title: 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 recently discovered role of CIAS1 in the regulation of interleukin-1 (IL-1), we found evidence of increased IL-1beta, as well as tumor necrosis factor, IL-3, IL-5, and IL-6, but not transforming growth factor beta, in a mutation-positive patient compared with normal controls.
  
  
  CONCLUSIONS
  Our data increase the total number of known germline mutations in CIAS1 to 20, causing a spectrum of diseases ranging from familial cold autoinflammatory syndrome to Muckle-Wells syndrome to NOMID/CINCA syndrome. Mutations in CIAS1 were only found in approximately 50% of the cases identified clinically as NOMID/CINCA syndrome, which raises the possibility of genetic heterogeneity. IL-1 regulation by CIAS1 suggests that IL-1 receptor blockade may constitute a rational approach to the treatment of NOMID/CINCA syndrome.
authors.affiliation: National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, Maryland 20892, USA.
authors.forename: Ivona
authors.initials: I
authors.lastname: Aksentijevich
authors.forename: Miroslawa
authors.initials: M
authors.lastname: Nowak
authors.forename: Mustapha
authors.initials: M
authors.lastname: Mallah
authors.forename: Jae Jin
authors.initials: JJ
authors.lastname: Chae
authors.forename: Wendy T
authors.initials: WT
authors.lastname: Watford
authors.forename: Sigrun R
authors.initials: SR
authors.lastname: Hofmann
authors.forename: Leonard
authors.initials: L
authors.lastname: Stein
authors.forename: Ricardo
authors.initials: R
authors.lastname: Russo
authors.forename: Donald
authors.initials: D
authors.lastname: Goldsmith
authors.forename: Peter
authors.initials: P
authors.lastname: Dent
authors.forename: Helene F
authors.initials: HF
authors.lastname: Rosenberg
authors.forename: Frances
authors.initials: F
authors.lastname: Austin
authors.forename: Elaine F
authors.initials: EF
authors.lastname: Remmers
authors.forename: James E
authors.initials: JE
authors.lastname: Balow
authors.forename: Sergio
authors.initials: S
authors.lastname: Rosenzweig
authors.forename: Hirsh
authors.initials: H
authors.lastname: Komarow
authors.forename: Nitza G
authors.initials: NG
authors.lastname: Shoham
authors.forename: Geryl
authors.initials: G
authors.lastname: Wood
authors.forename: Janet
authors.initials: J
authors.lastname: Jones
authors.forename: Nadira
authors.initials: N
authors.lastname: Mangra
authors.forename: Hector
authors.initials: H
authors.lastname: Carrero
authors.forename: Barbara S
authors.initials: BS
authors.lastname: Adams
authors.forename: Terry L
authors.initials: TL
authors.lastname: Moore
authors.forename: Kenneth
authors.initials: K
authors.lastname: Schikler
authors.forename: Hal
authors.initials: H
authors.lastname: Hoffman
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Lovell
authors.forename: Robert
authors.initials: R
authors.lastname: Lipnick
authors.forename: Karyl
authors.initials: K
authors.lastname: Barron
authors.forename: John J
authors.initials: JJ
authors.lastname: O'Shea
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Kastner
authors.forename: Raphaela
authors.initials: R
authors.lastname: Goldbach-Mansky
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D001798:Blood Proteins / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D016207:Cytokines / Q000378:metabolism*; D003598:Cytoskeletal Proteins; D004252:DNA Mutational Analysis; D005260:Female; D018740:Genetic Heterogeneity; D006801:Humans; D007231:Infant, Newborn; D007249:Inflammation / Q000000981:diagnostic imaging / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D009154:Mutation; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D011506:Proteins / Q000378:metabolism*; D000071198:Pyrin; D011859:Radiography; D013577:Syndrome
chemical_list: D001798:Blood Proteins; D002352:Carrier Proteins; D016207:Cytokines; D003598:Cytoskeletal Proteins; C000604192:MEFV protein, human; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; D011506:Proteins; D000071198:Pyrin