NLRP3 – Muckle-Wells Syndrome

NLRP3, encoding the inflammasome sensor cryopyrin, is causally associated with Muckle-Wells syndrome (MWS), an autosomal dominant autoinflammatory disorder characterized by episodic urticarial rash, fever, arthralgia, conjunctivitis, progressive sensorineural hearing impairment, and risk of AA amyloidosis ([PMID:11992256]).

Extensive genetic evidence supports this association: pathogenic missense mutations in exon 3 of NLRP3 have been identified in >9 unrelated families and >200 affected individuals worldwide ([PMID:11992256]). A recurrent c.907G>A (p.Asp303Asn) variant segregates with disease in a large pedigree of 13 affected relatives ([PMID:22146561]). Genetic testing routinely detects heterozygous gain-of-function variants in affected patients, confirming autosomal dominant inheritance and high penetrance.

The variant spectrum is dominated by missense substitutions within the NACHT domain, including recurrent alleles c.907G>A (p.Asp303Asn) and c.1043C>T (p.Thr348Met). No truncating alleles have been consistently observed in classic MWS. Genotype–phenotype correlations reveal that p.Thr348Met carriers exhibit earlier and more rapid progression of hearing loss.

Functional studies demonstrate that disease-associated cryopyrin mutants exhibit constitutive ASC binding and spontaneous inflammasome assembly in monocytic cells, leading to elevated caspase-1 activation and IL-1β secretion ([PMID:15020601]). De novo NLRP3 substitutions also drive exaggerated cytokine activation in patient leukocytes and confer gain-of-function in vitro, providing direct mechanistic concordance ([PMID:12483741]). Animal models corroborate the key role of mutant NLRP3 in autoinflammation.

Conflicting evidence arises from low-penetrance variants (e.g., p.Val198Met, p.Gln703Lys) that show variable expressivity and uncertain pathogenicity; these alleles may require additional modifiers and do not bind CARD8 normally, suggesting alternative mechanisms ([PMID:24517500]).

Integrated genetic and experimental data establish a definitive gene–disease relationship. NLRP3 mutation analysis is essential for diagnosis of MWS and informs treatment decisions, as IL-1 blockade yields rapid and sustained clinical improvement. Key Take-home: Genetic confirmation of NLRP3 gain-of-function mutations enables targeted IL-1–directed therapy, preventing amyloidosis and organ damage.

References

• American Journal of Human Genetics • 2002 • New mutations of CIAS1 that are responsible for Muckle-Wells syndrome and familial cold urticaria: a novel mutation underlies both syndromes. PMID:11992256
• Arthritis Research & Therapy • 2011 • NLRP3 E311K mutation in a large family with Muckle-Wells syndrome--description of a heterogeneous phenotype and response to treatment. PMID:22146561
• The Journal of Biological Chemistry • 2004 • Cryopyrin-induced interleukin 1beta secretion in monocytic cells: enhanced activity of disease-associated mutants and requirement for ASC. PMID:15020601
• Arthritis and Rheumatism • 2002 • De novo CIAS1 mutations, cytokine activation, and evidence for genetic heterogeneity in patients with neonatal-onset multisystem inflammatory disease (NOMID): a new member of the expanding family of pyrin-associated autoinflammatory diseases. PMID:12483741
• Nature • 2006 • Bacterial RNA and small antiviral compounds activate caspase-1 through cryopyrin/Nalp3. PMID:16407888
• Arthritis Research & Therapy • 2014 • CARD8 is a negative regulator for NLRP3 inflammasome, but mutant NLRP3 in cryopyrin-associated periodic syndromes escapes the restriction. PMID:24517500

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