De novo CIAS1 mutations, cytokine activation, and evidence for genetic heterogeneity in patients with neonatal‐onset multisystem inflammatory disease (NOMID): A new member of the expanding family of pyrin‐associated autoinflammatory diseases

Abstract

Objective. Neonatal-onset multisystem inflammatory disease (NOMID; also known as chronic infantile neurologic, cutaneous, articular [CINCA] syndrome) is characterized by fever, chronic meningitis, uveitis, sensorineural hearing loss, urticarial skin rash, and a characteristic deforming arthropathy. We investigated whether patients with this disorder have mutations in CIAS1, the gene which causes Muckle-Wells syndrome and familial cold autoinflammatory syndrome, two dominantly inherited disorders with some similarities to NOMID/CINCA syndrome.Methods. Genomic DNA from 13 patients with classic manifestations of NOMID/CINCA syndrome and their available parents was screened for CIAS1 mutations by automated DNA sequencing. Cytokine messenger RNA (mRNA) levels were assessed by real-time polymerase chain reaction on peripheral blood leukocyte mRNA, and serum cytokine levels were assayed by enzyme-linked immunosorbent assay. Protein expression was assessed by Western blotting of lysates from plastic-adherent peripheral blood mononuclear cells.Results. In 6 of the 13 patients, we found 6 heterozygous missense substitutions in CIAS1. Five of the 6 mutations are novel. None of these sequence changes was observed in a panel of >900 chromosomes from healthy controls. Two distinct nucleotide changes in a single codon in unrelated patients resulted in the same amino acid change. In 4 mutation-positive children whose parental DNA was available, no mutation was found in the parental DNA, supporting the conclusion that the mutations arose de novo. Consistent with

The inflammasomes in health and disease: from genetics to molecular mechanisms of autoinflammation and beyond

“…75,89 Some autoinflammatory syndromes resembling CAPS have been correlated with mutations in inflammasome or IL-1 pathway regulators. NLRP12 mutations are associated with hereditary periodic fever syndromes, and while NLRP12 shares strong homology with NLRP3, it is not involved in inflammasome formation but regulates the NF-kB cascade.…”

Response to anakinra in a de novo case of neonatal‐onset multisystem inflammatory disease

“…As in most complex diseases, the genetic component for host susceptibility is still unknown. Genomewide linkage studies have proven unable to pinpoint with enough confidence genomic regions other than HLA, thus leaving the main portion of the genetic influence unidentified (2)(3)(4)(5). For this reason, the "positional candidate" strategy has been regarded as the dominant approach to investigate genetic associations with RA.…”

Protein misfolding and dysregulated protein homeostasis in autoinflammatory diseases and beyond

“…Pathogenic mutations, predominantly found in exon 3, affect the NBD within NLRP3 leading to spontaneous oligomerization and a reduced requirement for the second stimulus, ATP, for IL-1secretion after activation by innate immune stimuli [41]. NLRP3 mutations lead to a spectrum of diseases ranging from the relatively mild familial cold autoinflammatory syndrome (FCAS), through Muckle-Wells syndrome (MWS), which includes cochlear inflammation leading to hearing loss, to the neonatal-onset multisystem inflammatory disease (NOMID), in which there is multi-organ inflammation including sterile meningitis which can lead to neurological impairment and can be fatal without treatment [42][43][44][45][46]. It has recently become apparent that autophagy plays a physiological role in disposing of the components of the activated NLRP3 inflammasome through targeting of ubiquitinated components to the inflammasome and recruitment of the autophagy adapter p62 [47][48][49].…”