住 千佳子
  • Organizer: 第23回DNA複製・組換え・修復ワークショップ
  • Place of Presentation: 焼津グランドホテル（静岡県焼津市）
  • Year and Date: 2015-10-20 – 2015-10-20
• [Presentation] XRCC4 deficiency in human subjects causes a marked neurological phenotype but no overt immunodeficiency (2015)
  • Author(s): 郭 朝万、中沢由華、嶋田繭子、賈 楠、唐田清伸、 岡 泰由、宮崎仁美、千住千佳子、荻 朋男.
  • Organizer: 第23回DNA複製・組換え・修復ワークショップ
  • Place of Presentation: 焼津グランドホテル（静岡県焼津市）
  • Year and Date: 2015-10-20 – 2015-10-20
• [Remarks] 長崎大学原爆後障害医療研究所HP
  • URL: http://www-sdc.med.nagasaki-u.ac.jp/index-sjis.html