GSE168721
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. Overall design: 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.