UBA1的體細(xì)胞突變和嚴(yán)重成人發(fā)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
成人發(fā)病的炎癥綜合癥通常表現(xiàn)出重疊的臨床特征,。此前與自身炎癥性疾病有關(guān)的泛素相關(guān)基因變異可能定義新疾病,。
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
我們分析了獨(dú)立于臨床表型和遺傳模式的外周血外顯子組序列數(shù)據(jù)，以鑒定泛素相關(guān)基因中的有害突變,。進(jìn)行桑格測(cè)序,、免疫印跡,、免疫組織化學(xué)檢測(cè)、流式細(xì)胞術(shù),、轉(zhuǎn)錄組和細(xì)胞因子數(shù)據(jù)分析,。crispr - cas9系統(tǒng)編輯的斑馬魚被用作評(píng)估基因功能的體內(nèi)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.
結(jié)果
我們認(rèn)定25名具有影響UBA1蛋氨酸-41體細(xì)胞突變的男性UBA1是引發(fā)泛素化,。(UBA1基因位于X染色體上,。)在這些患者在成年晚期通常會(huì)出現(xiàn)一種致命的、難治性的炎癥綜合征,，伴有發(fā)燒,、細(xì)胞減少、髓系和紅系前體細(xì)胞特征性空泡,、骨髓發(fā)育不良,、中性粒細(xì)胞性皮膚和肺部炎癥、軟骨炎和血管炎,。25例患者大多符合炎癥綜合征(復(fù)發(fā)性多軟骨炎,、Sweet氏綜合征、結(jié)節(jié)性多發(fā)性動(dòng)脈炎或巨細(xì)胞動(dòng)脈炎)或血液病(骨髓增生異常綜合征或多發(fā)性骨髓瘤)或兩者兼有的臨床標(biāo)準(zhǔn),。一半以上患者的造血干細(xì)胞發(fā)現(xiàn)突變,，包括外周血髓細(xì)胞，但淋巴細(xì)胞或成纖維細(xì)胞未發(fā)現(xiàn),。影響p.Met41突變導(dǎo)致了UBA1典型細(xì)胞質(zhì)亞型的缺失,，并表達(dá)了一種新型催化受損的始于p.Met67亞型。突變的外周血細(xì)胞顯示泛素化程度降低,，先天免疫通路激活,。斑馬魚細(xì)胞質(zhì)UBA1同源異構(gòu)體的敲除引起了系統(tǒng)性炎癥。
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.
結(jié)論
我們使用了基因型驅(qū)動(dòng)方法，確定了一種看似不相關(guān)的成人發(fā)病炎癥綜合征之間的聯(lián)系,。我們將這種疾病命名為VEXAS(空泡,、E1酶、x-連接,、自身炎癥,、體細(xì)胞)綜合征。
