SummaryBackground-Familial cold autoinflammatory syndrome (FCAS) is an autosomal dominant disorder characterised by recurrent episodes of rash, arthralgia, and fever after cold exposure. The genetic basis of this disease has been elucidated. Cryopyrin, the protein that is altered in FCAS, is one of the adaptor proteins that activate caspase 1, resulting in release of interleukin 1.

These results confirm the central role of IL-1beta in FCAS and support the use of IL-1 targeted therapy in these patients.

Mutations in the human CIAS1 (hCIAS1) gene have been identified in a continuum of inflammatory disorders including familial cold autoinflammatory syndrome (FCAS), MuckleWells syndrome (MWS), and neonatal onset multisystem inflammatory disease (NOMID). CIAS1 codes for the protein Cryopyrin, which appears to play a role in innate immune function by regulating the production of proinflammatory cytokines. Human and mouse Cryopyrin are highly conserved and consist of three functional domains including a pyrin domain, an NACHT domain, ☆ Supplementary data associated with this article can be found, in the online version, at doi: 10.1016/j.gene.2004.05.002.☆☆ The nucleotide sequence data reported in this paper have been submitted to GenBank and have been assigned the accession numbers for the three mouse strains (strain C57BL/6) CIAS1.mRNAThe primate sequence accession numbers are GgCIAS1.Exon1 AY337307, TgCIAS1.Exon1 AY337308, MsCIAS1.Exon1 AY337309, AbCIAS1.Exon1 AY337310, CjCIAS1.Exon1 AY337311, CmCIAS1.Exon1 AY337312, GgCIAS1.NBS AY338196, TgCIAS1.NBS AY338197, MsCIAS1.NBS AY338198, CcCIAS1.NBS AY338199, CgCIAS1.NBS AY338200, AbCIAS1.NBS AY338201, AaCIAS1.NBS AY338202, SsCIAS1.NBS AY338203, CaCIAS1.NBS AY338204, S.CIAS1.NBS AY338205, CjCIAS1.NBS AY338206, Cp.CIAS1.NBS AY338207, TbCIAS1.NBS AY338208, CmCIAS1.NBS AY338209, LcCIAS1.NBS AY338210, and VvCIAS1.NBS AY338211. The mammalian sequence accession numbers are LaCIAS1.NBS AY495378, EeCIAS1.NBS AY495379, and DnCIAS1.NBS AY495380. and a leucine-rich repeat (LRR) domain that are characteristics of the NALP family of proteins. The pyrin and NACHT domains of Cryopyrin and other NALP proteins are highly conserved among primate and nonprimate mammals, suggesting purifying selection throughout mammalian evolution. Cryopyrin expression is also very similar in human and mouse with mouse CIAS1 mRNA expression found primarily in peripheral blood leukocytes consistent with the postulated inflammatory function. We also detected significant expression in mouse eye and skin tissue, which is consistent with symptoms observed in human Cryopyrin-associated diseases. HHS Public Access

Mutations in NLRP3 (CIAS1) are identified in a continuum of related inflammatory disorders, known as cryopyrinopathies since NLRP3 codes for the protein cryopyrin. Approximately 40% of patients with classic presentation lack mutations in the coding region of NLRP3 suggesting heterogeneity or epigenetic factors. Cryopyrin is a key regulator of proinflammatory cytokine release. Therefore, variations in the NLRP3 promoter sequence may have effects on disease state in patients with cryopyrinopathies and other inflammatory diseases. In this report, we confirmed three 5′-untranslated region splice forms with two separate transcriptional start sites, and identified potential promoter regions and six new DNA promoter variants. One variant is unique to a mutation negative cryopyrinopathy patient and increases in vitro gene expression. Additional studies can now be performed to further characterize the NLRP3 promoter and sequence variants, which will lead to better understanding of the regulation of NLRP3 expression and its role in disease.