Fuente: PubMed "hive" JCI Insight. 2026 Mar 9;11(5):e194677. doi: 10.1172/jci.insight.194677. eCollection 2026 Mar 9.ABSTRACTNext-generation sequencing technologies are increasingly used to diagnose genetic disorders, particularly immunological diseases with broad and overlapping immune dysregulation. Cryopyrin-associated periodic syndromes (CAPS) are caused by gain-of-function mutations in NLRP3 and include 3 autoinflammatory diseases spanning a continuum of severity: familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and neonatal-onset multisystem inflammatory disease (NOMID). Linking NLRP3 variants to protein dysfunction and clinical phenotype remains challenging because of genetic modifiers and environmental factors. We report the generation and phenotyping of 5 mouse lines expressing either the common human NLRP3 allele or 1 of 4 CAPS mutations spanning the disease spectrum from FCAS to NOMID. In these lines, the murine Nlrp3 locus is replaced by syntenic integration of the human NLRP3 locus, yielding 1 line with the common allele and 4 lines each carrying a distinct CAPS mutation. Unlike models in which a human mutation is introduced into the mouse protein, these lines recapitulate the spectrum of disease severity observed in humans. These findings support a model in which evaluation of nonsynonymous mutations in mice is optimized when introduced in the context of the human gene. This suggests that species-specific regulation and/or intramolecular epistasis may impact modeling of disease-associated variants.PMID:41797712 | DOI:10.1172/jci.insight.194677