Genetic, Clinical, and Laboratory Markers for DOCK8 Immunodeficiency Syndrome

Davis, Jeremiah C.; Dove, Christopher G.; Su, Helen C.

doi:10.1155/2010/972591

Cited by 63 publications

(16 citation statements)

References 81 publications

(165 reference statements)

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“…31 The neuronspecific methylation of DOCK2 was involved in the neural differentiation in brain tumors. 32 Besides, mutations of DOCK8, a 33 Also, the reduced DOCK8 expression is caused by the DNA methylation in human lung cancer. 34 In this study, the DOCK2 was downregulated in the blue module of PA, we speculated that aberrant methylation may decrease DOCK2 and DOCK8 expression levels, consequently decreases immune function of macrophages in the pediatric PA via the Fc gamma R-mediated phagocytosis pathway, and then lead to PA development.…”

Section: Discussionmentioning

confidence: 99%

Screening genes crucial for pediatric pilocytic astrocytoma using weighted gene coexpression network analysis combined with methylation data analysis

Zhao

Cai

et al. 2014

Cancer Gene Ther

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To identify novel genes associated with pediatric pilocytic astrocytoma (PA) for better understanding the molecular mechanism underlying the pediatric PA pathogenesis. Gene expression profile data of GSE50161 and GSE44971 and the methylation data of GSE44684 were downloaded from Gene Expression Omnibus. The differentially expressed genes (DEGs) between PA and normal control samples were screened using the limma package in R, and then used to construct weighted gene coexpression network (WGCN) using the WGCN analysis (WGCNA) package in R. Significant modules of DEGs were selected using the clustering analysis. Function enrichment analysis of the DEGs in significant modules were performed using the WGCNA package and clusterprofiler package in R. Correlation between methylation sites of DEGs and PA was analyzed using the CpGassoc package in R. Totally, 3479 DEGs were screened in PA samples. Thereinto, 3424 DEGs were used to construct the WGCN. Several significant modules of DEGs were selected based on the WGCN, in which the turquoise module was positively related to PA, whereas blue module was negatively related to PA. DEGs (for example, DOCK2 (dedicator of cytokinesis 2), DOCK8 and FCGR2A (Fc fragment of IgG, low affinity IIa)) in blue module were mainly involved in Fc gamma R-mediated phagocytosis pathway and natural killer cell-mediated cytotoxicity pathway. Methylations of 14 DEGs among the top 30 genes in blue module were related to PA. Our data suggest that DOCK2, DOCK8 and FCGR2A may represent potential therapeutic targets in PA that merits further investigation.

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Section: Discussionmentioning

confidence: 99%

Screening genes crucial for pediatric pilocytic astrocytoma using weighted gene coexpression network analysis combined with methylation data analysis

Zhao

Cai

et al. 2014

Cancer Gene Ther

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“…Defects in DOCK8 are known to lead to severe combined immunodeficiency syndromes, with morphological, developmental, and functional abnormalities of T-and B-cells (2). Compared to the controls, patients with DOCK8 deficiency and AD showed distinct differences between Ig isotype classes.…”

Section: Discussionmentioning

confidence: 96%

“…dedicator of cytokinesis 8 (DOCK8) is a guanine nucleotide exchange factor that regulates the activity of cell division cycle 42 (Cdc42) necessary for promoting actin binding, maintaining cytoskeletal integrity, and integrating signals from the cell membrane for appropriate cytoskeletal reorganization (1). Biallelic, homozygous, and heterozygous DOCK8 mutations have been reported with frequent large deletions and point mutations, leading to either loss of function or expression of trace amounts of protein (2). DOCK8 is a cytoskeletal protein, highly expressed in the hematopoietic cells and normal peripheral blood mononuclear cells, especially lymphocytes, neutrophils, and expressed in the placenta, kidney, lung, and pancreas (3).…”

Section: Introductionmentioning

confidence: 99%

Proteomics Profiling to Distinguish DOCK8 Deficiency From Atopic Dermatitis

et al. 2021

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Dedicator of cytokinesis 8 deficiency is an autosomal recessive primary immune deficiency disease belonging to the group of hyperimmunoglobulinemia E syndrome (HIES). The clinical phenotype of dedicator of cytokinesis 8 (DOCK8) deficiency, characterized by allergic manifestations, increased infections, and increased IgE levels, overlaps with the clinical presentation of atopic dermatitis (AD). Despite the identification of metabolomics and cytokine biomarkers, distinguishing between the two conditions remains clinically challenging. The present study used a label-free untargeted proteomics approach using liquid-chromatography mass spectrometry with network pathway analysis to identify the differentially regulated serum proteins and the associated metabolic pathways altered between the groups. Serum samples from DOCK8 (n = 10), AD (n = 9) patients and healthy control (Ctrl) groups (n = 5) were analyzed. Based on the proteomics profile, the PLS-DA score plot between the three groups showed a clear group separation and sample clustering (R2 = 0.957, Q2 = 0.732). Significantly differentially abundant proteins (p < 0.05, FC cut off 2) were identified between DOCK8-deficient and AD groups relative to Ctrl (n = 105, and n = 109) and between DOCK8-deficient and AD groups (n = 85). Venn diagram analysis revealed a differential regulation of 24 distinct proteins from among the 85 between DOCK8-deficient and AD groups, including claspin, haptoglobin-related protein, immunoglobulins, complement proteins, fibulin, and others. Receiver-operating characteristic curve (ROC) analysis identified claspin and haptoglobin-related protein, as potential biomarkers with the highest sensitivity and specificity (AUC = 1), capable of distinguishing between patients with DOCK8 deficiency and AD. Network pathway analysis between DOCK8-deficiency and AD groups revealed that the identified proteins centered around the dysregulation of ERK1/2 signaling pathway. Herein, proteomic profiling of DOCK8-deficiency and AD groups was carried out to determine alterations in the proteomic profiles and identify a panel of the potential proteomics biomarker with possible diagnostic applications. Distinguishing between DOCK8-deficiency and AD will help in the early initiation of treatment and preventing complications.

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“…2 In our case, the c.646-647delCT is a novel mutation in the Human Gene Mutation Database (HGMD). As most DOCK8 deficiency is caused by large deletions, 4 it is noteworthy that multiplex ligationdependent probe amplification assays (MLPAs) and q-PCR are more reliable in identifying these large deletions rather than Sanger sequencing. 2 In our patients, the exons 1-48 large deletion will abolish any DOCK8 protein expression and impairs coordination ability of migration in T cells, causing T-cell death (na€ ıve CD4 cells and na€ ıve CD8 cells in particular), 2,4 which could explain patients' lymphopenia and selective decreases in na€ ıve CD4 cells and na€ ıve CD8 cells, as well as virus susceptibility.…”

Section: Editormentioning

confidence: 99%