Jacob Minnie, Gu Xinyun, Luo Xian, Al-Mousa Hamoud, Arnaout Rand, Al-Saud Bandar, L Lopata Andreas, Li Liang, Dasouki Majed, Rahman Anas M Abdel
Department of Genetics, King Faisal Specialist Hospital and Research Center (KFSH-RC), Riyadh 11211, Saudi Arabia.
Australian Institute of Tropical Health and Medicine, James Cook University, Townsville QLD 4814, Australia.
Metabolites. 2019 Nov 12;9(11):274. doi: 10.3390/metabo9110274.
Bi-allelic mutations in the dedicator of cytokinesis 8 () are responsible for a rare autosomal recessive primary combined immunodeficiency syndrome, characterized by atopic dermatitis, elevated serum Immunoglobulin E (IgE) levels, recurrent severe cutaneous viral infections, autoimmunity, and predisposition to malignancy. The molecular link between DOCK8 deficiency and atopic skin inflammation remains unknown. Severe atopic dermatitis (AD) and DOCK8 deficiency share some clinical symptoms, including eczema, eosinophilia, and increased serum IgE levels. Increased serum IgE levels are characteristic of, but not specific to allergic diseases. Herein, we aimed to study the metabolomic profiles of DOCK8-deficient and AD patients for potential disease-specific biomarkers using chemical isotope labeling liquid chromatography-mass spectrometry (CIL LC-MS). Serum samples were collected from DOCK8-deficient ( = 10) and AD ( = 9) patients. Metabolomics profiling using CIL LC-MS was performed on patient samples and compared to unrelated healthy controls ( = 33). Seven metabolites were positively identified, distinguishing DOCK8-deficient from AD patients. Aspartic acid and 3-hydroxyanthranillic acid (3HAA, a tryptophan degradation pathway intermediate) were up-regulated in DOCK8 deficiency, whereas hypotaurine, leucyl-phenylalanine, glycyl-phenylalanine, and guanosine were down-regulated. Hypotaurine, 3-hydroxyanthranillic acid, and glycyl-phenyalanine were identified as potential biomarkers specific to DOCK8 deficiency. Aspartate availability has been recently implicated as a limiting metabolite for tumour growth and 3HAA; furthermore, other tryptophan metabolism pathway-related molecules have been considered as potential novel targets for cancer therapy. Taken together, perturbations in tryptophan degradation and increased availability of aspartate suggest a link of DOCK8 deficiency to oncogenesis. Additionally, perturbations in taurine and dipeptides metabolism suggest altered antixidation and cell signaling states in DOCK8 deficiency. Further studies examining the mechanisms underlying these observations are necessary.
胞质分裂 dedicator 8（DOCK8）的双等位基因突变可导致一种罕见的常染色体隐性原发性联合免疫缺陷综合征，其特征为特应性皮炎、血清免疫球蛋白 E（IgE）水平升高、复发性严重皮肤病毒感染、自身免疫以及易患恶性肿瘤。DOCK8 缺乏与特应性皮肤炎症之间的分子联系尚不清楚。严重特应性皮炎（AD）和 DOCK8 缺乏有一些共同的临床症状，包括湿疹、嗜酸性粒细胞增多和血清 IgE 水平升高。血清 IgE 水平升高是过敏性疾病的特征，但并非其特有。在此，我们旨在使用化学同位素标记液相色谱 - 质谱法（CIL LC - MS）研究 DOCK8 缺乏患者和 AD 患者的代谢组学谱，以寻找潜在的疾病特异性生物标志物。从 DOCK8 缺乏患者（n = 10）和 AD 患者（n = 9）中采集血清样本。使用 CIL LC - MS 对患者样本进行代谢组学分析，并与无关的健康对照（n = 33）进行比较。确定了七种代谢物可区分 DOCK8 缺乏患者和 AD 患者。天冬氨酸和 3 - 羟基邻氨基苯甲酸（3HAA，色氨酸降解途径中间体）在 DOCK8 缺乏时上调，而次牛磺酸、亮氨酰 - 苯丙氨酸、甘氨酰 - 苯丙氨酸和鸟苷下调。次牛磺酸、3 - 羟基邻氨基苯甲酸和甘氨酰 - 苯丙氨酸被确定为 DOCK8 缺乏特有的潜在生物标志物。最近已表明天冬氨酸可用性是肿瘤生长和 3HAA 的限制代谢物；此外，其他色氨酸代谢途径相关分子已被视为癌症治疗的潜在新靶点。综上所述，色氨酸降解的扰动和天冬氨酸可用性的增加表明 DOCK8 缺乏与肿瘤发生有关。此外，牛磺酸和二肽代谢的扰动表明 DOCK8 缺乏时抗氧化和细胞信号状态改变。有必要进一步研究这些观察结果背后的机制。
