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
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
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DOI：
10.1002/art.10688
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发表时间：
2002-12-01
影响因子：
--
通讯作者：
Goldbach-Mansky, R
中科院分区：
文献类型：
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作者：
Aksentijevich, I;Nowak, M;Goldbach-Mansky, R
目标。新生儿多系统炎症性疾病（NOMID，也称为慢性婴儿神经、皮肤、关节[CINCA]综合征）以发热、慢性脑膜炎、葡萄膜炎、感音神经性听力丧失、荨麻疹皮疹和特征性变形关节病为特征。我们调查了该疾病患者是否存在与NOMID/CINCA综合征有一些相似之处的显性遗传性疾病Muckle-Wells综合征和家族性感冒自身炎症综合征的基因CIAS1突变。对13例具有NOMID/CINCA综合征典型表现的患者及其可用父母进行基因组DNA自动测序，筛选CIAS1突变。采用外周血白细胞mRNA实时聚合酶链反应检测细胞因子信使RNA （mRNA）水平，采用酶联免疫吸附法检测血清细胞因子水平。用免疫印迹法检测外周血单核细胞塑料贴壁裂解物的蛋白表达。13例患者中有6例在CIAS1中发现6个杂合错义替换，其中5个是新突变。在健康对照的bbbb900染色体组中未观察到这些序列变化。在不相关的患者中，单个密码子的两个不同的核苷酸变化导致相同的氨基酸变化。在4例可获得亲本DNA的突变阳性儿童中，未发现亲本DNA突变，支持突变是从头产生的结论。与最近发现的CIAS1在调节白细胞介素-1 （IL-1）中的作用一致，我们发现与正常对照相比，突变阳性患者的IL-1 β、肿瘤坏死因子、IL-3、IL-5和IL-6增加，但转化生长因子β没有增加。我们的数据将已知的CIAS1种生殖系突变总数增加到20个，导致一系列疾病，从家族性感冒自身炎症综合征到Muckle-Wells综合征到NOMID/CINCA综合征。在临床鉴定为NOMID/CINCA综合征的病例中，只有接近50%的病例发现了CIAS1突变，这增加了遗传异质性的可能性。CIAS1对IL-1的调控提示IL-1受体阻断可能是治疗NOMID/CINCA综合征的合理途径。
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.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 similar to50% 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.