Virtually all cases are due to a mutation in the<unk>  Fever <unk> V) gene on the chromosome 16, which codes for a protein called pyrin or marenostrin. Various mutations of this gene lead to<unk> , although some mutations cause a more severe picture than others. Mutations occur mainly in exons 2, 3, 5 and 10. The function of pyrin has not been completely elucidated, but in short, it is a protein that binds to the adaptor ASC and the pro form of the enzyme caspase-1 to generate multiprotein complexes called inflammasomes in response to certain infections. In healthy individuals, pyrin-mediated inflammasome assembly (which leads to the caspase 1) dependent processing and secretion of the pro-inflammatory cytokines (such as interleukin-18 (IL-18) and IL-1β) is a response to enterotoxins from certain bacteria. The gain-of-function mutations in the<unk> V gene render Pyrin hyperactive, and subsequently, the formation of the inflammasomes becomes more frequent. The pathophysiology of<unk>  has recently undergone significant advances: at basal state, pyrin is kept inactive by a chaperone protein (belonging to the family of 14.3.3 proteins) linked to pyrin through phosphorylated serine residues. The dephosphoration of pyrin is an essential prerequisite for the activation of the pyrin inflammasome. Inactivation of RhoA GTPases (by bacterial toxins, for example) leads to the inactivation of PKN1 / PKN2 kinases and dephosphoration of pyrin. In healthy subjects, the dephosphorylation step alone does not cause activation of the pyrin inflammasome. In contrast, in<unk>  patients, the dephosphorylation of serines is sufficient to trigger the activation of the pyrin inflammasome. This suggests that there is a two-level regulation and that the second regulatory mechanism (independent of (de)phosphorylation) is deficient in<unk>  patients. This deficient mechanism is probably located at the level of the B30.2 domain (exon 10) where most of the pathogenic mutations associated with<unk>  are located. It is probably the interaction of this domain with the cytoskeleton (microtubules) that is failing, as suggested by the efficacy of colchicine. It is not conclusively known what exactly sets off the attacks, and why overproduction of IL-1 would lead to particular symptoms in particular organs (e.g. joints or the peritoneal cavity).
Familial Mediterranean fever
Chilaiditi syndrome
Scleroderma
Hereditary angioedema
Kawasaki disease
Sjögren syndrome
Chilblain lupus erythematosus
Periodic fever syndrome