Elucidate the pathophysiology of a novel syndrome caused by genes involving ATM signal pathway

• Project/Area Number: 21K15907
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 52050:Embryonic medicine and pediatrics-related
• Research Institution: Yokohama City University
• Principal Investigator: UCHIYAMA Yuri 横浜市立大学, 附属病院, 助教 (50829794)
• Project Period (FY): 2021-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2022: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000); Fiscal Year 2021: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: ATM signaling pathway / 成長障害 / 発達障害 / 造血障害 / NGS解析 / ATMパスウェイ / 汎血球減少症 / 全エクソーム解析 / ゲノム不安定性 / 成長発達障害 / 小脳失調 / 小脳失調症

Outline of Research at the Start

染色体不安定症候群では、DNAの二重鎖切断(DSB)が生じた際の修復応答を構成する遺伝子群の異常により小脳失調、成長障害と易感染性，高発癌性等の症状を示す。DNA損傷時の修復応答経路の詳細が明らかになりつつあるにも関わらず、構成する遺伝子の機能不全に対する根治治療はまだ確立されていない。
DNAにDSBが生じた際に活性化されるATMシグナルパスウェイ上にある遺伝子A及びBの機能不全が予測される家系をそれぞれ同定した。DNA修復機構を構成する遺伝子の機能異常により引き起こされた疾患病態を解明することは、それぞれの遺伝子群の相関関係を明らかにし、診断及び治療法確立に大きく寄与すると期待される。

Outline of Final Research Achievements

In this study, RNA sequencing was performed to evaluate the functional changes of downstream genes caused by variants identified in two genes on the ATM signaling pathway, but there were no significant expression changes.
We conducted exome sequencing for 45 families with similar neurodevelopmental disorders with or without immunodeficiencies, focusing on genes on the ATM signaling pathway, and detected pathogenic variants causing neurodevelopmental disorders.
In addition, somatic variants of the UBA1 gene, strongly associated with the ATM signaling pathway, cause VEXAS syndrome. We established efficient detection methods for these variants and clarified the characteristics related to autoinflammation and hematopoietic disorders of VEXAS syndrome.

Academic Significance and Societal Importance of the Research Achievements

原因不明の先天性疾患の遺伝学的病態が解明されることで、新たな治療法開拓にも大きくつながる。また、既知疾患の遺伝学的診断がなされることにより、今後の経過の予測や、治療方針の決定に寄与することができる。効率的なバリアント検出法の確立により、より簡便に、そして精度高く診断可能となり、非常に有意義である。

