Pathogenic variants in the NLRP3 LRR domain at position 861 are responsible for a boost-dependent atypical CAPS phenotype.

International audienceBackground: Cryopyrin-associated periodic syndrome (CAPS) is associated with NLRP3 pathogenic variants, mostly located in the NACHT domain. Cold induced urticarial rash is one of the main clinical features. We however identified a series of 14 patients with pathogenic variants of the Y861 residue (p.Tyr861) of the LRR domain of NLRP3 and minimal prevalence of cold-induced urticarial rash.Objective: We aimed to address a possible genotype / phenotype correlation for CAPS patients and to investigate at the cellular levels the impact of the Y861C substitution (p.Tyr861Cys) on NLRP3 activation.Methods: Clinical features of 14 CAPS patients with heterozygous substitution at position 861 in the LRR domain of NLRP3 were compared to clinical features of 48 CAPS patients with pathogenic variants outside the LRR domain of NLRP3. IL-1β secretion by PBMCs and purified monocytes from patients and healthy donors was evaluated following LPS and MSU stimulation.Results: Patients with substitution at position 861 of NLRP3 demonstrated a higher prevalence of sensorineural hearing loss while being less prone to skin urticarial. In contrast to classical CAPS patients, cells from patients with a pathogenic variant at position 861 required an activation signal to secrete IL-1β but produced more IL-1β during the early and late phase of secretion than cells from healthy donors.Conclusion: Pathogenic variants of Y861 of NLRP3 drive a boost-dependent over secretion of IL-1β associated with an atypical CAPS phenotype