title: The clinical continuum of cryopyrinopathies: novel CIAS1 mutations in North American patients and a new cryopyrin model.
abstract: OBJECTIVE
  The cryopyrinopathies are a group of rare autoinflammatory disorders that are caused by mutations in CIAS1, encoding the cryopyrin protein. However, cryopyrin mutations are found only in 50% of patients with clinically diagnosed cryopyrinopathies. This study was undertaken to investigate the structural effect of disease-causing mutations on cryopyrin, in order to gain better understanding of the impact of disease-associated mutations on protein function.
  
  
  METHODS
  We tested for CIAS1 mutations in 22 patients with neonatal-onset multisystem inflammatory disease/chronic infantile neurologic, cutaneous, articular syndrome, 12 with Muckle-Wells syndrome (MWS), 18 with familial cold-induced autoinflammatory syndrome (FCAS), and 3 probands with MWS/FCAS. In a subset of mutation-negative patients, we screened for mutations in proteins that are either homologous to cryopyrin or involved in the caspase 1/interleukin-1beta signaling pathway. CIAS1 and other candidate genes were sequenced, models of cryopyrin domains were constructed using structurally homologous proteins as templates, and disease-causing mutations were mapped.
  
  
  RESULTS
  Forty patients were mutation positive, and 7 novel mutations, V262A, C259W, L264F, V351L, F443L, F523C, and Y563N, were found in 9 patients. No mutations in any candidate genes were identified. Most mutations mapped to an inner surface of the hexameric ring in the cryopyrin model, consistent with the hypothesis that the mutations disrupt a closed form of cryopyrin, thus potentiating inflammasome assembly. Disease-causing mutations correlated with disease severity only for a subset of known mutations.
  
  
  CONCLUSIONS
  Our modeling provides insight into potential molecular mechanisms by which cryopyrin mutations can inappropriately activate an inflammatory response. A significant number of patients who are clinically diagnosed as having cryopyrinopathies do not have identifiable disease-associated mutations.
authors: National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, Maryland.
authors: Ivona
authors: I
authors: Aksentijevich
authors: University of California San Diego School of Medicine, La Jolla.
authors: Christopher D
authors: CD
authors: Putnam
authors: National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, Maryland.
authors: Elaine F
authors: EF
authors: Remmers
authors: University of California San Diego School of Medicine, La Jolla.
authors: James L
authors: JL
authors: Mueller
authors: National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, Maryland.
authors: Julie
authors: J
authors: Le
authors: University of California San Diego School of Medicine, La Jolla.
authors: Richard D
authors: RD
authors: Kolodner
authors: National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, Maryland.
authors: Zachary
authors: Z
authors: Moak
authors: National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, Maryland.
authors: Michael
authors: M
authors: Chuang
authors: National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, Maryland.
authors: Frances
authors: F
authors: Austin
authors: National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, Maryland.
authors: Raphaela
authors: R
authors: Goldbach-Mansky
authors: University of California San Diego School of Medicine, La Jolla.
authors: Hal M
authors: HM
authors: Hoffman
authors: National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, Maryland.
authors: Daniel L
authors: DL
authors: Kastner
mesh_terms: D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D002648:Child; D002908:Chronic Disease; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D003872:Dermatitis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D007223:Infant; D007249:Inflammation / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D007592:Joint Diseases / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D009656:North America; D016415:Sequence Alignment; D013577:Syndrome
chemical_list: D002352:Carrier Proteins; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human