Protein structure of cryopyrin (9). All of the 20 mutations that cause familial cold autoinflammatory syndrome (FCAS), Muckle-Wells Syndrome (MWS), and/or neonatal-onset multisystem inflammatory disease (NOMID)/chronic infantile neurologic, cutaneous, and articular (CINCA) syndrome have been identified in exon 3 of CIAS1, which encodes the NACHT domain. Fourteen of the 20 mutations are located within the NACHT domain, and 6 mutations are found in the region of cryopyrin, which flanks the NACHT domain. Mutations shown in red cause NOMID/CINCA syndrome, those in blue cause MWS, those in green cause FCAS, and those in black are observed in more than one disease. The D303N mutation was identified in 2 unrelated NOMID/CINCA syndrome patients (ref. 33 and the present study) and has been reported in 1 MWS patient (35). The R260W mutation has been reported in 2 FCAS and 2 MWS families (35). LRR = leucine-rich repeat.