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UBA1的体细胞突变与严重成人自身炎症性疾病相关
作者:小柯机器人 发布时间:2020/10/31 21:34:50

美国国立卫生研究院Peter C. Grayson团队研究了UBA1的体细胞突变与严重成人自身炎症性疾病的关系。2020年10月27日,该研究发表在《新英格兰医学杂志》上。

成人发病的炎症综合症通常表现出重叠的临床特征。此前与自身炎症性疾病有关的泛素相关基因变异可能定义新疾病。

研究组分析了独立于临床表型和遗传模式的外周血外显子组序列数据,以鉴定泛素相关基因中的有害突变。CRISPR-Cas9编辑的斑马鱼被用作评估基因功能的体内模型。

研究组鉴定了25名具有影响UBA1中蛋氨酸-41(p.Met41)体细胞突变的男性,UBA1是引发泛素化的主要E1酶,UBA1基因位于X染色体上。这类患者在成年后期会出现一种致命的、难以治疗的炎症综合征,伴有发热、细胞减少、髓系和红系前体细胞特征性空泡、骨髓发育不良、中性粒细胞性皮肤和肺部炎症、软骨炎和血管炎。

这25名患者中的大多数符合炎症综合症(复发性软骨炎、Sweet氏综合症、结节性多发性动脉炎或巨细胞性动脉炎)或血液系统疾病(骨髓增生异常综合症或多发性骨髓瘤)或两者兼有的临床标准。在超过一半的造血干细胞中发现了突变,包括外周血髓样细胞,但在淋巴细胞或成纤维细胞未发现突变。

影响p.Met41的突变导致了UBA1典型细胞质亚型的丢失,并表达了一种新的、催化受损的、始于p.Met67的亚型。突变的外周血细胞显示泛素化降低和先天免疫通路激活。斑马鱼的胞质UBA1亚型同源物的敲除导致了系统性炎症。

利用基因型驱动的方法,研究组确定了一种看似不相关的成人发病炎症综合征之间的联系,并将这种疾病命名为VEXAS(空泡、E1酶、x -连接、自身炎症、体细胞)综合征。

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

期刊信息

The New England Journal of Medicine:《新英格兰医学杂志》,创刊于1812年。隶属于美国麻省医学协会,最新IF:70.67
官方网址:http://www.nejm.org/
投稿链接:http://www.nejm.org/page/author-center/home