Clinical Implications of a New DDX58 Pathogenic Variant That Causes Lupus Nephritis due to RIG-I Hyperactivation
Clinical Implications of a New DDX58 Pathogenic Variant That Causes Lupus Nephritis due to RIG-I Hyperactivation
复制标题
DOI：
10.1681/asn.2022040477
复制
发表时间：
2022-11-09
影响因子：
13.6
通讯作者：
Liu, Zhihong
中科院分区：
文献类型：
--
作者：
Peng, Jiahui;Wang, Yusha;Liu, Zhihong
狼疮性肾炎（LN）是系统性红斑狼疮最严重的并发症之一，具有异质性表型和对治疗的不同反应。确定LN的遗传原因可以促进更多的个体化治疗策略。方法我们对一组中国LN患者进行了全外显子组测序，并鉴定了致病基因的变异。广泛的生物化学，免疫学和功能分析评估了I型IFN信号的变体的效果。我们进一步研究了使用单细胞RNA测序的靶向治疗的有效性。结果在5个无血缘关系的LN家系中发现了一种新的致病性DDX 58变异体R109 C。DDX 58 R109 C变体是一种功能获得性突变，由于自身抑制减少而提高I型IFN信号传导，这导致RIG-I超活化、RIG-I K63泛素化增加和MAVS聚集。转录组分析显示患者单核细胞中IFN信号增加。开始JAK抑制剂治疗（baricitinib 2 mg/d）有效抑制了1例患者的IFN信号。结论一种新的导致LN的DDX 58 R109 C变异体将IFN病和LN联系起来，提示在致病性的基础上进行靶向治疗。
Background Lupus nephritis (LN) is one of the most severe complications of systemic lupus erythematosus, with heterogeneous phenotypes and different responses to therapy. Identifying genetic causes of LN can facilitate more individual treatment strategies. Methods We performed whole-exome sequencing in a cohort of Chinese patients with LN and identified variants of a disease-causing gene. Extensive biochemical, immunologic, and functional analyses assessed the effect of the variant on type I IFN signaling. We further investigated the effectiveness of targeted therapy using single-cell RNA sequencing. Results We identified a novel DDX58 pathogenic variant, R109C, in five unrelated families with LN. The DDX58 R109C variant is a gain-of-function mutation, elevating type I IFN signaling due to reduced autoinhibition, which leads to RIG-I hyperactivation, increased RIG-I K63 ubiquitination, and MAVS aggregation. Transcriptome analysis revealed an increased IFN signature in patient monocytes. Initiation of JAK inhibitor therapy (baricitinib 2 mg/d) effectively suppressed the IFN signal in one patient. Conclusions A novel DDX58 R109C variant that can cause LN connects IFNopathy and LN, suggesting targeted therapy on the basis of pathogenicity.