Dominant-negative mutations in the DNA-binding domain of STAT3 cause hyper-IgE syndrome
Dominant-negative mutations in the DNA-binding domain of STAT3 cause hyper-IgE syndrome
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DOI：
10.1038/nature06096
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发表时间：
2007-08-30
期刊：
影响因子：
64.8
通讯作者：
Karasuyama, Hajime
中科院分区：
文献类型：
--
作者：
Minegishi, Yoshiyuki;Saito, Masako;Karasuyama, Hajime
高免疫球蛋白 E 综合征 (HIES) 是一种复合原发性免疫缺陷病，其特征是血清 IgE 高度升高、复发性葡萄球菌皮肤脓肿和囊肿形成性肺炎，伴有异常轻微的炎症反应（称为冷脓肿）和骨骼异常 (1)。尽管已有一些常染色体显性或隐性遗传的家族性HIES病例报道，但大多数HIES病例是散发性的，其发病机制长期以来仍然是个谜。在这里，我们展示了人类信号转导子和转录激活子 3 (STAT3) 基因的显性失活突变导致了经典的多系统 HIES。我们发现，十五名不相关的非家族性 HIES 患者中有八名具有杂合 STAT3 突变，但他们的父母和兄弟姐妹没有突变的 STAT3 等位基因，表明这些是新生突变。发现了五种不同的突变，所有这些突变都位于 STAT3 DNA 结合域中。患者的外周血细胞对白细胞介素（IL）-6和IL-10等细胞因子的反应出现缺陷，并且这些细胞中STAT3的DNA结合能力大大减弱。所有五个突变体本身均无功能，并且在与野生型 STAT3 共表达时表现出显性负效应。这些结果强调了 STAT3 在人类中发挥的多重作用，并强调多种细胞因子途径在 HIES 发病机制中的关键参与。
Hyper-immunoglobulin E syndrome (HIES) is a compound primary immunodeficiency characterized by a highly elevated serum IgE, recurrent staphylococcal skin abscesses and cyst-forming pneumonia, with disproportionately milder inflammatory responses, referred to as cold abscesses, and skeletal abnormalities(1). Although some cases of familial HIES with autosomal dominant or recessive inheritance have been reported, most cases of HIES are sporadic, and their pathogenesis has remained mysterious for a long time. Here we show that dominant-negative mutations in the human signal transducer and activator of transcription 3 (STAT3) gene result in the classical multisystem HIES. We found that eight out of fifteen unrelated non-familial HIES patients had heterozygous STAT3 mutations, but their parents and siblings did not have the mutant STAT3 alleles, suggesting that these were de novo mutations. Five different mutations were found, all of which were located in the STAT3 DNA-binding domain. The patients' peripheral blood cells showed defective responses to cytokines, including interleukin (IL)-6 and IL-10, and the DNA-binding ability of STAT3 in these cells was greatly diminished. All five mutants were non-functional by themselves and showed dominant-negative effects when co-expressed with wild-type STAT3. These results highlight the multiple roles played by STAT3 in humans, and underline the critical involvement of multiple cytokine pathways in the pathogenesis of HIES.