Somatic Mutations in UBA1 and Severe Adult-Onset Autoinflammatory Disease.
Somatic Mutations in UBA1 and Severe Adult-Onset Autoinflammatory Disease.
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DOI：
10.1056/nejmoa2026834
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发表时间：
2020-12-31
期刊：
影响因子：
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通讯作者：
Grayson PC
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作者：
Beck DB;Ferrada MA;Sikora KA;Ombrello AK;Collins JC;Pei W;Balanda N;Ross DL;Ospina Cardona D;Wu Z;Patel B;Manthiram K;Groarke EM;Gutierrez-Rodrigues F;Hoffmann P;Rosenzweig S;Nakabo S;Dillon LW;Hourigan CS;Tsai WL;Gupta S;Carmona-Rivera C;Asmar AJ;Xu L;Oda H;Goodspeed W;Barron KS;Nehrebecky M;Jones A;Laird RS;Deuitch N;Rowczenio D;Rominger E;Wells KV;Lee CR;Wang W;Trick M;Mullikin J;Wigerblad G;Brooks S;Dell'Orso S;Deng Z;Chae JJ;Dulau-Florea A;Malicdan MCV;Novacic D;Colbert RA;Kaplan MJ;Gadina M;Savic S;Lachmann HJ;Abu-Asab M;Solomon BD;Retterer K;Gahl WA;Burgess SM;Aksentijevich I;Young NS;Calvo KR;Werner A;Kastner DL;Grayson PC
成人发病的炎症综合征往往表现出重叠的临床特征。以前与自身炎症性疾病有关的泛素相关基因的变异可能会定义新的疾病。我们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，以确定泛素相关基因的有害突变。进行了桑格测序、免疫印迹、免疫组织化学检测、流式细胞术、转录组和细胞因子分析。使用CRISPR-Cas9编辑的斑马鱼作为体内模型来评估基因功能。我们确定了25名男性的体细胞突变影响蛋氨酸-41（p.Met41）在UBA 1，主要的E1酶，启动泛素化。(The基因UBA 1位于X染色体上。在这类患者中，通常在成年后期发生致命的难治性炎性综合征，伴有发热、血细胞减少、髓系和红系前体细胞中的特征性空泡、骨髓发育不良、嗜中性皮肤和肺部炎症、腹膜炎和血管炎。这25例患者中的大多数符合炎症综合征（复发性多动脉炎、Sweet综合征、结节性多动脉炎或巨细胞动脉炎）或血液学疾病（骨髓增生异常综合征或多发性骨髓瘤）或两者的临床标准。在超过一半的造血干细胞中发现了突变，包括外周血骨髓细胞，但没有淋巴细胞或成纤维细胞。影响p.Met41的突变导致UBA 1的典型胞质亚型的丢失，并导致在p.Met67开始的一种新的催化受损亚型的表达。突变的外周血细胞表现出降低的泛素化和激活的先天免疫途径。在斑马鱼中敲除细胞质UBA 1同种型同源物引起全身性炎症。使用基因型驱动的方法，我们确定了一种疾病，连接看似无关的成人发病炎症综合征。我们将这种疾病命名为VEXAS（空泡，E1酶，X连锁，自身炎症，体细胞）综合征。（由NIH校内研究计划和欧盟地平线2020研究和创新计划资助。
Adult-onset inflammatory syndromes often manifest with overlapping clinical features. Variants in ubiquitin-related genes, previously implicated in autoinflammatory disease, may define new disorders. 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. 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. 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. (Funded by the NIH Intramural Research Programs and the EU Horizon 2020 Research and Innovation Program.)