A genotype-first approach reveals the molecular basis of pyrin inflammasome activation.

A genotype-first approach identified 265 MEFV variants, revealing multiple pathways of pyrin inflammasome activation and clarifying mechanisms underlying autoinflammatory diseases.

• Why it matters: Understanding the molecular basis of pyrin activation is crucial for accurate diagnosis and treatment of PAADs, yet most MEFV variants are of uncertain significance, hindering clinical progress.
• What they did: Researchers used a cell-based pyroptosis assay to classify 265 MEFV missense variants and studied their interaction with CDC42, a regulator of pyrin activation, uncovering diverse activation pathways.
• The result: The findings demonstrate that different MEFV variants hyperactivate pyrin via CDC42-dependent and independent mechanisms, paving the way for improved genetic diagnosis and targeted therapies.