Mutations in proteasome subunit β type 8 cause chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature with evidence of genetic and phenotypic heterogeneity.
Mutations in proteasome subunit β type 8 cause chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature with evidence of genetic and phenotypic heterogeneity.
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DOI：
10.1002/art.33368
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发表时间：
2012-03
影响因子：
--
通讯作者：
Zlotogorski, Abraham
中科院分区：
文献类型：
--
作者：
Liu, Yin;Ramot, Yuval;Torrelo, Antonio;Paller, Amy S.;Si, Nuo;Babay, Sofia;Kim, Peter W.;Sheikh, Afzal;Lee, Chyi-Chia Richard;Chen, Yongqing;Vera, Angel;Zhang, Xue;Goldbach-Mansky, Raphaela;Zlotogorski, Abraham
慢性非典型嗜酸性皮肤病伴脂肪营养不良和体温升高（CANDLE）综合征是最近报道的儿童自身炎症综合征。我们调查了9例CANDLE患者的临床表型、遗传病因和免疫功能失调。对所有患者的基因组DNA进行PSMB 8（蛋白酶体亚基β 8型）突变筛查。血清细胞因子水平进行了测量，从四个病人。对皮肤活检进行免疫化学评价，并对血液微阵列谱（n=4）和stat-1磷酸化（n=3）进行评估。1例患者为PSMB 8中新的无义突变（c.405C>A）的纯合子，表明蛋白质截短，4例患者为先前报道的错义突变（c.224C>T）的纯合子，2例为杂合子，1例患者未显示突变。在750名健康对照的染色体中没有观察到这些序列变化。在具有相同突变的四个患者中，只有两个具有相同的单倍型，表明突变热点。PSMB 8突变阳性和阴性患者表达高IP-10（干扰素γ诱导蛋白10）水平。MCP-1、IL-6和IL-1 Ra水平中度升高。微阵列特征和单核细胞stat-1激活提示了独特的干扰素（IFN）信号转导特征，与其他自身炎症性疾病不同。CANDLE是由PSMB 8突变引起的，PSMB 8是一种最近报道的导致成人JMP综合征（关节挛缩、肌肉萎缩和脂膜炎诱导的脂肪营养不良）的基因。我们扩展了这种新型自身炎症综合征的临床和致病性描述，从而扩大了PSMB 8相关疾病的临床和遗传疾病谱。IFN可能是炎症反应的关键介质，并可能提供治疗靶点。
Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) syndrome is an autoinflammatory syndrome recently described in children. We investigated the clinical phenotype, genetic cause and the immune dysregulation in nine CANDLE patients. Genomic DNA from all patients was screened for PSMB8 (Proteasome subunit beta type-8) mutations. Serum cytokine levels were measured from four patients. Skin biopsies were evaluated immunohistochemically and blood microarray profile (n=4) and stat-1 phosphorylation (n=3) were assessed. One patient was homozygous for a novel nonsense mutation in PSMB8 (c.405C>A) suggesting a protein truncation, four patients were homozygous and two were heterozygous for a previously reported missense mutation (c.224C>T), and one patient showed no mutation. None of these sequence changes was observed in chromosomes from 750 healthy controls. Of the four patients with the same mutation, only two share the same haplotype indicating a mutational hot spot. PSMB8 mutation-positive and -negative patients expressed high IP-10 (Interferon gamma-induced protein 10) levels. Levels of MCP-1, IL-6, and IL-1Ra were moderately elevated. Microarray profiles and monocyte stat-1 activation suggested a unique interferon (IFN) signaling signature, unlike in other autoinflammatory disorders. CANDLE is caused by mutations in PSMB8, a gene recently reported to cause JMP syndrome (joint contractures, muscle atrophy and panniculitis induced lipodystrophy) in adults. We extend the clinical and pathogenic description of this novel autoinflammatory syndrome, thereby expanding the clinical and genetic disease spectrum of PSMB8-associated disorders. IFN may be a key mediator of the inflammatory response and may present a therapeutic target.
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影响因子：
15.8
作者：
McGonagle D;McDermott MF
通讯作者：
McDermott MF
影响因子：
3
作者：
Bonville CA;Percopo CM;Dyer KD;Gao J;Prussin C;Foster B;Rosenberg HF;Domachowske JB
通讯作者：
Domachowske JB
影响因子：
5.2
作者：
Goldbach-Mansky R
通讯作者：
Goldbach-Mansky R
影响因子：
5.4
作者：
Moebius, Jacqueline;van den Broek, Maries;Basler, Michael
通讯作者：
Basler, Michael
影响因子：
13.8
作者：
Torrelo, Antonio;Patel, Sapna;Paller, Amy S.
通讯作者：
Paller, Amy S.