The data shown are means SD (*, P 0.05; = 5). hyperactivation of innate immune cells (Chen and Nu?ez, 2010; Park et al., 2012). Several studies, including those from our group, have identified the causative genes BET-BAY 002 for familial autoinflammatory syndromes (McDermott et al., 1999; Jru et al., 2008; Masters et al., 2009; Agarwal et al., 2010; Kitamura et al., 2011; Liu et al., 2012; Park et BET-BAY 002 al., 2012). Among these genes, mutations in cause autoinflammatory syndromes, including familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and neonatal onset multisystem inflammatory disease (NOMID; Hoffman et al., 2001; Jru et al., 2008; Masters et al., 2009; Aksentijevich and Kastner, 2011; Park et al., 2012). These diseases are named cryopyrin-associated periodic syndromes (CAPS). FCAS, the mildest of the CAPS, is characterized by rash, fever, and arthralgia by exposure to cold stimuli. Patients with MWS have more frequent inflammatory episodes and they frequently develop progressive sensorineural hearing loss and systemic amyloidosis. NOMID is the most severe of the three syndromes and is characterized by severe chronic inflammation involving the joints and nervous system. However, there are still significant numbers of CAPS without any mutations in (Aksentijevich et al., 2007). Heterozygous mutations in result in overactivation of caspase 1. This enzyme cleaves the precursors of IL-1 and IL-18 (members of the IL-1 family of cytokines) into their active forms (Masters et al., 2009; Aksentijevich and Kastner, 2011). The recombinant IL-1 receptor antagonist anakinra, canakinumab, and the IL-1 receptor type I fusion protein rilonacept have induced clinical response in CAPS, demonstrating that signaling via the IL-1 receptor is crucial for the pathogenesis of CAPS (Aksentijevich and Kastner, 2011; Dinarello and van der Meer, 2013). Recent studies have provided evidence that heterozygous mutations in cause FCAS-like symptoms (Jru et al., 2008). The mutations are reported to inhibit NF-B or activate caspase 1, depending on the genetic variation (Jru et al., 2008; Jru et al., 2011). In the current study, we used exome resequencing to analyze candidate genes of patients in one Japanese family with cold-induced urticaria and arthritis but without mutations in or We identified a heterozygous missense mutation in in mice causes severe dermatitis, arthritis, and splenomegaly with augmented infiltration of neutrophils as well as cold-induced exanthema. The inflammation depended on IL-1 and IL-17A produced by neutrophils but not T cells. These data indicate BET-BAY 002 that is a causative gene for this disease and highlight the crucial roles of NLRC4 not only in the innate immune response to bacterial infections but also in the pathogenesis of human inflammatory diseases. RESULTS Linkage and exome analyses of a Japanese family with a history of FCAS revealed a missense mutation in is a causative gene for FCAS. (a) The pedigree of a Japanese family with FCAS. The genomes of the patients or healthy members with a number inside of the square or circle were IL-15 evaluated. (b) An image of the urticarial-like rash that patient number 3 3 developed at the age of 7 mo. Bar, 10 mm. (c) The genotypes of family members #1 and 6 (wild-type; left) or #2, 3, 4, 5, and 7 (heterozygote; right) are shown. The red arrows indicate position 1589. (d) The structure of NLRC4 consists of a caspase recruitment domain (CARD), a nucleotide-binding oligomerization domain (NOD), and a leucine-rich repeat (LRR). The black arrowhead indicates the BET-BAY 002 mutation from histidine to proline at position 443 of NLRC4. (e) The amino.