MEFV

Related conditions

More than 80 MEFV mutations that cause familial Mediterranean fever have been identified. A few mutations delete small amounts of DNA from the MEFV gene, which can lead to an abnormally small protein. Most MEFV mutations, however, change one of the protein building blocks (amino acids) used to make pyrin. The most common mutation replaces the amino acid methionine with the amino acid valine at protein position 694 (written as Met694Val or M694V). Among people with familial Mediterranean fever, this particular mutation is also associated with an increased risk of developing amyloidosis, a complication in which abnormal protein deposits can lead to kidney failure. Some evidence suggests that another gene, called SAA1, can further modify the risk of developing amyloidosis among people with the M694V mutation.

MEFV mutations lead to reduced amounts of pyrin or a malformed pyrin protein that cannot function properly. As a result, pyrin cannot perform its presumed role in controlling inflammation, leading to an inappropriate or prolonged inflammatory response. Fever and inflammation in the abdomen, chest, joints, or skin are signs of familial Mediterranean fever. Pyrin forms an inflammasome which senses RhoA GTPases inactivation and subsequent kinases (PKN1 and PKN2) inactivation. These kinases phosphorylate two serine residues located in the linker encoded by MEFV exon 2, allowing proteins 14.3.3 to keep pyrin inflammasome in an inactive state. Mutations in these serine residues are responsible for Pyrin-Associated Autoinflammation with Neutrophilic Dermatosis (PAAND). Recently, it has been shown that pyrin dephosphorylation is sufficient to trigger inflammasome activation in familial Mediterranean fever patients. Furthermore, while the trigger of FMF flares remain unknown, steroid hormone catabolites (pregnanolone and etiocholanaolone) have been shown to activate the pyrin inflammasome, in vitro, by interacting with the B30.2 domain (coded by exon 10).

References

References

1. (2011-04-07). "MEFV - Mediterranean fever". US National Library of Medicine, National Institutes of Health, Department of Health & Human Services.
2. (August 2016). "Pyrin inflammasome activation and RhoA signaling in the autoinflammatory diseases FMF and HIDS". Nature Immunology.
3. (December 2017). "A novel Pyrin-Associated Autoinflammation with Neutrophilic Dermatosis mutation further defines 14-3-3 binding of pyrin and distinction to Familial Mediterranean Fever". Annals of the Rheumatic Diseases.
4. (November 2019). "Pyrin dephosphorylation is sufficient to trigger inflammasome activation in familial Mediterranean fever patients". EMBO Molecular Medicine.
5. (October 2022). "Steroid hormone catabolites activate the pyrin inflammasome through a non-canonical mechanism". Cell Reports.
6. (July 2014). "A novel insertion mutation identified in exon 10 of the MEFV gene associated with Familial Mediterranean Fever". BMC Medical Genetics.