DOCK8 Deficiency Presenting as an IPEX-Like Disorder
DOCK8 Deficiency Presenting as an IPEX-Like Disorder
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DOI：
10.1007/s10875-017-0451-1
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发表时间：
2017-11-01
影响因子：
9.1
通讯作者：
Chatila, Talal A.
中科院分区：
文献类型：
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作者：
Alroqi, Fayhan J.;Charbonnier, Louis-Marie;Chatila, Talal A.
胞质分裂 8 (DOCK8) 缺陷的奉献者是一种常染色体隐性联合免疫缺陷，其临床谱包括反复感染、自身免疫、恶性肿瘤、血清 IgE 升高、湿疹和食物过敏。在这里，我们报告了患有功能丧失的 DOCK8 突变患者，伴有严重的免疫失调，提示免疫失调、多内分泌病、肠病、X 连锁 (IPEX) 样疾病。通过流式细胞术评估淋巴细胞亚群的免疫表型和 DOCK8 蛋白表达分析。通过细胞分选分离调节性 T (T-reg) 细胞，并通过流式细胞术分析其抑制活性。通过全外显子组和桑格测序进行基因突变分析。患者 1 (P1) 在 10 个月大时出现慢性严重腹泻和活动性结肠炎（没有感染触发因素）、严重湿疹伴血清 IgE 升高以及自身免疫性溶血性贫血（提示存在 IPEX 相关疾病）。全外显子组测序揭示了 DOCK8 中 DOCK 同源区 (DHR)-1 处的纯合无义突变（c.1498C > T；p. R500X）。患者 P2 是 P1 的表亲，携带相同的 DOCK8 无义突变，在婴儿早期出现湿疹和反复耳部感染，并在 3 岁时出现持续性腹泻。 P3 患者出现淋巴细胞增生、严重湿疹伴过敏性失调以及慢性腹泻伴结肠炎。她携带纯合性 DOCK8 功能丧失突变 (c.2402 -1G -> A)。 DOCK8 突变严重损害了 T reg 细胞功能。DOCK8 缺陷可能会出现严重的免疫失调，其特征可能与 IPEX 和其他 IPEX 样疾病的特征重叠。
The dedicator of cytokinesis 8 (DOCK8) deficiency is an autosomal recessive-combined immunodeficiency whose clinical spectra include recurrent infections, autoimmunity, malignancies, elevated serum IgE, eczema, and food allergies. Here, we report on patients with loss of function DOCK8 mutations with profound immune dysregulation suggestive of an immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX)-like disorder.Immunophenotyping of lymphocyte subpopulations and analysis of DOCK8 protein expression were evaluated by flow cytometry. T regulatory (T-reg) cells were isolated by cell sorting, and their suppressive activity was analyzed by flow cytometry. Gene mutational analysis was performed by whole-exome and Sanger sequencing.Patient 1 (P1) presented at 10 months of age with chronic severe diarrhea and active colitis in the absence of an infectious trigger, severe eczema with elevated serum IgE, and autoimmune hemolytic anemia, suggestive of an IPEX-related disorder. Whole-exome sequencing revealed a homozygous nonsense mutation in DOCK8 at the DOCK-homology region (DHR)-1 (c.1498C > T; p. R500X). Patient P2, a cousin of P1 who carries the same DOCK8 nonsense mutation, presented with eczema and recurrent ear infections in early infancy, and she developed persistent diarrhea by 3 years of age. Patient P3 presented with lymphoproliferation, severe eczema with allergic dysregulation, and chronic diarrhea with colitis. She harbored a homozygous loss of function DOCK8 mutation (c.2402 -1G -> A). T-reg cell function was severely compromised by both DOCK8 mutations.DOCK8 deficiency may present severe immune dysregulation with features that may overlap with those of IPEX and other IPEX-like disorders.