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Objective  To determine the molecular and cellular bases of autoinflammatory syndromes in a multigenerational French family with Muckle‐Wells syndrome and in a patient originating from Portugal with familial cold autoinflammatory syndrome.    Methods  Sequencing of   NLRP 3  exon 3 was performed in all accessible patients. Microsatellite and whole‐genome single nucleotide polymorphism genotyping was used i) to test the intrafamilial segregation of the identified variant and ii) to look for a founder effect. Functional analyses included the study of i) apoptosis‐associated speck‐like protein containing a  CARD  ( ASC ) speck formation in  HEK 293T cells (stably expressing  ASC –green fluorescent protein and pro‐caspase 1‐ FLAG ) transiently expressing the wild‐type or mutated  NLRP 3 protein, ii) levels of  IL ‐1β secreted from transfected  THP ‐1 cells, and iii) inflammasome‐related gene expression and cytokine secretion from monocytes isolated from patients in crisis (probands from the two families), related patients out of crisis, and from controls.    Results  The same heterozygous mutation (c.1322C>T, p.A441V) located in the  NACHT  domain, segregating with the disease within the first family, was identified in the two families. This mutation was found to be associated with different core haplotypes.  NLRP 3‐A441V led to increased  ASC  speck formation and high levels of secreted  IL ‐1β. Monocyte inflammasome‐related gene expression and cytokine secretion, which were within the normal range in patients out of crisis, were found to be differentially regulated between the two probands, correlating with their phenotypic status.    Conclusion  These molecular and cellular findings, which indicate a recurrent mutational event, clearly demonstrate the pathogenicity of the p.A441V missense mutation in   NLRP 3 ‐associated autoinflammatory disease and point to the interest of studying patients’ primary cells to assess disease activity.

acr open rheumatology

The NLRP3 p.A441V Mutation in  NLRP3 ‐AID Pathogenesis: Functional Consequences, Phenotype‐Genotype Correlations and Evidence for a Recurrent Mutational Event