The clinical continuum of cryopyrinopathies: novel CIAS1 mutations in North American patients and a new cryopyrin model

Arthritis Rheum. 2007 Apr;56(4):1273-1285. doi: 10.1002/art.22491.

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.

Conclusion: 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Amino Acid Sequence
  • Carrier Proteins / genetics*
  • Carrier Proteins / metabolism
  • Child
  • Chronic Disease
  • Cohort Studies
  • DNA Mutational Analysis
  • Dermatitis / genetics*
  • Dermatitis / metabolism
  • Dermatitis / pathology
  • Female
  • Humans
  • Infant
  • Inflammation / genetics*
  • Inflammation / metabolism
  • Inflammation / pathology
  • Joint Diseases / genetics*
  • Joint Diseases / metabolism
  • Joint Diseases / pathology
  • Male
  • Middle Aged
  • Molecular Sequence Data
  • Mutation
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • North America
  • Sequence Alignment
  • Syndrome

Substances

  • Carrier Proteins
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • NLRP3 protein, human