Researchers have uncovered the molecular mechanism that triggers inflammation in familial Mediterranean fever, according to an Aug. 7 report. Familial Mediterranean fever is a hereditary autoinflammatory disease caused by mutations in the MEFV gene, which encodes the protein pyrin. Pyrin forms part of an inflammasome complex inside cells that detects threats and triggers inflammation.
Under normal conditions, pyrin activity is restrained by a cellular 'brake.' This brake can be released by bacterial toxins, certain drugs, or genetic mutations affecting pyrin or its regulators. Once released, pyrin clusters together and sends inflammatory signals leading to disease flares. Despite identification of MEFV mutations since 1997, it was previously unclear what partner protein interacts with pyrin to assemble its inflammatory complex.
Two new studies addressed this question by focusing on CDC42, a small GTPase involved in cell shape and movement. The first study identified six patients from three unrelated families with severe symptoms who carried a newly reported T43I mutation in CDC42. Using AI-based modeling and biochemical tests, researchers found that this mutation alters CDC42's structure so it binds tightly to the B30.2 domain of pyrin. This abnormal interaction causes excessive activation of the inflammasome: affected cells form abnormal clumps, release high levels of IL-1β and IL-18 cytokines, and rupture.
A companion study introduced 265 MEFV variants into human cells to assess their impact on inflammation using a cell-based assay. Researchers mapped these variants onto a 3D model of pyrin and found classical FMF mutations clustered at the same B30.2 domain region contacted by CDC42. These mutations made pyrin grip CDC42 more tightly than normal—again accelerating formation of inflammatory clumps within cells—while other non-FMF mutations activated pyrin through different mechanisms.
Together these findings show that both CDC42 mutations (the 'key') and specific changes in the B30.2 domain of pyrin (the 'keyhole') can trigger runaway inflammasome activation underlying FMF attacks. The studies provide a functional atlas for hundreds of MEFV variants and clarify which ones are likely disease-causing.
The discoveries may enable faster diagnosis for patients with uncertain genetic results and point toward precision medicine approaches targeting specific molecular subtypes.
