The NLRP3 p.A441V Mutation in NLRP3-AID Pathogenesis: Functional Consequences, Phenotype-Genotype Correlations and...

Area of Science:

• Genetics and Molecular Biology
• Immunology
• Human Disease

Background:

• Autoinflammatory syndromes are a group of rare genetic disorders characterized by recurrent episodes of inflammation.
• Muckle-Wells syndrome and familial cold autoinflammatory syndrome are distinct autoinflammatory conditions.
• The NLRP3 inflammasome plays a critical role in innate immunity and inflammatory diseases.

Purpose of the Study:

• To investigate the molecular and cellular underpinnings of autoinflammatory syndromes in two unrelated families.
• To identify the genetic basis of Muckle-Wells syndrome and familial cold autoinflammatory syndrome in the studied families.
• To explore the functional consequences of identified genetic variants on inflammasome activation.

Main Methods:

• Sequencing of NLRP3 exon 3 and microsatellite/SNP genotyping to identify and track variants.
• In vitro functional assays including ASC speck formation and IL-1β secretion in transfected cell lines.
• Analysis of inflammasome-related gene expression and cytokine secretion from patient-derived monocytes.

Main Results:

• A recurrent heterozygous NLRP3 mutation (c.1322C>T, p.A441V) was identified in both families, segregating with the disease.
• The NLRP3-A441V variant led to increased ASC speck formation and elevated IL-1β secretion.
• Monocyte inflammasome activity varied between patients, correlating with clinical status and suggesting disease activity assessment through primary cells.

Conclusions:

• The p.A441V missense mutation in NLRP3 is pathogenic and recurrently causes autoinflammatory disease.
• These findings underscore the role of NLRP3 in autoinflammatory syndromes.
• Studying primary patient cells is valuable for assessing disease activity in NLRP3-associated disorders.