Laboratory of Host Defenses, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), Bethesda, Md.
Human Immunology Section, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), Bethesda, Md.
J Allergy Clin Immunol. 2014 Jun;133(6):1667-75. doi: 10.1016/j.jaci.2014.03.025. Epub 2014 May 3.
Autosomal recessive loss-of-function mutations in dedicator of cytokinesis 8 (DOCK8) cause a combined immunodeficiency characterized by atopy, recurrent infections, and cancer susceptibility. A genotype-phenotype explanation for the variable disease expression is lacking.
We investigated whether reversions contributed to the variable disease expression.
Patients followed at the National Institutes of Health's Clinical Center were studied. We performed detailed genetic analyses and intracellular flow cytometry to detect DOCK8 protein expression within lymphocyte subsets.
We identified 17 of 34 DOCK8-deficient patients who had germline mutations with variable degrees of reversion caused by somatic repair. Somatic repair of the DOCK8 mutations resulted from second-site mutation, original-site mutation, gene conversion, and intragenic crossover. Higher degrees of reversion were associated with recombination-mediated repair. DOCK8 expression was restored primarily within antigen-experienced T cells or natural killer cells but less so in naive T or B cells. Several patients exhibited multiple different repair events. Patients who had reversions were older and had less severe allergic disease, although infection susceptibility persisted. No patients were cured without hematopoietic cell transplantation.
In patients with DOCK8 deficiency, only certain combinations of germline mutations supported secondary somatic repair. Those patients had an ameliorated disease course with longer survival but still had fatal complications or required hematopoietic cell transplantation. These observations support the concept that some DOCK8-immunodeficient patients have mutable mosaic genomes that can modulate disease phenotype over time.
常染色体隐性失能性突变 dedicator of cytokinesis 8(DOCK8)导致联合免疫缺陷,其特征为特应性、反复感染和癌症易感性。缺乏对可变疾病表现的基因型-表型解释。
我们研究了回复突变是否导致了可变的疾病表现。
我们研究了在国立卫生研究院临床中心就诊的患者。我们进行了详细的遗传分析和细胞内流式细胞术,以检测淋巴细胞亚群中 DOCK8 蛋白的表达。
我们在 34 名 DOCK8 缺陷患者中发现了 17 名患者存在种系突变,具有不同程度的回复突变,这些突变是由体细胞修复引起的。DOCK8 突变的体细胞修复是由第二点突变、原始点突变、基因转换和基因内交叉引起的。较高程度的回复与重组介导的修复有关。DOCK8 表达主要在抗原经验的 T 细胞或自然杀伤细胞中得到恢复,但在幼稚的 T 或 B 细胞中恢复程度较低。一些患者表现出多种不同的修复事件。有回复突变的患者年龄较大,过敏疾病较轻,尽管感染易感性仍然存在。没有患者未经造血细胞移植而治愈。
在 DOCK8 缺陷患者中,只有某些种系突变组合支持继发性体细胞修复。这些患者的疾病过程得到改善,生存时间延长,但仍有致命并发症或需要造血细胞移植。这些观察结果支持这样一种观点,即某些 DOCK8 免疫缺陷患者的基因组具有可变性,随着时间的推移可以调节疾病表型。