The MEFV Gene and the Pyrin Inflammasome: Insights into Autoinflammatory Disorders

The MEFV gene, located on chromosome 16, encodes the protein pyrin, which plays a crucial role in the regulation of the innate immune system and the development of autoinflammatory disorders. Autoinflammatory diseases (AIDs) are a group of rare genetic conditions characterized by recurrent episodes of systemic inflammation, often without a clear trigger or autoimmune component.

Familial Mediterranean Fever (FMF) is the prototypic AID and is caused by pathogenic variants in the MEFV gene. FMF is characterized by recurring short episodes of fever, abdominal pain, joint pain, and skin rashes, and can lead to the development of amyloidosis, a serious complication.

The pyrin protein, encoded by the MEFV gene, is a key component of the pyrin inflammasome, a multiprotein complex that senses cellular distress signals and triggers the release of proinflammatory cytokines, such as interleukin-1β (IL-1β). Pyrin specifically detects modifications in the activity of the small GTPase RhoA, which is involved in regulating various cellular processes, including the cytoskeleton.

Pathogenic variants in the MEFV gene can lead to the dysregulation of the pyrin inflammasome, resulting in the uncontrolled activation of the inflammatory response. These variants can be inherited in either a dominant or recessive manner, depending on their location and effect on the pyrin protein.

Variants in the C-terminal B30.2/SPRY domain of pyrin, which is responsible for the activation of caspase-1 and the subsequent release of IL-1β, are typically considered recessive. However, even heterozygous carriers of these variants may exhibit a subclinical inflammatory phenotype.

On the other hand, heterozygous mutations in other domains of pyrin, such as the N-terminal pyrin domain or the α-helical coiled-coil domain, can lead to a constitutively active inflammasome, even in the absence of a clear trigger. These variants affect residues critical for the inhibition or oligomerization of pyrin, resulting in the uncontrolled release of proinflammatory cytokines.

The most common MEFV variants associated with FMF are M694V, M694I, V726A, and M680I, which are located in the B30.2/SPRY domain and are linked to more severe disease manifestations . These variants account for approximately 75% of all FMF cases.

Understanding the role of the MEFV gene and the pyrin inflammasome in the pathogenesis of autoinflammatory disorders has led to significant advancements in the development of targeted therapies, such as IL-1 inhibitors, which have shown promising results in the management of these complex and debilitating conditions.

In conclusion, the MEFV gene and the pyrin inflammasome are central to the understanding of autoinflammatory disorders, particularly FMF. Ongoing research continues to elucidate the intricate mechanisms underlying the dysregulation of the pyrin inflammasome and the development of novel therapeutic strategies to improve the lives of patients affected by these rare and often challenging conditions.

Reference:
Schnappauf, O., Chae, J. J., Kastner, D. L., & Aksentijevich, I. (2019). The pyrin inflammasome in health and disease. Frontiers in immunology, 10, 465008.
Tufan, A., & LACHMANN, H. (2020). Familial Mediterranean fever, from pathogenesis to treatment: a contemporary review. Turkish Journal of Medical Sciences, 50(10), 1591-1610.
La Bella, S., Di Ludovico, A., Di Donato, G., Basaran, O., Ozen, S., Gattorno, M., ... & Breda, L. (2024). The pyrin inflammasome, a leading actor in pediatric autoinflammatory diseases. Frontiers in Immunology, 14, 1341680.