肿瘤坏死因子受体相关周期性综合征（TRAPS）是一种罕见的常染色体显性遗传疾病，在亚洲发病率较低。最常见的临床表现包括发烧、皮疹、肌痛、关节痛和腹痛。由于该疾病的临床和遗传变异性，误诊率很高。 TRAPS 的发病机制很复杂，尚未完全明确。早期基因诊断是精准治疗的关键。本研究对一个疑似TRAPS的中国家系进行了全基因组SNP基因分型、连锁分析和靶向测序，以鉴定致病基因的突变。为了研究已识别基因突变的致病性，我们对突变位点进行了保守性分析和蛋白质结构分析。采用流式细胞术检测TNFRSF1A脱落，采用定量实时PCR评估突变携带者和健康个体中未折叠蛋白反应（UPR）的激活情况。典型的TRAPS家族史，具有常染色体显性遗传模式，导致鉴定出 TNFRSF1A 基因 (c.G374A [p.Cys125Tyr]) 中的罕见突变，其意义未知。患者对皮质类固醇反应良好，长期使用秋水仙碱治疗可有效减少炎症发作。 6年随访期间未出现淀粉样蛋白并发症。计算机蛋白质分析表明，突变位点高度保守，并且突变阻止了蛋白质中链内二硫键的形成。尽管p.C125Y突变的TRAPS患者中受刺激的单核细胞中TNFRSF1A蛋白正常脱落，但CHOP的表达和XBP1的剪接显着高于健康对照，表明存在激活的UPR。这是第一份报告一个中国家庭的 TNFRSF1A 具有罕见的 p.C125Y 突变。 p.C125Y 突变不会导致异常受体脱落，而是与这些 TRAPS 患者中激活的 UPR 相关，这可能为 TRAPS 中这种罕见突变的发病机制提供新的见解。版权所有 © 2024Qian, Zhou, Wu,张、余、徐、杨、周、杨、邵、张、江、阮。

Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) is a rare autosomal dominant disorder with a low incidence in Asia. The most frequent clinical manifestations include fever, rash, myalgia, joint pain and abdominal pain. Misdiagnosis rates are high because of the clinical and genetic variability of the disease. The pathogenesis of TRAPS is complex and yet to be fully defined. Early genetic diagnosis is the key to precise treatment.In this study, a Chinese family with suspected TRAPS were analyzed by genome-wide SNP genotyping, linkage analysis and targeted sequencing for identification of mutations in causative genes. To study the pathogenicity of the identified gene mutation, we performed a conservation analysis of the mutation site and protein structure analysis. Flow cytometry was used to detect TNFRSF1A shedding and quantitative real-time PCR were used to assess the activation of unfolded protein response (UPR) in the mutation carriers and healthy individuals.A typical TRAPS family history, with a pattern of autosomal dominant inheritance, led to the identification of a rare mutation in the TNFRSF1A gene (c.G374A [p.Cys125Tyr]) with unknown significance. The patient responded well to corticosteroids, and long-term therapy with colchicine effectively reduced the inflammatory attacks. No amyloid complications occurred during the 6-year follow-up. In silico protein analysis showed that the mutation site is highly conversed and the mutation prevents the formation of intrachain disulfide bonds in the protein. Despite a normal shedding of the TNFRSF1A protein from stimulated monocytes in the TRAPS patients with p.C125Y mutation, the expression of CHOP and the splicing of XBP1 was significantly higher than healthy controls, suggesting the presence of an activation UPR.This is the first report of a Chinese family with the rare p.C125Y mutation in TNFRSF1A. The p.C125Y mutation does not result in aberrant receptor shedding, but instead is associated with an activated UPR in these TRAPS patients, which may provide new insights into the pathogenesis of this rare mutation in TRAPS.Copyright © 2024 Qian, Zhou, Wu, Zhang, Yu, Xu, Yang, Zhou, Yang, Shao, Zhang, Jiang and Ruan.