Open AccessDe 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
Author(s) -
Aksentijevich Ivona,
Nowak Miroslawa,
Mallah Mustapha,
Chae Jae Jin,
Watford Wendy T.,
Hofmann Sigrun R.,
Stein Leonard,
Russo Ricardo,
Goldsmith Donald,
Dent Peter,
Rosenberg Helene F.,
Austin Frances,
Remmers Elaine F.,
Balow James E.,
Rosenzweig Sergio,
Komarow Hirsh,
Shoham Nitza G.,
Wood Geryl,
Jones Janet,
Mangra Nadira,
Carrero Hector,
Adams Barbara S.,
Moore Terry L.,
Schikler Kenneth,
Hoffman Hal,
Lovell Daniel J.,
Lipnick Robert,
Barron Karyl,
O'Shea John J.,
Kastner Daniel L.,
GoldbachMansky Raphaela
Publication year - 2002
Publication title -
arthritis & rheumatism
Language(s) - English
Resource type - Journals
eISSN - 1529-0131
pISSN - 0004-3591
DOI - 10.1002/art.10688
Subject(s) - immunology , medicine , missense mutation , familial mediterranean fever , cytokine , peripheral blood mononuclear cell , tumor necrosis factor alpha , mutation , genetics , biology , disease , gene , in vitro
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‐1β, as well as tumor necrosis factor, IL‐3, IL‐5, and IL‐6, but not transforming growth factor β, in a mutation‐positive patient compared with normal controls. Conclusion 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 ∼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.