Last update 01 Nov 2024

DOCK8

Last update 01 Nov 2024

Basic Info

Synonyms

dedicator of cytokinesis 8, Dedicator of cytokinesis protein 8, DOCK8

+ [4]

Introduction

Guanine nucleotide exchange factor (GEF) which specifically activates small GTPase CDC42 by exchanging bound GDP for free GTP (PubMed:28028151, PubMed:22461490). During immune responses, required for interstitial dendritic cell (DC) migration by locally activating CDC42 at the leading edge membrane of DC (By similarity). Required for CD4(+) T-cell migration in response to chemokine stimulation by promoting CDC42 activation at T cell leading edge membrane (PubMed:28028151). Is involved in NK cell cytotoxicity by controlling polarization of microtubule-organizing center (MTOC), and possibly regulating CCDC88B-mediated lytic granule transport to MTOC during cell killing (PubMed:25762780).

Drugs associated with DOCK8

MR-022

Target

DOCK8 x KRT8

Mechanism

DOCK8 inhibitors [+1]

Active Org.-

Originator Org.

Centre Léon Bérard Lyon et Rhône-Alpes

Active Indication-

Inactive Indication

Colorectal Cancer

Drug Highest PhasePending

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with DOCK8

100 Translational Medicine associated with DOCK8

0 Patents (Medical) associated with DOCK8

330

Literatures (Medical) associated with DOCK8

01 Dec 2024·Cellular and Molecular Neurobiology

Analysis and Regulatory Mechanisms of Platelet-Related Genes in Patients with Ischemic Stroke

Article

Author: Shu, Yuanlu ; Li, Yuan ; Ni, Ruihan ; Yu, Kun ; Chu, Lan

It was found that ischemic stroke (IS) was associated with abnormal platelet activity and thrombosis. However, the potential significance of platelet-related genes (PRGs) in IS still needs to be more thorough. This study extracted IS-related transcriptome datasets from the Gene Expression Omnibus (GEO) database. The target genes were obtained by intersecting the differentially expressed genes (DEGs), the module genes related to IS, and PRGs, where the key genes of IS were screened by two machine learning algorithms. The key genes-based diagnostic model was constructed. Gene set enrichment analysis (GSEA) and the immune microenvironment analyses were analyzed targeting key genes in IS. The co-expression, TF-mRNA, and competitive endogenous RNAs (ceRNA) regulatory networks were constructed to reveal the potential regulation of key genes. Potential drugs targeting key genes were predicted as well. Totals of eight target genes were obtained and were associated with immune-related functions. Four platelet-related key genes were acquired, which were related to immunity and energy metabolism. The abnormal expressions of DOCK8, GIMAP5, ICOS were determined by the quantitative real-time polymerase chain reaction (qRT-PCR), and the significant correlations among these key genes were identified. Notably, hsa-miR-17-3p, hsa-miR-3158-3p, hsa-miR-423-3p, and hsa-miR-193a-8p could regulate all key genes at the same time. In addition, Caffeine, Carboplatin, and Vopratelimab were the targeted drugs of these key genes. This study identified four platelet-related key genes of IS, which might help to deepen the understanding of the role of platelet-related genes in the molecular mechanism of IS.

01 Nov 2024·Journal of Clinical Immunology

A Novel Case of IFNAR1 Deficiency Identified a Common Canonical Splice Site Variant in DOCK8 in Western Polynesia: The Importance of Validating Variants of Unknown Significance in Under-Represented Ancestries

Review

Author: Sullivan, Anna ; O'Young, Patrick ; Zhang, Qian ; Hobbs, Matthew ; Huynh, Aimee ; Wainwright, Luke H ; Hsiao, Kuang-Chih ; Pinzon-Charry, Alberto ; Gray, Paul E ; Bastard, Paul ; Guerin, Antoine ; Casanova, Jean-Laurent ; Higgins, Megan ; Noon, Fallon ; Ma, Cindy S ; McManus, Sam ; Rao, Geetha ; Mackie, Joseph ; Wong, Melanie ; Hollway, Georgina ; Pathmanandavel, Karrnan ; Enthoven, Karen ; Tangye, Stuart G ; Mina, Erika Della

AbstractAdvanced genomic technologies such as whole exome or whole genome sequencing have improved diagnoses and disease outcomes for individuals with genetic diseases. Yet, variants of unknown significance (VUS) require rigorous validation to establish disease causality or modification, or to exclude them from further analysis. Here, we describe a young individual of Polynesian ancestry who in the first 13 mo of life presented with SARS-CoV-2 pneumonia, severe enterovirus meningitis and adenovirus gastroenteritis, and severe adverse reaction to MMR vaccination. Genomic analysis identified a previously reported pathogenic homozygous variant in IFNAR1 (c.1156G > T, p.Glu386* LOF), which is common in Western Polynesia. Moreover, a new and putatively deleterious canonical splice site variant in DOCK8 was also found in homozygosity (c.3234 + 2T > C). This DOCK8 variant is common in Polynesians and other under-represented ancestries in large genomic databases. Despite in silico bioinformatic predictions, extensive in vitro and ex vivo analysis revealed the DOCK8 variant likely be neutral. Thus, our study reports a novel case of IFNAR1 deficiency, but also highlights the importance of functional validation of VUS, including those predicted to be deleterious, and the pressing need to expand our knowledge of the genomic architecture and landscape of under-represented populations and ancestries.

01 Nov 2024·Clinical Immunology

DOCK8 deficiency due to a deep intronic variant in two kindreds with hyper-IgE syndrome

Article

Author: Keles, Sevgi ; Gungor, Hatice Eke ; Cansever, Murat ; Wang, Muyun ; Can, Salim ; Baris, Safa ; Schmitz-Abe, Klaus ; Chatila, Talal A. ; Eke Gungor, Hatice ; Chatila, Talal A ; Benamar, Mehdi ; Oktelik, Fatma Betul ; Karakoc-Aydiner, Elif

Dedicator of cytokinesis 8 (DOCK8) deficiency underlies the majority of cases of patients with autosomal recessive form of the hyper-immunoglobulin E syndrome (HIES). Most DOCK8 mutations involve deletions and splice junction mutations that abrogate protein expression. However, a few patients whose presentation is reminiscent of DOCK8 deficiency have no identifiable mutations. Using Whole Exome Sequencing (WES), we identified a deep intronic homozygous DOCK8 variant located in intron 36 (c.4626 + 76 A > G) in two unrelated patients with features of HIES that resulted in an in-frame 75 base pair intronic sequence insertion in DOCK8 cDNA, resulting in a premature stop codon (p.S1542ins6Ter). This variant resulted in variable decrease in DOCK8 expression that was associated with impaired T cell receptor-triggered actin polymerization, decreased IL-6-induced STAT3 phosphorylation, reduced expression of the Th17 cell markers CCR6 and IL-17, and higher frequencies of GATA3⁺ T cells indicative of Th2 skewing. Our approach extends the reach of WES in identifying disease-related intronic variants. It highlights the role of non-coding mutations in immunodeficiency disorders, including DOCK8 deficiency, and emphasizes the need to explore these mutations in unexplained inborn errors of immunity.

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