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: 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. CONCLUSION:
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Authors | Ivona Aksentijevich, Miroslawa Nowak, Mustapha Mallah, Jae Jin Chae, Wendy T Watford, Sigrun R Hofmann, Leonard Stein, Ricardo Russo, Donald Goldsmith, Peter Dent, Helene F Rosenberg, Frances Austin, Elaine F Remmers, James E Balow Jr, Sergio Rosenzweig, Hirsh Komarow, Nitza G Shoham, Geryl Wood, Janet Jones, Nadira Mangra, Hector Carrero, Barbara S Adams, Terry L Moore, Kenneth Schikler, Hal Hoffman, Daniel J Lovell, Robert Lipnick, Karyl Barron, John J O'Shea, Daniel L Kastner, Raphaela Goldbach-Mansky |
Journal | Arthritis and rheumatism
(Arthritis Rheum)
Vol. 46
Issue 12
Pg. 3340-8
(Dec 2002)
ISSN: 0004-3591 [Print] United States |
PMID | 12483741
(Publication Type: Journal Article)
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Chemical References |
- Blood Proteins
- Carrier Proteins
- Cytokines
- Cytoskeletal Proteins
- MEFV protein, human
- NLR Family, Pyrin Domain-Containing 3 Protein
- NLRP3 protein, human
- Proteins
- Pyrin
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Topics |
- Adolescent
- Adult
- Age of Onset
- Blood Proteins
(genetics)
- Carrier Proteins
(genetics)
- Child
- Child, Preschool
- Cohort Studies
- Cytokines
(metabolism)
- Cytoskeletal Proteins
- DNA Mutational Analysis
- Female
- Genetic Heterogeneity
- Humans
- Infant, Newborn
- Inflammation
(diagnostic imaging, epidemiology, genetics, pathology, physiopathology)
- Male
- Mutation
- NLR Family, Pyrin Domain-Containing 3 Protein
- Proteins
(metabolism)
- Pyrin
- Radiography
- Syndrome
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