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DOCK8
dedicator of cytokinesis 8
The DOCK8 gene provides instructions for a protein critical to the normal development and function of immune system cells, particularly T cells, B cells, and NK cells. The DOCK8 gene encodes the dedicator of cytokinesis 8 protein, which is vital for immune cell activity, including cell structure, movement, and signalling.
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, plays a crucial role in the human immune system. It provides instructions for making a protein that helps regulate the structure and movement of various immune cells, including T cells, B cells, and natural killer (NK) cells. These cells are essential components of the immune response, responsible for identifying and eliminating pathogens.
Dysfunction of the DOCK8 gene is associated with DOCK8 deficiency, a primary immunodeficiency characterised by recurrent severe infections and other immune system issues.
What the gene does
The DOCK8 protein belongs to the DOCK family, which functions as guanine nucleotide exchange factors (GEFs). GEFs are proteins that activate other proteins called GTPases, which are key players in cellular signalling pathways. Specifically, DOCK8 protein activation of GTPases typically influences the arrangement of the cell's internal structural framework, known as the cytoskeleton. By controlling the cytoskeleton's shape, DOCK family proteins are involved in cell structure and movement.
Predominantly found in immune cells, DOCK8 is critical for the survival and proper functioning of T cells, NK cells, and B cells. It helps maintain the structural integrity of T cells and NK cells and aids their migration to infection sites, particularly in the skin. Additionally, DOCK8 is involved in signalling pathways that promote the maturation of B cells and their production of antibodies.
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Chromosome location
The DOCK8 gene is located on chromosome 9 at position 9p24.3. This precise location on the short arm of chromosome 9 indicates where the gene can be found within the human genome.
Protein structure
The DOCK8 protein is composed of 2099 amino acids. It features several important domains that contribute to its function. These include a C2 DOCK-type domain, spanning amino acids 560-729, which is typically involved in membrane targeting or protein-protein interactions. Additionally, a DOCKER domain, located between amino acids 1632-2066, is characteristic of DOCK family proteins and plays a role in activating GTPases.
Key variants
Variants within the DOCK8 gene can impact its ability to produce a functional protein, leading to disrupted immune cell development and function. These genetic changes can range from small alterations in the DNA sequence to larger deletions or duplications. The specific clinical presentation often depends on the type and location of the variant, and its effect on protein expression or activity.
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.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.6022C>T | p.Arg2008Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Combined immunodeficiency due to DOCK8 deficiency |
g.271628_464219del | - | Pathogenic | ★☆☆☆ | Combined immunodeficiency due to DOCK8 deficiency |
c.3339dup | p.Met1114fs | Pathogenic | ★☆☆☆ | Combined immunodeficiency due to DOCK8 deficiency |
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 primarily associated with DOCK8 deficiency, an autosomal recessive immune system disorder. This condition is characterised by a range of immune dysregulations, including recurrent severe infections, particularly of the skin and respiratory tract. Individuals with DOCK8 deficiency may also experience other immune-related problems such as allergies, asthma, and inflammation.
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 included in several Green RAG (Red Amber Green) rated panels within the NHS Genomic Medicine Service's PanelApp. These include panels for COVID-19 research, DDG2P (developmental disorders), Gastrointestinal epithelial barrier disorders, Haematological malignancies (both cancer susceptibility and 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. This indicates its recognised clinical relevance in the UK.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the DOCK8 gene?
The DOCK8 gene provides instructions for making the dedicator of cytokinesis 8 protein, which is essential for the proper development and function of immune cells such as T cells, B cells, and NK cells. It helps regulate cell structure, movement, and signalling within the immune system.
What is DOCK8 deficiency?
DOCK8 deficiency is an inherited immune system disorder caused by pathogenic variants in the DOCK8 gene. It results in a weakened immune response, leading to recurrent severe infections, particularly affecting the skin and respiratory system, and can be associated with allergies and asthma.
How is the DOCK8 gene involved in immune function?
The DOCK8 protein acts as a guanine nucleotide exchange factor (GEF), activating other proteins that control the cytoskeleton of immune cells. This function is vital for maintaining the structure and integrity of T cells and NK cells, facilitating their movement to infection sites, and promoting B cell maturation and antibody production.
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