Somatic mosaicism of CIAS1 in a patient with chronic infantile neurologic, cutaneous, articular syndrome
Somatic mosaicism of CIAS1 in a patient with chronic infantile neurologic, cutaneous, articular syndrome
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DOI：
10.1002/art.21404
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发表时间：
2005-11-01
影响因子：
--
通讯作者：
Nakahata, T
中科院分区：
文献类型：
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作者：
Saito, M;Fujisawa, A;Nakahata, T
慢性婴儿神经、皮肤、关节综合征（CINCA综合征）是一种严重的炎症性疾病，最近发现与CL 4S 1突变有关。然而，仅在一半的CINCA综合征患者中检测到CIAS 1突变，目前尚不清楚哪些基因导致其余患者的综合征。我们在这里描述了一个病人与CINCA综合征谁展出CIAS 1体嵌合体。我们对患者的各种血细胞和颊粘膜中的CIAS 1基因进行了遗传分析。通过酶联免疫吸附试验测定外周血单个核细胞（PBMC）的白细胞介素-1 β（IL-1 β）的产生，并评估突变型CL 4 S1基因增强ASC依赖性NF-κ B活化的能力，以确认发现的CIAS 1突变与患者CINCA综合征的临床表现有关。该患者在CIAS 1外显子3中有1个异源单核苷酸多态性587 G>A（S196 N）和1个异源突变t709 A>G（Y 570 C）。后一个突变被发现发生体细胞嵌合。患者的PBMC在没有刺激的情况下产生大量的IL-10，不像对照组或他母亲的PBMC，他们也携带S196 N多态性。此外，与野生型基因或单独携带S196 N多态性的基因不同，Y 570 C突变（有或没有S196 N多态性）增加了CIAS 1诱导ASC依赖性NF-κ B活化的能力。该患者的研究结果表明，体细胞嵌合体是CIAS 1突变在一些CINCA综合征患者中未检测到的原因之一。
Chronic infantile neurologic, cutaneous, articular syndrome (CINCA syndrome) is a severe inflammatory disease that was recently found to be associated with mutations in CL4S1. However, CIAS1 mutations have been detected in only half of CINCA syndrome patients, and it remains unclear which genes are responsible for the syndrome in the remaining patients. We describe here a patient with CINCA syndrome who exhibited CIAS1 somatic mosaicism. We genetically analyzed the CIAS1 gene in various blood cells and the buccal mucosa of the patient. The production of interleukin-1 beta (IL-1 beta) by peripheral blood mononuclear cells (PBMCs) was measured by enzyme-linked immunosorbent assay, and the ability of the mutant CL4S1 gene to enhance ASC-dependent NF-kappa B activation was assessed to confirm that the mutations of CIAS1 found were responsible for the patient's clinical manifestations of the CINCA syndrome. The patient had 1 heterologous single-nucleotide polymorphism, 587G>A (S196N), and 1 heterologous mutation, t709A>G (Y570C), in exon 3 of CIAS1. The latter mutation was found to occur as somatic mosaicism. The patient's PBMCs produced a large amount of IL-10 in the absence of stimulation, unlike those from controls or front his mother, who also bore the S196N polymorphism. In addition, the Y570C mutation (with or without the S196N polymorphism) increased the ability of CIAS1 to induce ASC-dependent NF-kappa B activation, unlike the wild-type gene or the gene bearing the S196N polymorphism alone. The findings in this patient indicate that somatic mosaicism is one reason CIAS1 mutations have not been detected in some patients with CINCA syndrome.