Figure 3.

The evolution and structural ramifications of ancestral mutations in pyrin. (a) This figure highlights both that pyrin mutations are very common in several Mediterranean populations and that it is not the same mutation that is expanded in each population. Blue and red lines indicate the migration of populations carrying the M649V and V726A mutations, respectively, while the E148Q mutation ( purple) is common to countries along the medieval trade route (the Silk Road) that extended from the Middle East through to Japan. Pie diagrams indicate the carrier frequencies of selected mutations in Ashkenazi Jewish, Sephardi Jewish, and Japanese populations. (b) A model for the structure of the B30.2/SPRY domain of pyrin (based on that of TRIM21) indicates the preponderance of FMF mutations (cyan) affecting one side of the molecule that is thought to present a protein-binding pocket. A phenotype-genotype correlation is proposed that links the more severe disease-causing mutations (M694V blue, M680I green) to the putative binding site, whereas a less severe mutation (V726A red ) is located further away from this region.