A Novel In-Frame Deletion in the Leucine Zipper Domain of C/EBPε Leads to Neutrophil-Specific Granule Deficiency
A Novel In-Frame Deletion in the Leucine Zipper Domain of C/EBPε Leads to Neutrophil-Specific Granule Deficiency
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DOI：
10.4049/jimmunol.1402222
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发表时间：
2015-07-01
影响因子：
4.4
通讯作者：
Yachie, Akihiro
中科院分区：
文献类型：
--
作者：
Wada, Taizo;Akagi, Tadayuki;Yachie, Akihiro
嗜中性粒细胞特异性颗粒缺乏症（SGD）是一种罕见的常染色体隐性遗传性原发性免疫缺陷病，其特征是中性粒细胞功能障碍、双叶中性粒细胞核和缺乏嗜中性粒细胞特异性颗粒。骨髓特异性转录因子CCAAT/增强子结合蛋白-β（C/EBP β）的缺陷已在两例纯合移码突变导致亮氨酸拉链结构域丢失的病例中得到鉴定。在这项研究中，我们报告了一个55岁的妇女与SGD的影响所造成的一个新的纯合2-aa缺失（Δ RS）在亮氨酸拉链结构域的C/EBP β基因。患者表现出特征性中性粒细胞异常和复发性皮肤感染;但是，无深部器官感染病史。生化分析表明，在相反的两个移码突变，DRS突变体保持正常的细胞定位，DNA结合活性，和二聚化，和所有三个突变体表现出显着的转录活性降低。DRS突变体在与Gata 1和PU.1的关联以及嗜酸性粒细胞主要碱性蛋白的异常合作转录激活方面存在缺陷。因此，DRS可能会损害蛋白质与其他转录因子的相互作用，导致转录激活的丧失。这些结果进一步支持了C/EBP的亮氨酸拉链结构域对于其基本功能的重要性，并表明多种分子机制导致SGD。
Neutrophil-specific granule deficiency (SGD) is a rare autosomal recessive primary immunodeficiency characterized by neutrophil dysfunction, bilobed neutrophil nuclei and lack of neutrophil-specific granules. Defects in a myeloid-specific transcription factor, CCAAT/enhancer binding protein-epsilon (C/EBP epsilon), have been identified in two cases in which homozygous frameshift mutations led to loss of the leucine zipper domain. In this study, we report a 55-y-old woman affected with SGD caused by a novel homozygous 2-aa deletion (Delta RS) in the leucine zipper domain of the C/EBP epsilon gene. The patient showed characteristic neutrophil abnormalities and recurrent skin infections; however, there was no history of deep organ infections. Biochemical analysis revealed that, in contrast to the two frameshift mutations, the DRS mutant maintained normal cellular localization, DNA-binding activity, and dimerization, and all three mutants exhibited marked reduction in transcriptional activity. The DRS mutant was defective in its association with Gata1 and PU.1, as well as aberrant cooperative transcriptional activation of eosinophil major basic protein. Thus, the DRS likely impairs protein-protein interaction with other transcription factors, resulting in a loss of transcriptional activation. These results further support the importance of the leucine zipper domain of C/EBP epsilon for its essential function, and indicate that multiple molecular mechanisms lead to SGD.