The clinical continuum of cryopyrinopathies: novel CIAS1 mutations in North American patients and a new cryopyrin model.
Ivona Aksentijevich,Christopher D. Putnam,Elaine F. Remmers,James L. Mueller,Julie Le,Richard D. Kolodner,Zachary Moak,Michael Chuang,Frances Austin,Raphaela Goldbach-Mansky,Hal M. Hoffman,Daniel L. Kastner +11 more
TLDR
Investigation of the structural effect of disease-causing mutations on cryopyrin provides insight into potential molecular mechanisms by which cryopyrsin mutations can inappropriately activate an inflammatory response.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-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.read more
Citations
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Use of canakinumab in the cryopyrin-associated periodic syndrome.
Helen J. Lachmann,Isabelle Koné-Paut,Jasmin B Kuemmerle-Deschner,Kieron S. Leslie,Eric Hachulla,Pierre Quartier,Xavier Gitton,A Widmer,N Patel,Philip N. Hawkins +9 more
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Non-transcriptional Priming and Deubiquitination Regulate NLRP3 Inflammasome Activation
Christine Juliana,Teresa Fernandes-Alnemri,Seokwon Kang,Andrew Farias,Fengsong Qin,Emad S. Alnemri +5 more
TL;DR: In mouse macrophages, signaling by the pattern recognition receptor TLR4 through MyD88 can rapidly and non-transcriptionally prime NLRP3 by stimulating its deubiquitination, which could explain how NL RP3 is activated by diverse danger signals.
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NLRP3 inflammasome: From a danger signal sensor to a regulatory node of oxidative stress and inflammatory diseases
Amna Abderrazak,Tatiana Syrovets,Dominique Couchie,Khadija El Hadri,Bertrand Friguet,Thomas Simmet,Mustapha Rouis,Mustapha Rouis,Mustapha Rouis +8 more
TL;DR: This review has updated knowledge on NLRP3 inflammasome assembly and activation and on the pyrin domain inNLRP3 that could represent a drug target to treat sterile inflammatory diseases, and reported mutations in NL RP3 that were found to be associated with certain diseases.
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