Metabolomics distinguishes DOCK8 deficiency from atopic dermatitis: towards a biomarker discovery

Jacob, Minnie, Gu, Xinyun, Luo, Xian, Al-Mousa, Hamoud, Arnaout, Rand, Al-Saud, Bandar, Lopata, Andreas L., Li, Liang, Dasouki, Majed, and Abdel Rahman, Anas M. (2019) Metabolomics distinguishes DOCK8 deficiency from atopic dermatitis: towards a biomarker discovery. Metabolites, 9 (11). 274.

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Bi-allelic mutations in the dedicator of cytokinesis 8 (DOCK8) 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 (n = 10) and AD (n = 9) patients. Metabolomics profiling using CIL LC-MS was performed on patient samples and compared to unrelated healthy controls (n = 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.

Item ID: 61691
Item Type: Article (Research - C1)
ISSN: 2218-1989
Keywords: 3-hydroxyanthranilic acid, Dansylation, Dedicator of cytokinesis, Hypotaurine, Liquid chromatography-mass spectrometry, Metabolomics
Copyright Information: © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open accessarticle distributed under the terms and conditions of the Creative Commons Attribution(CC BY) license (
Funders: King Faisal Hospital and Research Center (KFSHRC), James Cook University, National Health and Medical Research Council of Australia (NHMRC)
Date Deposited: 06 Feb 2020 02:41
FoR Codes: 32 BIOMEDICAL AND CLINICAL SCIENCES > 3205 Medical biochemistry and metabolomics > 320501 Medical biochemistry - amino acids and metabolites @ 25%
32 BIOMEDICAL AND CLINICAL SCIENCES > 3204 Immunology > 320403 Autoimmunity @ 50%
32 BIOMEDICAL AND CLINICAL SCIENCES > 3204 Immunology > 320401 Allergy @ 25%
SEO Codes: 92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920108 Immune System and Allergy @ 50%
92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920110 Inherited Diseases (incl. Gene Therapy) @ 50%
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