Research Products

• [Journal Article] Three KINSSHIP syndrome patients with mosaic and germline AFF3 variants (2023)
  • Author(s): Inoue Yuta、Tsuchida Naomi、Okamoto Nobuhiko、Shuichi Shimakawa、Ohashi Kei、Saitoh Shinji、Ogawa Atsushi、Hamada Keisuke、Sakamoto Masamune、Miyake Noriko、Hamanaka Kohei、Fujita Atsushi、Koshimizu Eriko、Miyatake Satoko、Mizuguchi Takeshi、Ogata Kazuhiro、Uchiyama Yuri、Matsumoto Naomichi
  • Journal Title: Clinical Genetics Volume: 103 Issue: 5 Pages: 590-595
  • DOI: 10.1111/cge.14292
  • Peer Reviewed
• [Journal Article] A novel NONO variant that causes developmental delay and cardiac phenotypes (2023)
  • Author(s): Itai T、Sugie A、Nitta Y、Maki R、Suzuki T、Shinkai Y、Watanabe Y、Nakano Y、Ichikawa K、Okamoto N、Utsuno Y、Koshimizu E、Fujita A、Hamanaka K、Uchiyama Y、Tsuchida N、Miyake N、Misawa K、Mizuguchi T、Miyatake S、Matsumoto N
  • Journal Title: Scientific Reports Volume: 13 Issue: 1 Pages: 975-975
  • DOI: 10.1038/s41598-023-27770-6
  • Peer Reviewed / Open Access
• [Journal Article] Distal arthrogryposis in a girl arising from a novel TNNI2 variant inherited from paternal somatic mosaicism (2023)
  • Author(s): R. Seyama, Y. Uchiyama, Y. Kaneshi, K. Hamanaka, A. Fujita, N. Tsuchida, E. Koshimizu, K. Misawa, S. Miyatake, T. Mizuguchi, S. Makino, A. Itakura, N. Okamoto and N. Matsumoto
  • Journal Title: J Hum Genet Volume: 68 Issue: 5 Pages: 363-367
  • DOI: 10.1038/s10038-022-01117-x
  • Peer Reviewed
• [Journal Article] Imagawa-Matsumoto syndrome: SUZ12-related overgrowth disorder. (2023)
  • Author(s): Imagawa E, Seyama R, Aoi H, Uchiyama Y, Marcarini BG, Furquim I, Honjo RS, Bertola DR, Kim CA, Matsumoto N.
  • Journal Title: Clinical Genetics Volume: 103 Issue: 4 Pages: 383-391
  • DOI: 10.1111/cge.14296
  • Peer Reviewed
• [Journal Article] Pathogenic variants in SLF2 and SMC5 cause segmented chromosomes and mosaic variegated hyperploidy (2022)
  • Author(s): Grange Laura J.、... Natsume Toyoaki、... Stewart Grant S.
  • Journal Title: Nature Communications Volume: 13 Issue: 1 Pages: 6664-6664
  • DOI: 10.1038/s41467-022-34349-8
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Pathogenic variants detected by RNA sequencing in Cornelia de Lange syndrome (2022)
  • Author(s): Seyama R, Uchiyama Y, Ceroni JRM, Kim VEH, Furquim I, Honjo RS, Castro MAA, Pires LVL, Aoi H, Iwama K, Hamanaka K, Fujita A, Tsuchida N, Koshimizu E, Misawa K, Miyatake S, Mizuguchi T, Makino S, Itakura A, Bertola DR, Kim CA, Matsumoto N.
  • Journal Title: Genomics Volume: Sep;114(5) Issue: 5 Pages: 110468-110468
  • DOI: 10.1016/j.ygeno.2022.110468
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A case of VEXAS syndrome with Sweet's disease and pulmonary involvement (2022)
  • Author(s): Matsubara Akihiro、Tsuchida Naomi、Sakurai Mai、Maeda Ayaka、Uchiyama Yuri、Sasaki Kaneshige、Haji Yoichiro、Kirino Yohei、Matsumoto Naomichi、Morita Akimichi
  • Journal Title: The Journal of Dermatology Volume: 49 Issue: 5
  • DOI: 10.1111/1346-8138.16311
  • Peer Reviewed
• [Journal Article] VEXAS syndrome (2022)
  • Author(s): Uchino Kaori、Kanasugi Jo、Enomoto Megumi、Kitamura Fumiya、Tsuchida Naomi、Uchiyama Yuri、Maeda Ayaka、Kirino Yohei、Matsumoto Naomichi、Takami Akiyoshi
  • Journal Title: International Journal of Hematology Volume: 116 Issue: 4 Pages: 463-464
  • DOI: 10.1007/s12185-022-03448-z
  • Peer Reviewed
• [Journal Article] Case Report: Coexistence of Multiple Myeloma and Auricular Chondritis in VEXAS Syndrome (2022)
  • Author(s): Matsumoto Haruki、Fujita Yuya、Fukatsu Masahiko、Ikezoe Takayuki、Yokose Kohei、Asano Tomoyuki、Kawashima Kazumasa、Shakespear Norshalena、Uchiyama Yuri、Watanabe Hiroshi、Kirino Yohei、Matsumoto Naomichi、Migita Kiyoshi
  • Journal Title: Frontiers in Immunology Volume: 13 Pages: 1-6
  • DOI: 10.3389/fimmu.2022.897722
  • Peer Reviewed / Open Access
• [Journal Article] Behcet's disease with a somatic UBA1 variant: Expanding spectrum of autoinflammatory phenotypes of VEXAS syndrome (2022)
  • Author(s): Matsumoto H、Asano T、Tsuchida N、Maeda A、Yoshida S、Yokose K、Fujita Y、Temmoku J、Matsuoka N、Yashiro-Furuya M、Sato S、Irie K、Norikawa N、Yamamoto T、Endo M、Fukuchi K、Ohkawara H、Ikezoe T、Uchiyama Y、Kirino Y、Matsumoto N、Watanabe H、Migita K
  • Journal Title: Clinical Immunology Volume: 238 Pages: 108996-108996
  • DOI: 10.1016/j.clim.2022.108996
  • Peer Reviewed
• [Journal Article] Clinical images: VEXAS syndrome presenting as treatment‐refractory polyarteritis nodosa (2022)
  • Author(s): Itagane Masaki、Teruya Hiroyuki、Kato Tomohiro、Tsuchida Naomi、Maeda Ayaka、Kirino Yohei、Uchiyama Yuri、Matsumoto Naomichi、Kinjo Mitsuyo
  • Journal Title: Arthritis & Rheumatology Volume: 74 Issue: 11 Pages: 1863-1864
  • DOI: 10.1002/art.42257
  • Peer Reviewed
• [Journal Article] Acute heart failure due to left common iliac arteriovenous fistula: A case of VEXAS syndrome (2022)
  • Author(s): Yamaguchi Hiroki、Kobayashi Daisuke、Nakamura Gen、Aida Ryo、Horii Yosuke、Okamoto Takeshi、Murakami Shuichi、Kondo Daisuke、Tsuchida Naomi、Uchiyama Yuri、Maeda Ayaka、Kirino Yohei、Matsumoto Naomichi、Kurosawa Yoichi、Hasegawa Eriko、Wakamatsu Ayako、Narita Ichiei
  • Journal Title: Modern Rheumatology Case Reports Volume: 7 Issue: 1 Pages: 327-333
  • DOI: 10.1093/mrcr/rxac082
  • Peer Reviewed
• [Presentation] VEXAS症候群にみられる造血異常の特徴 (2022)
  • Author(s): 内山 由理，土田 奈緒美，前田 彩花，松本 聖生，浅野 智之，松原 章宏，伊藤 裕司，赤尾 敏之,萩山 裕之,林邉 廉, 國下 洋輔, 山崎 悦子, 國本 博義, 桐野 洋平, 松本 直通, 中島 秀明
  • Organizer: 第84回日本血液学会学術集会