Drs. Aksentijevich and Putnam contributed equally to this work
The clinical continuum of cryopyrinopathies: Novel CIAS1 mutations in North American patients and a new cryopyrin model
Article first published online: 28 MAR 2007
Copyright © 2007 by the American College of Rheumatology
Arthritis & Rheumatism
Volume 56, Issue 4, pages 1273–1285, April 2007
How to Cite
Aksentijevich, I., D. Putnam, C., Remmers, E. F., Mueller, J. L., Le, J., Kolodner, R. D., Moak, Z., Chuang, M., Austin, F., Goldbach-Mansky, R., Hoffman, H. M. and Kastner, D. L. (2007), The clinical continuum of cryopyrinopathies: Novel CIAS1 mutations in North American patients and a new cryopyrin model. Arthritis & Rheumatism, 56: 1273–1285. doi: 10.1002/art.22491
- Issue published online: 28 MAR 2007
- Article first published online: 28 MAR 2007
- Manuscript Accepted: 21 DEC 2006
- Manuscript Received: 26 SEP 2006
- National Institute of Arthritis and Musculoskeletal and Skin Diseases Intramural Research Program
- National Institute of Allergy and Infectious Diseases. Grant Number: R01-AI-52430
- Ludwig Institute of Cancer Research
- Postdoctoral Fellowship from the Damon Runyon Cancer Research Foundation
- Robert Black Charitable Trust
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.
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.
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.
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.