Open AccessThe clinical continuum of cryopyrinopathies: Novel CIAS1 mutations in North American patients and a new cryopyrin model
Author(s) -
Aksentijevich Ivona,
D. Putnam Christopher,
Remmers Elaine F.,
Mueller James L.,
Le Julie,
Kolodner Richard D.,
Moak Zachary,
Chuang Michael,
Austin Frances,
GoldbachMansky Raphaela,
Hoffman Hal M.,
Kastner Daniel L.
Publication year - 2007
Publication title -
arthritis & rheumatism
Language(s) - English
Resource type - Journals
eISSN - 1529-0131
pISSN - 0004-3591
DOI - 10.1002/art.22491
Subject(s) - nalp3 , pyrin domain , medicine , mutation , inflammasome , disease , gene , genetics , immunology , biology , inflammation
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‐1β 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.