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 cold [1][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 present [6][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 domain 9-11 , a nucleotide-binding site (NBS, NACHT subfamily 12 ) domain and a leucine-rich repeat (LRR) motif region 13 , suggesting a role in the regulation of inflammation and apoptosis.We previously identified a locus for FCAS on chromosome 1q44 between markers D1S423 and D1S2682 (ref. 5). We developed a physical contig of bacterial artificial chromosomes (BACs) and P1-derived artificial chromosomes and narrowed the critical region to less than 1 Mb using haplotype analysis (data not shown). We used ESTs mapping to this region and The four-generation family with FCAS (family 1; Fig. 1) has an apparent de novo mutation that first appeared in subject 4 on a chromosome inherited from her mother. Only the affected members of subsequent generations of the family (subjects 5, 9 and 11) inherited this chromosome. We found a missense mutation in subject 4 that segregated with the disease haplotype in subsequent generations (subjects 5, 9 and 11). This mutation was not present in either of her parents (subjects 1 and 2), even though the unaffected mother (subject 2) possessed the haplotype that segregates with disease in this family.The other two families with FCAS (families 2 and 3) also had different missense mutations in the same exon; these were present in all affected family members (Fig. 2). In the one family studied with affected members with a diagnosis of MWS (family 4), both affected individuals had sensorineural hearing loss (Fig. 2). This family also had a missense mutation in the same exon as the families with FCAS. As in family 1, the phenotype of family 4 resulted from a de novo mutation. The unaffected mother (DNA was not available from the father) in family 4 possessed the haplotype that segregates with the disease in subsequent generations (data not shown), but she did not have the mutation that was found in all of the affected family members. These missense mutations were not found in any unaffected individuals in thes...

Glyburide, a sulfonylurea drug commonly used to treat type 2 diabetes, shuts down IL-1β secretion by preventing Cyropyrin activation.

SUMMARY Cryopyrin (NALP3) mediates formation of the inflammasome, a protein complex responsible for cleavage of pro-IL-1β to its active form. Mutations in the cryopyrin gene, NLRP3, cause the autoinflammatory disease spectrum: cryopyrin-associated periodic syndromes (CAPS). The central role of IL-1β in CAPS is supported by the remarkable response to IL-1 targeted therapy. We developed two novel Nlrp3 mutant knock-in mouse strains to model CAPS to examine the role of other inflammatory mediators and adaptive immune responses in an innate immune driven disease. These mice had systemic inflammation and poor growth, similar to some human CAPS patients, and demonstrated early mortality, primarily mediated by myeloid cells. Mating these mutant mice to various knock-out backgrounds confirmed the mouse disease phenotype required an intact inflammasome, was only partially dependent on IL-1β, and was independent of T cells. This data suggests CAPS are true inflammasomopathies and provide insight for more common inflammatory disorders.

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.