RNF213-associated urticarial lesions with hypercytokinemia

Urticarial lesions are observed in both cutaneous and systemic disorders. Familial forms of urticarial syndromes are rare and can be encountered in systemic auto-inflammatory diseases. We investigated a large family with dominantly inherited chronic urticarial lesions associated with hypercytokinemia. We performed a genetic linkage analysis in 14 patients from a 5-generation family, as well as whole-exome sequencing, cytokine profiling and transcriptomic analyses on samples from two patients. The identified candidate protein was studied after in vitro expression of the corresponding normal and mutated recombinant proteins. An unsupervised proteomic approach was followed to unveil the associated protein network. The disease phenotype of the most affected family members is characterized by chronic urticarial flares associated with extremely high plasma levels of pro- (IL-1b, IL-6, TNF-a) and anti-inflammatory (IL-10, IL1-RA) cytokines, with no secondary organ dysfunction, no susceptibility to infections, no fever and normal C-reactive protein levels. Monocyte transcriptomic analyses identified an immunotolerant profile in the most affected patient. Affected family members carried a loss-of-function mutation in RNF213 that encodes mysterin, a protein of poorly known physiological role. We identified the deubiquitinase CYLD, a major regulator of inflammation, as an RNF213 partner and showed that CYLD expression is inhibited by wild-type but not mutant RNF213. We identified a new entity characterized by chronic urticarial lesions associated with a clinically-blunted hypercytokinemia. This disease, due to a loss of function of RNF213, reveals mysterin’s key role in the complex molecular network of innate immunity. We performed RNA-seq analysis on monocytes from two patients presenting a RNF213 loss-of-function mutation and compared them to two healthy individuals. In an attempt to identify a possible dysregulation of gene networks associated with the observed hypercytokinemia, we analyzed the lists of differentially expressed genes in the patients' monocytes.

荨麻疹皮损可见于皮肤疾病与系统性疾病两类范畴。荨麻疹综合征的家族性亚型较为罕见，可在系统性自身炎症性疾病中被检出。本研究针对一个大型家系展开探究，该家系存在显性遗传的慢性荨麻疹皮损，且伴随细胞因子血症（hypercytokinemia）。我们对一个5代家系中的14名患者开展了遗传连锁分析，并对2名患者的样本实施了全外显子组测序（whole-exome sequencing）、细胞因子谱分析及转录组学分析。针对鉴定出的候选蛋白，我们通过体外表达对应野生型与突变型重组蛋白开展了研究；随后采用无监督蛋白质组学方法，以揭示相关的蛋白质互作网络。病情最重的家系成员的疾病表型特征为慢性荨麻疹发作，伴随血浆促炎细胞因子（IL-1β、IL-6、TNF-α）与抗炎细胞因子（IL-10、IL-1RA）水平显著升高；该类患者无继发性器官功能障碍、无感染易感性、无发热症状，且C反应蛋白水平处于正常范围。单核细胞转录组学分析显示，病情最重的患者呈现免疫耐受表型。患病家系成员携带RNF213基因的功能丧失型突变，该基因编码神秘蛋白（mysterin）——一种生理功能尚不明确的蛋白质。我们鉴定出去泛素化酶CYLD（一种核心炎症调控因子）为RNF213的互作蛋白，并证实野生型RNF213可抑制CYLD的表达，而突变型RNF213无此调控作用。我们鉴定出一种全新的疾病实体，其特征为慢性荨麻疹皮损伴随临床表型弱化的细胞因子血症。该疾病由RNF213功能丧失所致，这一发现揭示了神秘蛋白在天然免疫复杂分子网络中的关键作用。我们对2名携带RNF213功能丧失型突变患者的单核细胞开展了RNA测序（RNA-seq）分析，并与2名健康个体进行对照比较。为探究与观测到的细胞因子血症相关的基因网络失调潜在机制，我们对患者单核细胞中的差异表达基因列表进行了分析。