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タイトル: | A de novo dominant-negative variant is associated with OTULIN-related autoinflammatory syndrome |
著者: | Takeda, Yukiko Ueki, Masahiro Matsuhiro, Junpei Walinda, Erik ![]() ![]() ![]() Tanaka, Takayuki Yamada, Masafumi Fujita, Hiroaki ![]() ![]() ![]() Takezaki, Shunichiro Kobayashi, Ichiro Tamaki, Sakura Nagata, Sanae Miyake, Noriko Matsumoto, Naomichi Osawa, Mitsujiro Yasumi, Takahiro Heike, Toshio Ohtake, Fumiaki Saito, Megumu K. Toguchida, Junya Takita, Junko ![]() ![]() ![]() Ariga, Tadashi Iwai, Kazuhiro ![]() ![]() ![]() |
著者名の別形: | 武田, 有紀子 植木, 将弘 松廣, 淳平 田中, 孝之 山田, 雅文 藤田, 宏明 竹崎, 俊一郎 小林, 一郎 玉置, さくら 永田, 早苗 三宅, 紀子 松本, 直通 大澤, 光次郎 八角, 高裕 平家, 俊男 大竹, 史明 齋藤, 潤 戸口田, 淳也 滝田, 順子 有賀, 正 岩井, 一宏 |
キーワード: | Human disease genetics Immunodeficiency |
発行日: | 2024 |
出版者: | Rockefeller University Press |
誌名: | Journal of Experimental Medicine |
巻: | 221 |
号: | 6 |
論文番号: | e2023194 |
抄録: | OTULIN-related autoinflammatory syndrome (ORAS), a severe autoinflammatory disease, is caused by biallelic pathogenic variants of OTULIN, a linear ubiquitin-specific deubiquitinating enzyme. Loss of OTULIN attenuates linear ubiquitination by inhibiting the linear ubiquitin chain assembly complex (LUBAC). Here, we report a patient who harbors two rare heterozygous variants of OTULIN (p.P152L and p.R306Q). We demonstrated accumulation of linear ubiquitin chains upon TNF stimulation and augmented TNF-induced cell death in mesenchymal stem cells differentiated from patient-derived iPS cells, which confirms that the patient has ORAS. However, although the de novo p.R306Q variant exhibits attenuated deubiquitination activity without reducing the amount of OTULIN, the deubiquitination activity of the p.P152L variant inherited from the mother was equivalent to that of the wild-type. Patient-derived MSCs in which the p.P152L variant was replaced with wild-type also exhibited augmented TNF-induced cell death and accumulation of linear chains. The finding that ORAS can be caused by a dominant-negative p.R306Q variant of OTULIN furthers our understanding of disease pathogenesis. |
記述: | 稀少遺伝性自己炎症性疾患: OTULIN関連自己炎症症候群の新たな病態を解明~既報の疾患に新たな視点を追加し、未診断患者の診断や炎症・細胞死研究の進展に期待~. 京都大学プレスリリース. 2024-04-25. |
著作権等: | © 2024 Takeda et al. This article is available under a Creative Commons License. |
URI: | http://hdl.handle.net/2433/287958 |
DOI(出版社版): | 10.1084/jem.20231941 |
PubMed ID: | 38652464 |
関連リンク: | https://www.kyoto-u.ac.jp/ja/research-news/2024-04-25-0 |
出現コレクション: | 学術雑誌掲載論文等 |
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