Nature Genetics
29, 301 - 305 (2001)
Published online: 22 October 2001; | doi:10.1038/ng756
Mutation of a new gene encoding a putative pyrin-like protein causes familial cold autoinflammatory syndrome and Muckle−Wells syndromeHal M. Hoffman1, 2, 3, James L. Mueller1, 2, 3, 4, David H. Broide2, 3, Alan A. Wanderer5
& Richard D. Kolodner1, 3, 41
Ludwig Institute for Cancer Research, University of California School of Medicine, San Diego, California, USA. 2
Division of Rheumatology, Allergy, and Immunology, University of California School of Medicine, San Diego, California, USA. 3
Department of Medicine, University of California School of Medicine, San Diego, California, USA. 4
Cancer Center, University of California School of Medicine, San Diego, California, USA. 5
Department of Pediatrics and Allergy, University of Colorado Health Sciences Center, Denver, Colorado, USA.
Correspondence should be addressed to Hal M. Hoffman hahoffman@ucsd.eduFamilial cold autoinflammatory syndrome (FCAS, MIM 120100), commonly known as familial cold urticaria (FCU), is an autosomal-dominant systemic inflammatory disease characterized by intermittent episodes of rash, arthralgia, fever and conjunctivitis after generalized exposure to cold1,
2,
3,
4. FCAS was previously mapped to a 10-cM region on chromosome 1q44 (refs. 5,6). Muckle−Wells 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 present6,
7,
8. To identify the genes for FCAS and MWS, we screened exons in the 1q44 region for mutations by direct sequencing of genomic DNA from affected individuals and controls. This resulted in the identification of four distinct mutations in a gene that segregated with the disorder in three families with FCAS and one family with MWS. This gene, called CIAS1, is expressed in peripheral blood leukocytes and encodes a protein with a pyrin domain9,
10,
11, a nucleotide-binding site (NBS, NACHT subfamily12) domain and a leucine-rich repeat (LRR) motif region13, suggesting a role in the regulation of inflammation and apoptosis.
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