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

作者：Ivona A Aksentijevich, Miroslawa Nowak, Mustapha Mallah, Jae Jin Chae, Wendy T. Watford, Sigrun R. Hofmann, Leonard D. Stein, Ricardo A. G. Russo, Donald P. Goldsmith, Peter B. Dent, Helene F. Rosenberg, Frances Austin, Elaine F. Remmers, James E. Balow, Sergio D. Rosenzweig, Hirsh D. Komarow, Nitza G. Shoham, Geryl Wood, Janet H. Jones, Nadira Mangra, Hector A Carrero, Barbara S. Adams, Terry L. Moore, Kenneth N. Schikler, Hal M. Hoffman, Daniel J. Lovell, ROBERT J. LIPNICK, Karyl S. Barron, John J. O’Shea, Daniel L. Kastner, Raphaela Goldbach‐Mansky · 发表于：Arthritis & Rheumatism · 年份：2002 · DOI：10.1002/art.10688 · 被引用次数：711 · 研究领域：Inflammasome and immune disorders、Autoimmune and Inflammatory Disorders Research、interferon and immune responses

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, su...