Department of Molecular Genetics, Rabe Rashidi Institute, Tabriz, Iran.
Molecular Genetics Division, GMG center, Tabriz, Iran.
J Mol Neurosci. 2021 Dec;71(12):2456-2461. doi: 10.1007/s12031-021-01843-5. Epub 2021 May 4.
DOCK8 immunodeficiency syndrome (DIDS) is a rare autosomal recessive (AR) disorder characterized by elevated serum IgE levels, eosinophilia, recurrent cutaneous infections, severe eczema, and sinopulmonary and gastrointestinal infections. This syndrome is a multisystem disease that is associated with both immune deficiency and neurological complications. In this study, we describe the clinical characteristics of two Iranian patients with DOCK8 deficiency and propose possible mechanisms for this condition. By using whole exome sequencing (WES), we identified two novel mutations, namely c.3233_3234del AG (p.Q1078fs) in exon 6 and a large deletion with 94 kb (c.405-3231 deletion, p.K135fs), in these two patients. These variations are confirmed with Sanger sequencing and CGH array. Subsequent co-segregation analysis is performed to identify inheritance patterns. Both patients were homozygote and their parents were heterozygote for the variations. For further investigation, prediction tools were applied to identify the pathogenicity of the variations and also for modeling the truncated proteins. The patients did not show neurological abnormalities associated with a deficiency of the N terminal region of DOCK8. The absence of neurological complications in the first patient is justifiable due to the maintenance of the proline-rich region in DOCK8, but for the second patient with expanded deletion which is almost like null DOCK8 protein, it is not presumable, pointing to the fact that the C terminal region of the protein might have functions in the proliferation and migration neurons in the peripheral nervous system. Alternatively, it is possible that neurological abnormalities follow an age-dependent pattern, leading to the appearance of related symptoms later in life. Further multiple functional studies are needed to model different identified variants in animal models to confirm our results and suggest possible mechanisms associated with DOCK8 deficiency in this study.
DOCK8 免疫缺陷综合征 (DIDS) 是一种罕见的常染色体隐性 (AR) 疾病，其特征是血清 IgE 水平升高、嗜酸性粒细胞增多、复发性皮肤感染、严重湿疹以及鼻旁窦和胃肠道感染。这种综合征是一种多系统疾病，与免疫缺陷和神经并发症均相关。在本研究中，我们描述了两名伊朗 DOCK8 缺乏症患者的临床特征，并提出了这种情况的可能机制。通过使用全外显子组测序 (WES)，我们在这两名患者中发现了两个新的突变，即第 6 外显子中的 c.3233_3234del AG (p.Q1078fs) 和一个 94kb 的大片段缺失 (c.405-3231 缺失，p.K135fs)。这些变异通过 Sanger 测序和 CGH 阵列得到确认。随后进行共分离分析以确定遗传模式。两名患者均为纯合子，其父母均为变异的杂合子。为了进一步研究，应用预测工具来鉴定变异的致病性，并对截断蛋白进行建模。这两名患者均未表现出与 DOCK8 N 端区域缺乏相关的神经异常。第一个患者没有神经并发症是合理的，因为 DOCK8 中的脯氨酸丰富区域得以保留，但对于第二个患者，其扩展缺失几乎类似于缺失 DOCK8 蛋白，这是不可想象的，这表明蛋白的 C 端区域可能在周围神经系统的神经元增殖和迁移中发挥作用。或者，神经异常可能遵循年龄依赖性模式，导致相关症状在以后的生活中出现。需要进一步进行多种功能研究，在动物模型中对不同鉴定的变体进行建模，以证实我们的结果，并提出与本研究中 DOCK8 缺乏相关的可能机制。
