UBA1的体细胞突变和严重成人发作的自身炎性疾病
Abstract 摘要
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.
背景
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。
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.
方法
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，以鉴定泛素相关基因中的有害突变。进行桑格测序、免疫印迹、免疫组织化学检测、流式细胞术、转录组和细胞因子数据分析。crispr - cas9系统编辑的斑马鱼被用作评估基因功能的体内模型。
RESULTS
We identified 25 men with somatic mutations affecting methionine-41 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 UBA1and 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.
结果
我们认定25名具有影响UBA1蛋氨酸-41体细胞突变的男性UBA1是引发泛素化。(UBA1基因位于X染色体上。)在这些患者在成年晚期通常会出现一种致命的、难治性的炎症综合征，伴有发烧、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。25例患者大多符合炎症综合征(复发性多软骨炎、Sweet氏综合征、结节性多发性动脉炎或巨细胞动脉炎)或血液病(骨髓增生异常综合征或多发性骨髓瘤)或两者兼有的临床标准。一半以上患者的造血干细胞发现突变，包括外周血髓细胞，但淋巴细胞或成纤维细胞未发现。影响p.Met41突变导致了UBA1典型细胞质亚型的缺失，并表达了一种新型催化受损的始于p.Met67亚型。突变的外周血细胞显示泛素化程度降低，先天免疫通路激活。斑马鱼细胞质UBA1同源异构体的敲除引起了系统性炎症。
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.
结论
我们使用了基因型驱动方法，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。我们将这种疾病命名为VEXAS(空泡、E1酶、x-连接、自身炎症、体细胞)综合征。
