Laboratory for Inborn Errors of Immunity, Department of Immunology and Microbiology, KU Leuven, Leuven, EU, Belgium.
Laboratory of Molecular Immunology, Department of Microbiology and Immunology, Rega Institute for Medical Research, University of Leuven, Leuven, EU, Belgium.
J Clin Immunol. 2019 Apr;39(3):298-308. doi: 10.1007/s10875-019-00603-w. Epub 2019 Mar 5.
DOCK2 is a guanine-nucleotide-exchange factor for Rac proteins. Activated Rac serves various cellular functions including the reorganization of the actin cytoskeleton in lymphocytes and neutrophils and production of reactive oxygen species in neutrophils. Since 2015, six unrelated patients with combined immunodeficiency and early-onset severe viral infections caused by bi-allelic loss-of-function mutations in DOCK2 have been described. Until now, the function of phagocytes, specifically neutrophils, has not been assessed in human DOCK2 deficiency. Here, we describe a new kindred with four affected siblings harboring a homozygous splice-site mutation (c.2704-2 A > C) in DOCK2. The mutation results in alternative splicing and a complete loss of DOCK2 protein expression. The patients presented with leaky severe combined immunodeficiency or Omenn syndrome. The novel mutation affects EBV-B cell migration and results in NK cell dysfunction similar to previous observations. Moreover, both cytoskeletal rearrangement and reactive oxygen species production are partially impaired in DOCK2-deficient neutrophils.
DOCK2 是 Rac 蛋白的鸟嘌呤核苷酸交换因子。激活的 Rac 具有多种细胞功能，包括淋巴细胞和中性粒细胞中肌动蛋白细胞骨架的重排以及中性粒细胞中活性氧物质的产生。自 2015 年以来，已经描述了 6 例无关联的患者，他们因 DOCK2 的双等位基因功能丧失突变而患有联合免疫缺陷和早期严重病毒感染。到目前为止，人类 DOCK2 缺乏症中尚未评估吞噬细胞（特别是中性粒细胞）的功能。在这里，我们描述了一个新的家系，其中有 4 个受影响的兄弟姐妹携带 DOCK2 中的纯合剪接位点突变（c.2704-2 A > C）。该突变导致选择性剪接和 DOCK2 蛋白表达完全缺失。患者表现为渗漏性严重联合免疫缺陷或 Omenn 综合征。该新突变影响 EBV-B 细胞迁移，并导致 NK 细胞功能障碍，与先前的观察结果相似。此外，DOCK2 缺陷中性粒细胞中的细胞骨架重排和活性氧物质产生均部分受损。
