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DOCK8
dedicator of cytokinesis 8
The DOCK8 gene provides instructions for a protein crucial for immune cell development, survival, and movement, particularly within T cells, NK cells, and B cells. The DOCK8 gene encodes a protein that acts as a guanine nucleotide exchange factor (GEF), essential for immune system function.
DOCK8 is located on the short (p) arm of chromosome 9, at band 9p24.3. Arm ratio per GRCh38 - banding schematic.
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Overview
The DOCK8 gene, or 'dedicator of cytokinesis 8', is a member of the DOCK family of proteins, which are important for cellular signalling. Its primary role involves acting as a guanine nucleotide exchange factor (GEF), facilitating the activation of other proteins called GTPases.
These GTPases are involved in controlling the cell's internal structural framework, known as the cytoskeleton. By influencing the cytoskeleton, DOCK8 contributes to cell shape and movement, with a particular focus on immune cells.
What the gene does
The DOCK8 protein is most abundant in immune system cells, where it is critical for their survival and proper function. It is essential for the activity of T cells and NK cells, which identify and eliminate foreign invaders like viruses to prevent infections. Additionally, DOCK8 supports B cells in their production of antibodies, proteins that target pathogens for destruction.
As a GEF, the DOCK8 protein helps maintain the structural integrity of T cells and NK cells. It also supports the migration of these immune cells to infection sites, notably in the skin. Furthermore, DOCK8 participates in signalling pathways that promote the maturation of B cells and their ability to produce antibodies. It is also involved in the normal development and survival of other immune cell types.
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Chromosome location
The DOCK8 gene is located on chromosome 9 at position 9p24.3. This genomic location specifies the precise region on the short (p) arm of chromosome 9 where the gene resides.
Protein structure
The DOCK8 protein is composed of 2099 amino acids. Its structure includes several key functional regions. Among these are the C2 DOCK-type domain, located from amino acids 560-729, and the DOCKER domain, found between amino acids 1632-2066. These domains are integral to its role as a guanine nucleotide exchange factor.
Key variants
Variants in the DOCK8 gene can alter the protein's structure or function, potentially impacting its crucial role in immune cell regulation. Such genetic changes can lead to a range of clinical manifestations, particularly affecting the immune system's ability to respond effectively to pathogens.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.1174C>T | p.Gln392Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Severe combined immunodeficiency disease |
c.1357G>T | p.Glu453Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Combined immunodeficiency due to DOCK8 deficiency |
c.1470del | p.Tyr491fs | Pathogenic | ★★☆☆ | DOCK8-related disorders |
c.1498C>T | p.Arg500Ter | Pathogenic | ★★☆☆ | Combined immunodeficiency due to DOCK8 deficiency |
c.1963C>T | p.Gln655Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Combined immunodeficiency due to DOCK8 deficiency |
c.2986C>T | p.Gln996Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Combined immunodeficiency due to DOCK8 deficiency |
c.3175dup | p.Leu1059fs | Pathogenic/Likely pathogenic | ★★☆☆ | Combined immunodeficiency due to DOCK8 deficiency |
c.3339del | p.Phe1113fs | Pathogenic/Likely pathogenic | ★★☆☆ | Combined immunodeficiency due to DOCK8 deficiency |
c.3339dup | p.Met1114fs | Pathogenic/Likely pathogenic | ★★☆☆ | Combined immunodeficiency due to DOCK8 deficiency |
c.4235dup | p.Asp1413fs | Pathogenic | ★★☆☆ | DOCK8-related disorders |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Pathogenic variants in the DOCK8 gene are associated with inherited conditions that primarily affect the immune system. One notable condition is DOCK8 deficiency, an autosomal recessive disorder. This condition is characterised by recurrent, severe infections, particularly affecting the skin and respiratory tract, along with other immune system dysregulations such as allergies and asthma.
Inheritance pattern
Conditions caused by pathogenic DOCK8 variants typically follow autosomal recessive inheritance.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
UK clinical status
The DOCK8 gene is recognised within the NHS Genomic Medicine Service due to its clinical significance. It is part of several "green" rated PanelApp entries, indicating strong evidence for its association with various conditions. These include COVID-19 research, DDG2P, gastrointestinal epithelial barrier disorders, haematological malignancies cancer susceptibility and for rare disease, infantile enterocolitis & monogenic inflammatory bowel disease, primary immunodeficiency or monogenic inflammatory bowel disease (R15), rare genetic inflammatory skin disorders (R332), and severe multi-system atopic disease with high IgE.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What does the DOCK8 gene do?
The DOCK8 gene provides instructions for a protein that is crucial for the function and survival of immune cells, including T cells, NK cells, and B cells. It acts as a guanine nucleotide exchange factor, helping to activate other proteins that regulate cell structure and movement.
What is DOCK8 deficiency?
DOCK8 deficiency is an inherited immune system disorder caused by pathogenic variants in the DOCK8 gene. Individuals with this condition typically experience recurrent severe infections, particularly of the skin and respiratory system, alongside other immune problems like allergies and asthma.
How is DOCK8 deficiency inherited?
DOCK8 deficiency is inherited in an autosomal recessive manner. This means an individual must inherit two copies of the altered gene, one from each parent, to develop the condition. Individuals with only one altered copy are generally carriers and do not show symptoms.
References
- Su HC, Jing H, Angelus P. Insights into immunity from clinical and basic science studies of DOCK8 immunodeficiency syndrome. Immunological reviews. 2019. PMID: 30565250
- Zhang Q, Jing H, Su HC. Recent Advances in DOCK8 Immunodeficiency Syndrome. Journal of clinical immunology. 2016. PMID: 27207373
- Zhang Q, Dove CG, Hor JL. DOCK8 regulates lymphocyte shape integrity for skin antiviral immunity. The Journal of experimental medicine. 2014. PMID: 25422492
- Crawford G, Enders A, Gileadi U. DOCK8 is critical for the survival and function of NKT cells. Blood. 2013. PMID: 23929855
- Harada Y, Tanaka Y, Terasawa M. DOCK8 is a Cdc42 activator critical for interstitial dendritic cell migration during immune responses. Blood. 2012. PMID: 22461490
- Jabara HH, McDonald DR, Janssen E. DOCK8 functions as an adaptor that links TLR-MyD88 signaling to B cell activation. Nature immunology. 2012. PMID: 22581261
- Lambe T, Crawford G, Johnson AL. DOCK8 is essential for T-cell survival and the maintenance of CD8+ T-cell memory. European journal of immunology. 2011. PMID: 21969276
- Randall KL, Lambe T, Johnson AL. Dock8 mutations cripple B cell immunological synapses, germinal centers and long-lived antibody production. Nature immunology. 2009. PMID: 19898472
- Engelhardt KR, McGhee S, Winkler S. Large deletions and point mutations involving the dedicator of cytokinesis 8 (DOCK8) in the autosomal-recessive form of hyper-IgE syndrome. The Journal of allergy and clinical immunology. 2009. PMID: 20004785