MEFVmutations affecting pyrin amino acid 577 cause autosomal dominant autoinflammatory disease

Abstract

Heterozygous mutations at amino acid position 577 of pyrin can induce an autosomal dominant autoinflammatory syndrome. This suggests that T577, located in front of the C-terminal B30.2/SPRY domain, is crucial for pyrin function.

A new autoinflammatory and autoimmune syndrome associated with NLRP1 mutations: NAIAD (NLRP1-associated autoinflammation with arthritis and dyskeratosis)

“…How both dominant and recessive mutations in MEFV lead to excessive processing of IL-1β and/or IL-18 is still unclear, but some hypotheses are emerging. The MEFV recessive mutations may be responsible for loss of function of its negative regulation on the NLRP3 inflammasome,46–48 whereas dominant MEFV mutations may act as gain-of-function mutations leading to a constitutive activation of the Pyrin inflammasome 44 45 49 50. As in Pyrin, recessive mutation in the linker region may affect an inhibitory function of NLRP1 and a dominant mutation in the FIIND may act directly on the NLRP1 inflammasome.…”

Molecular Mechanisms in Genetically Defined Autoinflammatory Diseases: Disorders of Amplified Danger Signaling

“…FMF is caused by autosomal recessive mutations in the MEFV gene (7, 8), although an autosomal dominant form has been postulated (49). More than 80 distinct missense mutations have been identified, the majority in exon 10, which encodes the B30.2 domain of the molecule.…”

Classic Autoinflammatory Diseases

“…105 There is evidence that the deletion mutation at codon 694 and the M694IÀE148Q complex allele, as well as mutations at residue 577, are associated with an autosomal dominant from of FMF. 105,107 Pathogenesis Pyrin is expressed in neutrophils, eosinophils, monocytes, dendritic cells, and synovial fibroblasts, but not at significant levels in lymphocytes. 130,131 Pyrin has a pyrin domain (PYD), an N-terminal homotypic interaction domain that binds the adaptor protein ASC (apoptosisassociated speck-like protein with a caspase recruitment domain), 132 which consists of an N-terminal PYD and a C-terminal CARD.…”