Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Department of Functional Genomics and Immunological Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Front Immunol. 2024 Oct 25;15:1475179. doi: 10.3389/fimmu.2024.1475179. eCollection 2024.
is a negative regulator of T cell activation and one of the key activators of type I interferon (IFN) and NFκB signaling via non-classical pathways. The upstream single nucleotide polymorphism of (rs2297550-G) is a genome-wide association study risk variant of systemic lupus erythematosus, and is associated with decreased expression in T cells by expression quantitative trait locus analysis.
A 48-year-old female had a remittent fever, arthritis, and oral ulcers for 20 years. She had a poor response to corticosteroids or disease-modifying antirheumatic drugs, including the tumor necrosis factor-α antagonist, etanercept, and the anti-interleukin-6 receptor antibody, tocilizumab.
She participated in the Initiative on Rare and Undiagnosed Disease (IRUD), and whole-exome sequencing (WES) was performed. Functional analyses were conducted by transfecting the identified variants into reporter cells to assess the activation of NFAT and NFκB signaling. Additionally, peripheral blood RNA- sequencing (RNA-seq) data were compared with those from healthy individuals to evaluate the gene expression profiles of immune cells.
WES identified a novel heterozygous c.1877G>A, p(Cys626Tyr) variant in . Functional analysis indicated that this variant led to increased activity of NFAT ( = 0.015) and decreased activity of NFκB and type I IFN ( = 0.00068 and 0.00044, respectively). The patient had a remarkably low proportion of Naïve CD4 T cells. RNA-seq of peripheral blood immune cell subsets revealed significant differences in gene expression, especially in T cells.
A novel functional heterozygous variant in is described in a patient with a remittent fever and arthritis. The data suggest that is an important negative regulator of inflammation, particularly in T cells, and this variant might be the underlying cause of a novel autoinflammatory pathology.
是 T 细胞活化的负调控因子，也是通过非经典途径激活 I 型干扰素 (IFN) 和 NFκB 信号的关键激活剂之一。 的上游单核苷酸多态性（rs2297550-G）是全身性红斑狼疮全基因组关联研究的风险变异，通过表达数量性状基因座分析与 T 细胞中 的表达降低有关。
一位 48 岁女性出现反复发热、关节炎和口腔溃疡 20 年。她对皮质类固醇或改善病情的抗风湿药物反应不佳，包括肿瘤坏死因子-α拮抗剂依那西普和抗白细胞介素-6 受体抗体托珠单抗。
她参加了罕见和未确诊疾病倡议 (IRUD)，并进行了全外显子组测序 (WES)。通过将鉴定出的变体转染到报告细胞中，评估 NFAT 和 NFκB 信号的激活，进行功能分析。此外，比较外周血 RNA-测序 (RNA-seq) 数据与健康个体的基因表达谱，评估免疫细胞的基因表达谱。
WES 在 中发现了一个新的杂合 c.1877G>A，p(Cys626Tyr) 变体。功能分析表明，该变体导致 NFAT 活性增加（=0.015），NFκB 和 I 型 IFN 活性降低（分别为 0.00068 和 0.00044）。患者的 Naïve CD4 T 细胞比例明显较低。外周血免疫细胞亚群的 RNA-seq 显示基因表达存在显著差异，尤其是在 T 细胞中。
描述了一名反复发热和关节炎患者中 的一个新的功能杂合变体。数据表明， 是炎症的重要负调控因子，特别是在 T 细胞中，该 变体可能是一种新的自身炎症病理的潜在原因。
