Pediatric Rheumatology Unit of Western Switzerland, Pediatric Department, Lausanne University Hospital (CHUV), Lausanne, Switzerland.
Pediatric Department, Geneva University Hospital (HUG), Geneva, Switzerland.
Front Immunol. 2020 May 14;11:877. doi: 10.3389/fimmu.2020.00877. eCollection 2020.
The inflammasome has been recognized as one of the key components of innate immunity. Gain-of-function mutations in the exon 3 of gene have been implicated in inflammatory diseases suggesting the presence of functionally important sites in this region. Q703K (c.2107C>A, p.Gln703Lys, also known in the literature as Q705K) is a common variant of , that has been considered to be both clinically unremarkable or disease-causing with a reduced penetrance. We aimed to investigate the potential genetic impact of the variant Q703K in patients with recurrent fever presenting with two autoinflammatory diseases: PFAPA (periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis) and CAPS (cryopyrin-associated periodic syndrome), as well as with undefined autoinflammatory disease (uAID). This is an international multicentric observational retrospective study characterizing the clinical phenotype of patients presenting with recurrent fever suspected to be of auto-inflammatory origin and where the Q703K variant was found. Monocytes of parents of 6 Q703K+ PFAPA patients were studied and levels of pro-inflammatory cytokines produced by monocytes of Q703K+ and Q703K- parents have been compared by ELISA. We report 42 patients with the Q703K genetic variant: 21 were PFAPA patients, 6 had a CAPS phenotype, and 15 had an uAID. The phenotypes of PFAPA, CAPS and uAID were quite similar between Q703K positive and negative patients with the exception of increased prevalence of pharyngitis in the Q703K positive CAPS population compared to the negative one. The production of IL-1β was not significantly different between Q703K+ and Q703K- monocytes from asymptomatic parents. The evidence we report in our study shows an increased prevalence of Q703K in patients with autoinflammatory diseases, suggesting an association between the Q703K variant and the risk of PFAPA, CAPS and uAID syndromes. However, we did not show a functional effect of this mutation on the inflammasome basal activity.
炎症小体已被认为是先天免疫的关键组成部分之一。在 基因的外显子 3 中发现的功能获得性突变与炎症性疾病有关，表明该区域存在功能重要的位点。Q703K（c.2107C>A，p.Gln703Lys，在文献中也称为 Q705K）是 的常见变体，被认为既有临床意义又无病，且外显率降低。我们旨在研究复发性发热患者中 变体 Q703K 的潜在遗传影响，这些患者患有两种自身炎症性疾病：PFAPA（周期性发热、口疮性口炎、咽炎和颈淋巴结炎）和 CAPS（冷吡啉相关周期性综合征），以及未定义的自身炎症性疾病（uAID）。这是一项国际多中心观察性回顾性研究，对复发性发热疑似自身炎症性疾病的患者的临床表型进行了特征描述，其中发现了 Q703K 变体。研究了 6 名 Q703K+PFAPA 患者的父母的单核细胞，并通过 ELISA 比较了 Q703K+和 Q703K-父母的单核细胞产生的促炎细胞因子水平。我们报告了 42 名携带 Q703K 遗传变异的患者：21 名是 PFAPA 患者，6 名是 CAPS 患者，15 名是 uAID 患者。除了 Q703K 阳性 CAPS 人群中咽炎的患病率高于阴性人群外，Q703K 阳性患者和阴性患者的 PFAPA、CAPS 和 uAID 表型非常相似。来自无症状父母的 Q703K+和 Q703K-单核细胞产生的 IL-1β 没有显著差异。我们在研究中报告的证据表明，自身炎症性疾病患者中 Q703K 的患病率增加，表明 Q703K 变体与 PFAPA、CAPS 和 uAID 综合征的风险之间存在关联。然而，我们没有显示该突变对炎症小体基础活性的功能影响。
