The following is a summary of “Pathogenic variants in the NLRP3 LRR domain at position 861 are responsible for a boost-dependent atypical CAPS phenotype,” published in the November 2023 issue of Allergy & Immunology by Fayand, et al.

For a study, researchers sought to delve into Cryopyrin-associated periodic syndrome (CAPS), a condition associated with pathogenic variants in the NLRP3 gene, often found in the NACHT domain. Notably, they focused on patients with pathogenic variants at the Y861 residue (p.Tyr861) in the LRR domain of NLRP3, a group displaying a distinct clinical presentation with a lower prevalence of cold-induced urticarial rash.

Fourteen patients with CAPS and a heterozygous substitution at position 861 in the NLRP3 LRR domain were compared to 48 CAPS patients with pathogenic variants outside the LRR domain. Clinical features were thoroughly examined, assessing differences in IL-1β secretion by PBMCs and purified monocytes from both patient groups and healthy donors, particularly in response to LPS and monosodium urate crystal stimulation.

Patients with the Y861 substitution exhibited a higher incidence of sensorineural hearing loss but were less susceptible to skin urticarial. In a departure from classical CAPS cases, cells from those with the Y861 pathogenic variant required an activation signal for IL-1β secretion. Notably, they produced elevated levels during both early and late phases compared to healthy donors.

Pathogenic variants at position Y861 in NLRP3 contribute to a boost-dependent oversecretion of IL-1β, resulting in an atypical CAPS phenotype characterized by distinct clinical manifestations, thus shedding light on CAPS’s genotype/phenotype correlation.

Source: jacionline.org/article/S0091-6749(23)00926-0/fulltext