Mutation of a New Gene Encoding a Putative Pyrin-Like Protein Causes Familial Cold Autoinflammatory Syndrome and Muckle-Wells Syndrome

Akaluck Thatayatikom; Andrew H. Liu

Purpose of the Study. To identify the genes for familial cold autoinflammatory syndrome (FCAS) and Muckle-Wells syndrome (MWS).

Study Population. Three families with FCAS and 1 family with MWS.

Methods. Genomic DNA isolation, identification of coding region, DNA sequencing, and mutation detection. Protein prediction programs were also performed.

Results. Four distinct mutations of the CIAS1 Gene on chromosome 1q44 were identified. The gene encodes a newly identified protein called cryopyrin.

Conclusion. Mutations of the CIAS1 Gene encoding cryopyrin cause at least two distinct but similar cold-sensitive diseases, including FCAS and MWS.

Reviewers’ Comments. This exciting discovery has led to the identification of a new protein, aptly named “cryopryin,” that links cold temperature exposure to inflammation. In this report, mutations of the cryopyrin gene were identified in family members with 2 rare autosomal dominant conditions that are “autoinflammatory” disorders (ie, conditions with recurrent inflammatory symptoms in the absence of autoantibodies): FCAS and MWS. Recently, FCAS—also known as familial cold urticaria and familial polymorphous cold eruption—has been well-described by the same authors. The FCAS clinical picture includes: skin rash (100%), arthralgia (96%), fever (93%), conjunctivitis (84%), disease onset in the first 6 months of life (95%), an average time delay between cold exposure and the onset of symptoms of 2.5 hours, and an average episode duration of 12 hours (Hoffman HM, et al. J Allergy Clin Immunol. 2001;108:615–620). In contrast, MWS leads to progressive sensorineural deafness, amyloidosis of the kidneys and other organs, fevers, chills, rigors, malaise, and chronic recurrent urticaria. The reason for the 2 distinct clinical entities associated with mutations in the same gene still need to be explored. For more discussion, see a brief editorial entitled “A fever gene comes in from the cold” by Kastner and O’Shea on pages 241–242 of the same issue.