Mutation of a new gene encoding a putative pyrin-like protein causes familial cold autoinflammatory syndrome and Muckle–Wells syndrome

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 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...

Cryopyrin and pyrin activate caspase-1, but not NF-κB, via ASC oligomerization

“…8,9 Among these diseases NOMID/CINCA syndrome display the most severe phenotype with neonatal onset, chronic polymorphonuclear meningitis leading to progressive neurologic impairment, and recurrent flare-ups of joint inflammation. 38 The molecular mechanisms for the development of these autoinflammatory diseases are not Figure 8 A hypothetical model illustrating the formation of the cryopyrin and pyrin inflammasomes in response to pathogen infection.…”

“…Mutations in the MEFV gene which encodes pyrin are associated with familial Mediterranean fever (FMF), 6,7 while mutations in the CIAS1 gene which encodes cryopyrin are responsible for three PFSs; familial cold autoinflammatory syndrome (FCAS)/familial cold urticaria (FCU), Muckle-Wells syndrome (MWS), and neonatalonset multisystem inflammatory disease (NOMID)/chronic infantile neurological cutaneous and articular syndrome (CIN-CA). 8,9 These diseases are characterized by recurrent episodes of inflammation and fever, and because of the lack of an apparent stimulus and the involvement of autoantibodies and autoreactive T cells, they are defined as autoinflammatory syndromes (reviewed in Gumucio et al, 1 Hull et al, 2 McDermott and Aksentijevich, 3 and Stehlik and Reed 4 ).…”

Inflammatory caspases and inflammasomes: master switches of inflammation

“…66,86,87 All three disorders are closely related autoinflammatory syndromes characterized by periodic fever, skin rashes, amyloidosis and in the case of CINCA, the eventual development of neurological complications. Mutations in NALP3 confer a gain of function to the protein, resulting in constitutively active NALP3 in Muckle Wells patients.…”

The SPRY domain of Pyrin, mutated in familial Mediterranean fever patients, interacts with inflammasome components and inhibits proIL-1β processing

“…[1][2][3] This group of diseases comprises three syndromes associated with mutations in NALP3, a key component of the inflammasome 4 : Muckle-Wells syndrome, familial cold urticaria 5 and chronic infantile neurological cutaneous and articular syndrome/ OMID, 6 as well as other syndromes like hyper-IgD, 7,8 PAPA syndrome, 9 TRAPS 10,11 and familial Mediterranean fever (FMF). 12,13 The latter is a recessively inherited disorder, in which mutations occur in the pyrin gene.…”