UMR S933, INSERM, Université Pierre et Marie Curie Paris 6, Hôpital Trousseau and AP-HP, Paris, France.
Arthritis Rheumatol. 2014 Sep;66(9):2621-7. doi: 10.1002/art.38727.
Autoinflammatory disorders are caused by a primary dysfunction of the innate immune system. Among these disorders are hereditary recurrent fevers, which are characterized by recurrent episodes of fever and inflammatory manifestations affecting multiple tissues. Hereditary recurrent fevers often lack objective diagnostic criteria, thereby hampering the identification of disease-causing genes. This study was undertaken to identify a gene responsible for hereditary recurrent fevers.
Copy number variations and point mutations were sought by array-comparative genomic hybridization and polymerase chain reaction sequencing, respectively. Serum cytokine levels were measured using Luminex technology. The effect of TNFRSF11A molecular defects on NF-κB signaling in cells expressing wild-type and mutated forms of the receptor was evaluated by luciferase assay.
A patient with multiple congenital anomalies and hereditary recurrent fever was found to carry a de novo heterozygous complex chromosomal rearrangement encompassing a duplication of TNFRSF11A, a gene known to regulate fever in rodents. We also identified a heterozygous frameshift mutation (p.Met416Cysfs*110) in TNFRSF11A in a mother and daughter with isolated hereditary recurrent fever. This mutation was associated with increased secretion of several inflammatory cytokines (tumor necrosis factor α [TNFα], interleukin-18 [IL-18], IL-1 receptor antagonist, interferon-γ) and altered the biologic effects of the receptor on NF-κB signaling. The disease in the patients described herein exhibits striking clinical similarities to TNF receptor-associated periodic syndrome, another hereditary recurrent fever involving a gene of the same family (TNFRSF1A).
The involvement of TNFRSF11A in hereditary recurrent fever highlights the key role of this receptor in innate immunity. The present results also suggest that TNFRSF11A screening could serve as a new diagnostic test for autoinflammatory disorders.
自身炎症性疾病是由先天免疫系统的主要功能障碍引起的。这些疾病包括遗传性复发性发热，其特征是反复发作的发热和影响多个组织的炎症表现。遗传性复发性发热往往缺乏客观的诊断标准，从而阻碍了致病基因的识别。本研究旨在鉴定导致遗传性复发性发热的基因。
通过比较基因组杂交和聚合酶链反应测序分别寻找拷贝数变异和点突变。使用 Luminex 技术测量血清细胞因子水平。通过荧光素酶测定评估 TNFRSF11A 分子缺陷对表达野生型和突变受体的细胞中 NF-κB 信号的影响。
发现一名患有多种先天性异常和遗传性复发性发热的患者携带一个新的杂合性复杂染色体重排，该重排包括 TNFRSF11A 的重复，该基因已知在啮齿动物中调节发热。我们还在一名患有孤立性遗传性复发性发热的母亲和女儿中发现了 TNFRSF11A 的杂合性移码突变（p.Met416Cysfs*110）。该突变与几种炎症细胞因子（肿瘤坏死因子-α[TNFα]、白细胞介素-18[IL-18]、IL-1 受体拮抗剂、干扰素-γ）的分泌增加有关，并改变了受体对 NF-κB 信号的生物学效应。本文所述患者的疾病与 TNF 受体相关周期性综合征具有显著的临床相似性，后者也是一种涉及同一家族（TNFRSF1A）基因的遗传性复发性发热。
TNFRSF11A 参与遗传性复发性发热突出了该受体在先天免疫中的关键作用。本研究结果还表明，TNFRSF11A 筛查可作为自身炎症性疾病的新诊断测试。
Zotero 插件