NLRP3 – Cryopyrin-Associated Periodic Syndrome

Cryopyrin-Associated Periodic Syndrome (CAPS) comprises a spectrum of autosomal dominant autoinflammatory disorders caused by gain-of-function variants in NLRP3, which encodes the inflammasome sensor cryopyrin. CAPS includes familial cold autoinflammatory syndrome, Muckle-Wells syndrome, and neonatal-onset multisystem inflammatory disease, with onset ranging from neonatal to adult ages and a prevalence estimated at ~1/360 000 in France ([PMID:21109514]). The cardinal features are periodic fever, urticarial rash, arthralgia/arthritis, headache, conjunctivitis and sensorineural hearing loss, all reflecting IL-1β–driven systemic inflammation.

Genetic evidence for NLRP3–CAPS association is definitive. Over 136 unrelated mutation-positive patients have been reported, harboring 31 different pathogenic NLRP3 variants, of which seven account for 78% of cases ([PMID:25038238]). Heterozygous germline mutations are most common, but somatic mosaicism occurs in 35–69% of conventionally “mutation-negative” patients with neonatal-onset disease ([PMID:21702021]). Segregation in large families (29 affected relatives) confirms autosomal dominant inheritance and high penetrance of cryopyrin variants ([PMID:27134254]).

Inheritance is autosomal dominant, with de novo events accounting for ~20% of cases. Familial clustering frequently reveals recurrent founder alleles (e.g., p.Ala439Val in European Muckle-Wells syndrome) and low-level mosaicism detectable by deep sequencing. Population screening of the NLRP3 promoter and coding regions has excluded common polymorphisms in healthy controls, reinforcing a pathogenic role for disease-associated variants.

Functional studies demonstrate that CAPS-associated NLRP3 mutations confer constitutive inflammasome activation and exaggerated IL-1β secretion. In THP-1 cells, the p.Met299Val mutant showed ~10-fold increased basal IL-1β release compared with wild-type ([PMID:20506209]), while mutant cryopyrin reliably co-immunoprecipitates with ASC and triggers caspase-1-dependent cytokine maturation and necrosis-like monocyte death ([PMID:15020601], [PMID:18063752]). Murine models of homologous Nlrp3 mutations recapitulate systemic and neurological CAPS phenotypes, underscoring a conserved gain-of-function mechanism.

Clinically, IL-1 blockade with anakinra or canakinumab induces rapid and sustained remission of fever, rash, arthralgia and aseptic meningitis, and may reverse early sensorineural hearing loss if administered promptly. Responses in ocular, renal AA amyloidosis and cardiac amyloidosis complications further confirm the central role of IL-1β in pathogenesis and the predictive value of functional inflammasome assays for therapeutic efficacy.

Variants of uncertain significance, such as p.Gln703Lys and p.Val198Met, exhibit intermediate inflammasome activation in ex vivo assays and associate with milder, low-penetrance CAPS-like phenotypes; these require careful genotype-phenotype correlation and confirmatory functional testing ([PMID:25596455]).

In summary, pathogenic NLRP3 variants drive inflammasome hyperactivation and IL-1β–mediated autoinflammation in CAPS. Comprehensive genetic testing—including deep sequencing for mosaicism—combined with functional inflammasome assays informs diagnosis, prognostic stratification and early initiation of IL-1–targeted therapy. Key take-home: NLRP3 mutation identification and IL-1 blockade are critical for preventing irreversible organ damage in CAPS.

References

• Arthritis and Rheumatism • 2010 • Two adult siblings with atypical cryopyrin-associated periodic syndrome due to a novel M299V mutation in NLRP3 PMID:20506209
• Blood • 2008 • Disease-associated CIAS1 mutations induce monocyte death, revealing low-level mosaicism in mutation-negative cryopyrin-associated periodic syndrome patients PMID:18063752
• Annals of the Rheumatic Diseases • 2015 • Phenotypic and genotypic characteristics of cryopyrin-associated periodic syndrome: a series of 136 patients from the Eurofever Registry PMID:25038238
• Arthritis and Rheumatism • 2004 • Cryopyrin-induced interleukin 1β secretion in monocytic cells: enhanced activity of disease-associated mutants and requirement for ASC PMID:15020601
• Clinical Immunology • 2015 • A functional inflammasome activation assay differentiates patients with pathogenic NLRP3 mutations and symptomatic patients with low penetrance variants PMID:25596455
• Arthritis and Rheumatism • 2011 • High incidence of NLRP3 somatic mosaicism in patients with chronic infantile neurologic, cutaneous, articular syndrome: results of an International Multicenter Collaborative Study PMID:21702021

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