UBA1的體細胞突變與嚴重成人自身炎症性疾病相關
作者:
小柯機器人發布時間:2020/10/31 21:34:50
美國國立衛生研究院Peter C. Grayson團隊研究了UBA1的體細胞突變與嚴重成人自身炎症性疾病的關係。2020年10月27日,該研究發表在《新英格蘭醫學雜誌》上。
成人發病的炎症綜合症通常表現出重疊的臨床特徵。此前與自身炎症性疾病有關的泛素相關基因變異可能定義新疾病。
研究組分析了獨立於臨床表型和遺傳模式的外周血外顯子組序列數據,以鑑定泛素相關基因中的有害突變。CRISPR-Cas9編輯的斑馬魚被用作評估基因功能的體內模型。
研究組鑑定了25名具有影響UBA1中蛋氨酸-41(p.Met41)體細胞突變的男性,UBA1是引發泛素化的主要E1酶,UBA1基因位於X染色體上。這類患者在成年後期會出現一種致命的、難以治療的炎症症候群,伴有發熱、細胞減少、髓系和紅系前體細胞特徵性空泡、骨髓發育不良、中性粒細胞性皮膚和肺部炎症、軟骨炎和血管炎。
這25名患者中的大多數符合炎症綜合症(復發性軟骨炎、Sweet氏綜合症、結節性多發性動脈炎或巨細胞性動脈炎)或血液系統疾病(骨髓增生異常綜合症或多發性骨髓瘤)或兩者兼有的臨床標準。在超過一半的造血幹細胞中發現了突變,包括外周血髓樣細胞,但在淋巴細胞或成纖維細胞未發現突變。
影響p.Met41的突變導致了UBA1典型細胞質亞型的丟失,並表達了一種新的、催化受損的、始於p.Met67的亞型。突變的外周血細胞顯示泛素化降低和先天免疫通路激活。斑馬魚的胞質UBA1亞型同源物的敲除導致了系統性炎症。
利用基因型驅動的方法,研究組確定了一種看似不相關的成人發病炎症症候群之間的聯繫,並將這種疾病命名為VEXAS(空泡、E1酶、x -連接、自身炎症、體細胞)症候群。
附:英文原文
Title: Somatic Mutations in UBA1 and Severe Adult-Onset Autoinflammatory Disease | NEJM
Author: David B. Beck, M.D., Ph.D.,, Marcela A. Ferrada, M.D.,, Keith A. Sikora, M.D.,, Amanda K. Ombrello, M.D.,, Jason C. Collins, Ph.D.,, Wuhong Pei, Ph.D.,, Nicholas Balanda, B.Sc.,, Daron L. Ross, M.D.,, Daniela Ospina Cardona, B.Sc.,, Zhijie Wu, M.D., Ph.D.,, Bhavisha Patel, M.D.,, Kalpana Manthiram, M.D.,, Emma M. Groarke, M.D.,, Fernanda Gutierrez-Rodrigues, Ph.D.,, Patrycja Hoffmann, N.P.,, Sofia Rosenzweig, B.Sc.,, Shuichiro Nakabo, M.D., Ph.D.,, Laura W. Dillon, Ph.D.,, Christopher S. Hourigan, D.M., D.Phil.,, Wanxia L. Tsai, M.S.,, Sarthak Gupta, M.D.,, Carmelo Carmona-Rivera, Ph.D.,, Anthony J. Asmar, Ph.D.,, Lisha Xu, M.S.,, Hirotsugu Oda, M.D., Ph.D.,, Wendy Goodspeed, R.N.,, Karyl S. Barron, M.D.,, Michele Nehrebecky, N.P.,, Anne Jones, R.N., B.S.N.,, Ryan S. Laird, B.Sc.,, Natalie Deuitch, M.S., C.G.C.,, Dorota Rowczenio, Ph.D.,, Emily Rominger, B.Sc.,, Kristina V. Wells, B.Sc.,, Chyi-Chia R. Lee, M.D.,, Weixin Wang, Ph.D.,, Megan Trick, B.Sc.,, James Mullikin, Ph.D.,, Gustaf Wigerblad, Ph.D.,, Stephen Brooks, Ph.D.,, Stefania Dell』Orso, Ph.D.,, Zuoming Deng, Ph.D.,, Jae J. Chae, Ph.D.,, Alina Dulau-Florea, M.D.,, May C.V. Malicdan, M.D., Ph.D.,, Danica Novacic, M.D.,, Robert A. Colbert, M.D., Ph.D.,, Mariana J. Kaplan, M.D.,, Massimo Gadina, Ph.D.,, Sinisa Savic, M.B., B.S., Ph.D.,, Helen J. Lachmann, M.B., B.Chir., M.D.,, Mones Abu-Asab, Ph.D.,, Benjamin D. Solomon, M.D.,, Kyle Retterer, M.S.,, William A. Gahl, M.D., Ph.D.,, Shawn M. Burgess, Ph.D.,, Ivona Aksentijevich, M.D.,, Neal S. Young, M.D.,, Katherine R. Calvo, M.D., Ph.D.,, Achim Werner, Ph.D.,, Daniel L. Kastner, M.D., Ph.D.,, and Peter C. Grayson, M.D.
Issue&Volume: 2020-10-27
Abstract:
Background
Adult-onset inflammatory syndromes often manifest with overlapping clinical features. Variants in ubiquitin-related genes, previously implicated in autoinflammatory disease, may define new disorders.
Methods
We analyzed peripheral-blood exome sequence data independent of clinical phenotype and inheritance pattern to identify deleterious mutations in ubiquitin-related genes. Sanger sequencing, immunoblotting, immunohistochemical testing, flow cytometry, and transcriptome and cytokine profiling were performed. CRISPR-Cas9–edited zebrafish were used as an in vivo model to assess gene function.
Results
We identified 25 men with somatic mutations affecting methionine-41 (p.Met41) in UBA1, the major E1 enzyme that initiates ubiquitylation. (The gene UBA1 lies on the X chromosome.) In such patients, an often fatal, treatment-refractory inflammatory syndrome develops in late adulthood, with fevers, cytopenias, characteristic vacuoles in myeloid and erythroid precursor cells, dysplastic bone marrow, neutrophilic cutaneous and pulmonary inflammation, chondritis, and vasculitis. Most of these 25 patients met clinical criteria for an inflammatory syndrome (relapsing polychondritis, Sweet’s syndrome, polyarteritis nodosa, or giant-cell arteritis) or a hematologic condition (myelodysplastic syndrome or multiple myeloma) or both. Mutations were found in more than half the hematopoietic stem cells, including peripheral-blood myeloid cells but not lymphocytes or fibroblasts. Mutations affecting p.Met41 resulted in loss of the canonical cytoplasmic isoform of UBA1 and in expression of a novel, catalytically impaired isoform initiated at p.Met67. Mutant peripheral-blood cells showed decreased ubiquitylation and activated innate immune pathways. Knockout of the cytoplasmic UBA1 isoform homologue in zebrafish caused systemic inflammation.
Conclusions
Using a genotype-driven approach, we identified a disorder that connects seemingly unrelated adult-onset inflammatory syndromes. We named this disorder the VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome.
DOI: 10.1056/NEJMoa2026834
Source: https://www.nejm.org/doi/full/10.1056/NEJMoa2026834