Abstract
Familial 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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Acknowledgements
We are extremely grateful to all of the family members who participated in this research effort. We are indebted to R. Townley, R. Simon and F. Shih for their referral of patients. We thank K. Woods, M. Tressierras, D. Lightfoot and M. Kane for technical assistance, J. Weger and J. Sansone for technical assistance with genotyping and sequencing, B. Stevenson and V. Jongeneel for database sequence analysis, B. Riegle for computer support, and S. Soefje for editorial support. We also thank M. McDermott, B. Ross, W. Cavenee, R. White, R. Das Gupta, W. Biggs, C. Putnam, F. Wright and G. Hampton for their helpful advice. The research was carried out with the support of National Institute of Health (NIAID 5-K08 AI01508), the American Academy of Allergy, Asthma, and Immunology Education and Research Trust Faculty Development Award, the Arthritis Foundation San Diego Chapter Research Award and the Ludwig Institute of Cancer Research.
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Hoffman, H., Mueller, J., Broide, D. et al. Mutation of a new gene encoding a putative pyrin-like protein causes familial cold autoinflammatory syndrome and Muckle–Wells syndrome. Nat Genet 29, 301–305 (2001). https://doi.org/10.1038/ng756
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DOI: https://doi.org/10.1038/ng756
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