Why the body's inflammatory alarm misfires in familial Mediterranean fever

Familial Mediterranean fever (FMF) is a hereditary autoinflammatory disease caused by mutations in the MEFV gene, which encodes a protein called pyrin. Pyrin is a key component of the inflammasome, a protein complex that detects threats and triggers inflammation to protect the body. Normally, pyrin is regulated by a brake that prevents it from forming large clumps and releasing powerful inflammatory signals.

However, when this brake is released, pyrin can assemble an inflammatory complex, leading to the painful flares characteristic of FMF. Although numerous mutations in the MEFV gene are linked to FMF, the mechanism by which pyrin engages with its inflammatory complex partner protein has remained unclear. Recent studies have identified CDC42, a small cellular GTPase, as the direct partner of pyrin.

Mutations in the CDC42 gene, such as the T43I mutation, can alter the interaction between pyrin and CDC42, leading to abnormal activation of the inflammatory response and exacerbation of FMF symptoms.

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