A Family with Non-syndromic Hearing Loss and a Novel Variant in NLRP3 – from Bedside to the Lab and Back

The NLRP3 inflammasome is an intracellular innate immune sensor that is expressed in immune cells, including monocytes and macrophages. Gain-of-function mutations in the NLRP3 gene, lead to activation of the NLRP3 inflammasome, resulting in the inappropriate release of inflammatory cytokines including IL-1β, and cause a spectrum of autosomal-dominant systemic autoinflammatory diseases (cryopyrin-associated periodic syndromes (CAPS).

Recently, a family, presented at the Pediatric Rheumatology Clinic at Schneider, with autosomal dominant, bilateral, progressive sensorineural hearing loss, accompanied by some autoinflammatory traits which are not consistent with typical CAPS, and a novel missense variant in NLRP3. Due to the phenotype-genotype correlation, we suspected that the novel variant was, in fact, a gain of function mutation, which caused this caps-like phenotype.

In order to explore this theory, we collaborated with Prof. Motti Gerlics` lab at TAU, and conducted a prospective study: "NLRP3 Inflammasome function assessment in a family with autosomal dominant hearing impairment and a novel variant in NLRP3". We conducted various functional studies of the NLRP3 inflammasome, on PBMCS (peripheral blood mononuclear cells) collected from carrier vs. healthy noncarrier family members (10, 5 respectively). We were able to prove that the NLRP3 inflammasome was significantly hyperactive among the carrier group, thus proving that the variant is a gain of function mutation and that these family members suffer from Atypical CAPS. These findings enabled us to initiate appropriate treatment for the symptomatic carriers with Anakinra (anti IL1), which will hopefully stop the hearing deterioration and prevent it among the carriers who are still asymptomatic.