title: Clinical presentation and pathogenesis of cold-induced autoinflammatory disease in a family with recurrence of an NLRP12 mutation.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Istituto G. Gaslini and University of Genoa, Genoa, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Borghini
authors.forename: S
authors.initials: S
authors.lastname: Tassi
authors.forename: S
authors.initials: S
authors.lastname: Chiesa
authors.forename: F
authors.initials: F
authors.lastname: Caroli
authors.forename: S
authors.initials: S
authors.lastname: Carta
authors.forename: R
authors.initials: R
authors.lastname: Caorsi
authors.forename: M
authors.initials: M
authors.lastname: Fiore
authors.forename: L
authors.initials: L
authors.lastname: Delfino
authors.forename: D
authors.initials: D
authors.lastname: Lasigliè
authors.forename: C
authors.initials: C
authors.lastname: Ferraris
authors.forename: E
authors.initials: E
authors.lastname: Traggiai
authors.forename: M
authors.initials: M
authors.lastname: Di Duca
authors.forename: G
authors.initials: G
authors.lastname: Santamaria
authors.forename: A
authors.initials: A
authors.lastname: D'Osualdo
authors.forename: M
authors.initials: M
authors.lastname: Tosca
authors.forename: A
authors.initials: A
authors.lastname: Martini
authors.forename: I
authors.initials: I
authors.lastname: Ceccherini
authors.forename: A
authors.initials: A
authors.lastname: Rubartelli
authors.forename: M
authors.initials: M
authors.lastname: Gattorno
mesh_terms: D000328:Adult; D000368:Aged; D003080:Cold Temperature / Q000009:adverse effects*; D056587:Cryopyrin-Associated Periodic Syndromes / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D005192:Family Health; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D053583:Interleukin-1beta / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000276:immunology; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000276:immunology / Q000378:metabolism; D020125:Mutation, Missense; D016328:NF-kappa B / Q000378:metabolism; D018384:Oxidative Stress / Q000276:immunology; D010375:Pedigree; D010641:Phenotype; D044465:White People / Q000235:genetics
chemical_list: D053583:Interleukin-1beta; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; C476731:NLRP12 protein, human