Wada Taizo, Akagi Tadayuki
Department of Pediatrics, School of Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan.
Department of Stem Cell Biology, School of Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan.
Crit Rev Immunol. 2016;36(4):349-358. doi: 10.1615/CritRevImmunol.2017019385.
Neutrophil-specific granule deficiency (SGD) is a rare autosomal recessive primary immunodeficiency characterized by bilobed neutrophil nuclei and lack of neutrophil-specific granule proteins such as lactoferrin. A deficiency of a myeloid-specific transcription factor, CCAAT/enhancer binding protein-epsilon (C/EBPε), has been identified as a cause of SGD. C/EBPε binds to DNA though its basic leucine zipper (bZIP) domain, and regulates terminal differentiation of neutrophils and expression of specific granule genes. Homozygous frameshift mutations resulting in loss of the bZIP domain have been reported in two patients with SGD. A recent observation showed that a homozygous 2-aa deletion in the bZIP domain with normal DNA-binding and dimerization abilities causes SGD by impairing protein-protein interactions with other transcription factors, indicating that multiple molecular mechanisms can lead to SGD. Studies of patient-derived mutations and analysis of C/EBPε knockout mice have shown the importance of the bZIP domain for the essential functions of C/EBPε.
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原发性免疫缺陷病，其特征为中性粒细胞核呈双叶状，且缺乏乳铁蛋白等中性粒细胞特异性颗粒蛋白。一种髓系特异性转录因子CCAAT/增强子结合蛋白ε（C/EBPε）的缺乏已被确定为SGD的病因。C/EBPε通过其碱性亮氨酸拉链（bZIP）结构域与DNA结合，并调节中性粒细胞的终末分化和特异性颗粒基因的表达。在两名SGD患者中报道了导致bZIP结构域缺失的纯合移码突变。最近的一项观察表明，bZIP结构域中发生纯合2个氨基酸缺失且具有正常DNA结合和二聚化能力的情况，会通过损害与其他转录因子的蛋白质-蛋白质相互作用而导致SGD，这表明多种分子机制可导致SGD。对患者来源突变的研究以及对C/EBPε基因敲除小鼠的分析表明，bZIP结构域对于C/EBPε的基本功能至关重要。
