Novel DOCK8 gene mutations lead to absence of protein expression in patients with hyper-IgE syndrome
Novel DOCK8 gene mutations lead to absence of protein expression in patients with hyper-IgE syndrome
复制标题
DOI：
10.1007/s12026-015-8745-y
复制
发表时间：
2016-02-01
影响因子：
4.4
通讯作者：
Zhao, Xiaodong
中科院分区：
文献类型：
--
作者：
Qin, Tao;An, Yunfei;Zhao, Xiaodong
由 DOCK8 缺陷引起的常染色体隐性高免疫球蛋白 E 综合征 (AR-HIES) 的特点是血清 IgE 水平反复升高、外周嗜酸性粒细胞计数升高、严重特应性、反复病毒和细菌感染以及早发恶性肿瘤。中国患者 DOCK8 突变的临床、遗传和免疫学特征尚未得到详细描述。在这项研究中，我们筛选了七名中国候选患者的 DOCK8 基因突变，并通过靶向深度测序鉴定了三个大型新纯合性缺失和四个新点突变。纯合缺失表现为常染色体隐性遗传，点突变呈散发性。使用流式细胞术和蛋白质印迹证实了 DOCK8 蛋白的缺失。 DOCK8突变患者除了具有DIDS典型的临床特征和免疫功能损伤外，淋巴细胞增殖、NK细胞的细胞毒功能以及调节性B细胞中IL-10的表达也严重受损，这可能与DIDS异常的免疫反应有关。这些发现将有助于DOCK8患者的早期诊断和治疗。
Autosomal recessive hyper-immunoglobulin E syndrome (AR-HIES) caused by DOCK8 defects is characterized by recurrent elevated serum IgE level, elevated peripheral eosinophil count, severe atopy, recurrent viral and bacterial infections, and early-onset malignancy. The clinical, genetic, and immunologic characteristics of DOCK8 mutations in Chinese patients have not been characterized in detail. In this research, we screened seven Chinese candidate patients for mutations within the DOCK8 gene and identified three large novel homozygous deletions and four novel point mutations by targeted deep sequencing. The homozygous deletions displayed autosomal recessive inheritance, and the point mutations were sporadic. Absence of DOCK8 protein was confirmed using flow cytometry and western blotting. Besides the typical clinical features and immunologic impairments of DIDS, proliferation of lymphocytes, cytotoxic function of NK cells, and expression of IL-10 in regulatory B cells were severely impaired in DOCK8 mutant patients which may be associated with abnormal immune responses in DIDS. These findings will contribute to the early diagnosis and treatment of DOCK8 patients.