Mutation of a new gene encoding a putative pyrin-like protein causes familial cold autoinflammatory syndrome and Muckle-Wells syndrome

Familial cold autoinflammatory syndrome (FCAS, MIM 120100), commonly known as familial cold urticaria (FCU), is an autosomal-dominant systemic inflamm atory disease characterized by intermittent episodes of rash, arthralgia, f ever and conjunctivitis after generalized exposure to cold(1-4). FCAS was p reviously mapped to a 10-cM region on chromosome 1q44 (refs. 5,6). Muckle-W ells syndrome (MWS; MIM 191900), which also maps to chromosome 1q44, is an autosomal-dominant periodic fever syndrome with a similar phenotype except that symptoms are not precipitated by cold exposure and that sensorineural hearing loss is frequently also present(6-8). To identify the genes for FCA S and MWS, we screened exons in the 1q44 region for mutations by direct seq uencing of genomic DNA from affected individuals and controls. This resulte d in the identification of four distinct mutations in a gene that segregate d with the disorder in three families with FCAS and one family with MWS. Th is gene, called CIAS1, is expressed in peripheral blood leukocytes and enco des a protein with a pyrin domain(9-11), a nucleotide-binding site (NBS, NA CHT subfamily(12)) domain and a leucine-rich repeat (LRR) motif region(13), suggesting a role in the regulation of inflammation and apoptosis.