Alt. symbols: FLJ00026 | FLJ00152 | ZIR8 | FLJ00346

Approved name: dedicator of cytokinesis 8
Alt. names: dedicator of cytokinesis protein 8 | 1200017A24Rik | epididymis luminal protein 205

Location: 9p24.3: 214854 - 465259 (+)
Gene type: protein_coding, 25 transcripts.

Scores: LoFtool: 0.630000 | pLI: 0.00013543 | LOEUF: 0.477

HGNC: 19191

NCBI: 81704, RefSeq: NG_017007.1

Ensembl: ENSG00000107099.18

LRG_196 | Status: public

OMIM: 611432

Expression | ProteinAtlas

DOCK8 is a guanine nucleotide exchange factor (GEF) that specifically activates small GTPase CDC42 by exchanging bound GDP for free GTP (PMID 28028151, 22461490). DOCK-stimulated signaling is necessary for cytoskeletal rearrangement, thus affecting cell polarity, signaling and migration. DOCK8 is particularly abundant in cells of the immune system, where it plays a critical role in the survival and function of many cell types, including T, B and NK cells. DOCK8 helps T and NK cells maintain their cellular structure and integrity and enables T cells and dendritic cells to migrate to sites of infection (PMID 28028151). It plays a role in B cell differentiation and maturation, as well as in the development and survival of other immune cell lineages. It plays a role in NK cell cytotoxicity by controlling microtubule-organizing center (MTOC) polarization and possibly regulating CCDC88B-mediated lytic granule transport to MTOC during cell killing (PMID 25762780).

Biallelic mutations in DOCK8 lead to an autosomal recessive form of Hyper-IgE syndrome (AR-HIES) [OMIM: 243700], featuring combined immunodeficiency resulting in recurrent skin and sinopulmonary infections involving bacteria, viruses and fungi, atopic disease with elevated serum IgE levels, and cancer susceptibility. The predisposition to viral infections, especially involving herpesviruses, is well-described for DOCK8 AR-HIES, as compared to STAT3 AD-HIES. In addition to CMV infections (PMID: 2 2968740), EBV-driven lymphoproliferation (PMID: 28293550, 31267431), and VZV-associated vasculopathy (PMID: 24418481, 30565250), this can also manifest as severe HSV infections of skin and mucocutaneous surfaces, resulting in conditions such as blepharoconjunctivitis and periodontitis (PMID: 24698314, 24767873, 25600604, 31970398). To date, more than 130 disease-causing mutations in DOCK8 have been described - many are large genomic deletions that include the DOCK8 gene, but frameshift, nonsense, missense and splice mutations have also been reported. These latter are distributed across the gene with no obvious clustering at specific mutational hotspots. These loss-of-function (LOF) mutations are thought to leave affected individuals with little to no functional DOCK8 protein, impairing normal immune cell development and function. Infection susceptibility is thought to arise from defective maturation into lymphoid lineages, quantitative deficits in their numbers, and impaired mature cell function. DOCK8 promotes naïve B cell maturation into plasma and memory B cells via TLR9-MyD88 signaling (PMID: 32542827). Studies in human patients and mouse models have suggested that DOCK8 is essential for the survival of germinal center B cells and CD8+ T cells (PMID: 22006977, 19898472). Moreover, Tangye et al. (2017) and others showed that DOCK8 deficiency biases naïve CD4+ T cells to a Th2 effector fate over Th1 and Th17 (PMID 27554822, 27350570), suggesting a potential pathophysiological mechanism for patients’ recurrent cutaneous infections, increased serum IgE levels, and severe atopic disease. DOCK8+ T follicular helper cells have been implicated in autoantibody generation in systemic lupus erythematosus (SLE) (PMID: 34977502). Moreover, there have been multiple case reports of patients with DOCK8 deficiency presenting with SLE-like autoimmune features (PMID: 33787566, 25332498, 16791602, 9714373, 9133954, 6411204). More recently, one group has suggested the possibility of dominant negatively acting DOCK8 variants through identification of rare heterozygous missense mutations in COVID-infected children with MIS-C (PMID: 35336791). The authors showed that foamy virus introduction of cDNA for the four DOCK8 variants into human NK-92 natural killer (NK) cells led to decreased CD107a expression (degranulation) and decreased NK cell lytic function in vitro, suggesting an HLH-like phenotype, but additional clinical and functional validation remains outstanding. Of note, IBD-like gastrointestinal involvement is recurrently described for patients with DOCK8 deficiency (PMID: 22476911, 23374272, 24203055, 29058101, 32084423), while DOCK8 variants have been identified via next-generation sequencing (NGS) in CVID patients but not functionally characterized (PMID: 27379089, 29867916, 31942606). [Load More]