Nearly 30-Year Mystery Solved: Scientists Discover How Familial Mediterranean Fever Begins

Scientists have identified the mechanism behind the inflammatory attacks associated with familial Mediterranean fever (FMF), a rare inherited disorder linked to dysfunction of the immune system. The discovery could help improve the accuracy of diagnosis and lead to more personalized approaches to treatment.

The findings of two studies were published in the journal Science Immunology.

FMF is caused by mutations in the MEFV gene, which is responsible for producing the pyrin protein. This protein plays a role in the body’s inflammatory response and is part of a specialized complex inside cells called the inflammasome, which helps respond to infections and other threats.

Normally, pyrin activity is controlled by a built-in “brake.” However, certain mutations disrupt this mechanism. The pyrin inflammasome becomes overactive, causing cells to release large amounts of inflammatory signals, which can lead to high fever and recurrent painful inflammation.

For nearly three decades, scientists have been unable to answer a key question: after this “brake” is removed, which protein does pyrin interact with? Researchers have now identified CDC42, a small protein previously known mainly for its role in regulating cell shape and movement, as pyrin’s key partner.

In one of the studies, scientists examined patients with severe inflammatory symptoms and identified a T43I mutation in the CDC42 gene. This mutation changes the structure of the protein, causing it to bind too strongly to pyrin. As a result, the cellular inflammatory mechanism is activated too easily, triggering an excessive immune response.

In the second study, researchers created a functional map of hundreds of MEFV gene mutations. They determined which variants actually cause the disease, which have no significant effect on cellular function, and which require further investigation.

The researchers found that the mutations most strongly associated with severe forms of familial Mediterranean fever are located in the same region of pyrin that interacts with CDC42. This provides further evidence that this region plays a key role in triggering inflammation.

According to the scientists, the discovery could improve diagnosis for patients whose genetic changes were previously difficult to interpret.

In addition, the newly identified interaction between CDC42 and pyrin could become a potential target for developing drugs capable of preventing excessive activation of the inflammatory system.

The researchers say the findings pave the way for more precise medicine. In the future, treatment could be selected based not only on a diagnosis but also on the specific molecular mechanism responsible for the disease.

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