Drs. Ceccherini, Rubartelli, and Gattorno contributed equally to this work.
Clinical presentation and pathogenesis of cold-induced autoinflammatory disease in a family with recurrence of an NLRP12 mutation†
Article first published online: 25 FEB 2011
Copyright © 2011 by the American College of Rheumatology
Arthritis & Rheumatism
Volume 63, Issue 3, pages 830–839, March 2011
How to Cite
Borghini, S., Tassi, S., Chiesa, S., Caroli, F., Carta, S., Caorsi, R., Fiore, M., Delfino, L., Lasigliè, D., Ferraris, C., Traggiai, E., Di Duca, M., Santamaria, G., D'Osualdo, A., Tosca, M., Martini, A., Ceccherini, I., Rubartelli, A. and Gattorno, M. (2011), Clinical presentation and pathogenesis of cold-induced autoinflammatory disease in a family with recurrence of an NLRP12 mutation. Arthritis & Rheumatism, 63: 830–839. doi: 10.1002/art.30170
Re-use of this article is permitted in accordance with the Terms and Conditions set out at http://wileyonlinelibrary.com/onlineopen#OnlineOpen_Terms
- Issue published online: 3 FEB 2011
- Article first published online: 25 FEB 2011
- Accepted manuscript online: 2 DEC 2010 12:01PM EST
- Manuscript Accepted: 18 NOV 2010
- Manuscript Received: 23 JUL 2010
- Italian Telethon. Grant Number: GGP09127
- Ministero Salute
- European Community Seventh Framework Programme (Coordination Theme 1 [Health]. Grant Number: HEALTH-F2-2008-200923 [Eurotraps]
NLRP12 mutations have been described in patients affected with peculiar autoinflammatory symptoms. This study was undertaken to characterize NLRP12 mutations in patients with autoinflammatory syndromes, particularly a novel missense mutation, p.D294E, affecting a protein sequence crucial for ATP binding, which was identified in a Caucasian family with familial cold-induced autoinflammatory syndrome in some family members.
Fifty patients were tested for NLRP12 mutations. A Caucasian family with the p.D294E missense mutation of NLRP12 in some family members was clinically characterized. In vitro analysis of the effects of the mutation on NF-κB activity was performed in HEK 293 cells after cotransfection of the cells with a luciferase NF-κB–responsive element and mutant or wild-type (WT) NLRP12 expression plasmids. NF-κB activity was also evaluated 24 hours after stimulation with tumor necrosis factor α in monocytes from individual family members carrying the mutation. Furthermore, secretion of interleukin-1β (IL-1β), production of reactive oxygen species (ROS), and activation of antioxidant systems in patient and healthy donor monocytes, under resting conditions and after stimulation with pathogen-associated molecular patterns (PAMPs), were also assessed.
In the family assessed, the p.D294E mutation segregated in association with a particular sensitivity to cold exposure (especially arthralgias and myalgia), but not always with an inflammatory phenotype (e.g., urticarial rash or fever). In vitro, the mutant protein maintained the same inhibitory activity as that shown by WT NLRP12. Consistently, NLRP12-mutated monocytes showed neither increased levels of p65-induced NF-κB activity nor higher secretion of IL-1β. However, the kinetics of PAMP-induced IL-1β secretion were significantly accelerated, and high production of ROS and up-regulation of antioxidant systems were demonstrated.
Even with a variable range of associated manifestations, the extreme sensitivity to cold represents the main clinical hallmark in an individual carrying the p.D294E mutation of the NLRP12 gene. Although regulation of NF-κB activity is not affected in patients, redox alterations and accelerated secretion of IL-1β are associated with this mild autoinflammatory phenotype.