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. 2002 Dec;46(12):3340-8.
doi: 10.1002/art.10688.

V体育ios版 - 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

Ivona Aksentijevich  1 , 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
Affiliations

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

"VSports手机版" Ivona Aksentijevich et al. Arthritis Rheum. 2002 Dec.

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 VSports手机版. 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 V体育安卓版. 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 V体育ios版. 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: 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 VSports最新版本. IL-1 regulation by CIAS1 suggests that IL-1 receptor blockade may constitute a rational approach to the treatment of NOMID/CINCA syndrome. .

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Figures

Figure 1
Figure 1
Characteristics of the 13 study patients with neonatal-onset multisystem inflammatory disease/chronic infantile neurologic, cutaneous, and articular syndrome. CIAS1 mutations were found in 6 of the 13 patients. ESR = erythrocyte sedimentation rate.
Figure 2
Figure 2
Clinical features of neonatal-onset multisystem inflammatory disease/chronic infantile neurologic, cutaneous, and articular syndrome in patient 922. Top left, Facial features. Top middle, Urticarial rash, which persisted throughout a week-long hospital visit. Top right, Contractures of the knees. Bottom left, Funduscopic image, demonstrating papilledema in the left eye (present bilaterally). Bottom middle, Skin biopsy sample, showing a mild perivascular leukocytic infiltrate, with some eosinophils but no epidermal changes. Bottom right, Magnetic resonance image of the right knee, demonstrating the absence of significant synovial enhancement and the presence of epiphyseal and patellar bony overgrowth.
Figure 3
Figure 3
a, Western blot analysis of interleukin-1β (IL-1β) expression in monocytes from patient 922 (JP) and from a healthy control subject. Monocytes were untreated or were stimulated with lipopolysaccharide (LPS) for 24 hours. IL-1β protein was constitutively expressed in the untreated cells from the patient but was undetectable in cells from the healthy controls (only 1 of 7 control samples tested is shown). b, Mean levels of IL-1 receptor antagonist (IL-1Ra) in samples obtained from patient 922 at 3 different visits were significantly higher compared with the mean level in samples from 4 healthy control subjects, as determined by enzyme-linked immunosorbent assay. c, Real-time polymerase chain reaction for the expression of IL-3, IL-5, IL-6, and transforming growth factor β1 (TGFβ1) mRNA in peripheral blood mononuclear cells obtained from patient 922. IL-3, IL-5, and IL-6 mRNA levels were significantly elevated compared with the levels in normal controls (horizontal line), and are expressed as relative cytokine levels. All samples were normalized to the internal GAPDH control.
Figure 4
Figure 4
Protein structure of cryopyrin (9). All of the 20 mutations that cause familial cold autoinflammatory syndrome (FCAS), Muckle-Wells Syndrome (MWS), and/or neonatal-onset multisystem inflammatory disease (NOMID)/chronic infantile neurologic, cutaneous, and articular (CINCA) syndrome have been identified in exon 3 of CIAS1, which encodes the NACHT domain. Fourteen of the 20 mutations are located within the NACHT domain, and 6 mutations are found in the region of cryopyrin, which flanks the NACHT domain. Mutations shown in red cause NOMID/CINCA syndrome, those in blue cause MWS, those in green cause FCAS, and those in black are observed in more than one disease. The D303N mutation was identified in 2 unrelated NOMID/CINCA syndrome patients (ref. and the present study) and has been reported in 1 MWS patient (35). The R260W mutation has been reported in 2 FCAS and 2 MWS families (35). LRR = leucine-rich repeat.
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References

    1. McDermott MF, Aksentijevich I, Galon J, McDermott EM, Ogunkolade BW, Centola M, et al. Germline mutations in the extracellular domains of the 55 kDa TNF receptor, TNFR1, define a family of dominantly inherited autoinflammatory syndromes. Cell. 1999;97:133–144. - PubMed
    1. Galon J, Aksentijevich I, McDermott MF, O’Shea JJ, Kastner DL. TNFRSF1A mutations and autoinflammatory syndromes. Curr Opin Immunol. 2000;12:479–486. - VSports注册入口 - PubMed
    1. Kastner DL, O’Shea JJ. A fever gene comes in from the cold. Nat Genet. 2001;29:241–242. - PubMed
    1. International FMF Consortium. Ancient missense mutations in a new member of the RoRet gene family are likely to cause familial Mediterranean fever. Cell. 1997;90:797–807. - PubMed
    1. French FMF Consortium. A candidate gene for familial Mediterranean fever. Nat Genet. 1997;17:25–31. - PubMed

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