significantMechanism
Pyrin inflammasome structural mechanism fully elucidated
Familial Mediterranean Fever →Summary
Structural biology studies resolved the pyrin inflammasome filament architecture, showing how FMF-associated MEFV mutations destabilize the autoinhibitory interaction between the pyrin SPRY domain and the B30.2 domain. This explained why gain-of-function mutations constitutively activate the inflammasome and provided a structural basis for rational drug design targeting pyrin.
Related genes
MEFVM694V (c.2080A>G, p.Met694Val)
The most common and most severe FMF mutation. Located in exon 10 (B30.2/SPRY domain). Homozygosity associated with earliest onset, highest attack frequency, most arthritis, and greatest risk of AA amyloidosis.MEFVM680I (c.2040G>A/C, p.Met680Ile)
Third most common FMF mutation. Located in exon 10. Homozygosity or compound heterozygosity with M694V associated with severe disease. M680I/M694V combination produces severe phenotype.MEFVV726A (c.2177T>C, p.Val726Ala)
Second most common FMF mutation. Located in exon 10. Heterozygosity generally associated with milder phenotype. However, V726A-E148Q complex allele can be severe.MEFVE148Q (c.442G>C, p.Glu148Gln)
Located in exon 2. Highly controversial — debated whether pathogenic variant or benign polymorphism. Extremely high frequency in general population. When part of a complex allele with V726A, significantly increases disease severity.MEFVM694I (c.2082G>A/C, p.Met694Ile)
Located in exon 10. Fifth founder mutation. Homozygosity associated with severe disease. M694I/M694I genotype identified as a specific risk factor for AA amyloidosis in Algerian patients.More from Familial Mediterranean Fever
significantTreatment update
JAK inhibitors (tofacitinib) emerging as potential third-line therapy
significantTreatment update
IL-1 blockade established as standard second-line therapy for colchicine-resistant FMF
significantTreatment update
EULAR/PReS 2024 updated management recommendations published
significantNew research
Colchicine resistance mechanisms linked to pyrin inflammasome microtubule independence
ID: familial-mediterranean-fever-update-9Type: mechanismImpact: significant