Dock8

DOCK8 ( D edicator o f c yto k inesis 8), also known as Zir3, is a large (~190 kDa) is_associated_with::protein involved in is_associated_with::intracellular signalling networks. It is a member of the DOCK-C subfamily of the DOCK family of is_associated_with::guanine nucleotide exchange factors (GEFs) which function as activators of small is_associated_with::G proteins.

Discovery
Dock8 was identified during a yeast two hybrid (YTH) screen for proteins that interact with the is_associated_with::Rho family small G protein is_associated_with::Cdc42. Subsequent is_associated_with::northern blot analysis revealed high levels of Dock8 expression in the is_associated_with::placenta, is_associated_with::lung, is_associated_with::kidney and is_associated_with::pancreas as well as lower levels in the is_associated_with::heart, is_associated_with::brain and is_associated_with::skeletal muscle.

Function
Dock8 shares the same core domain arrangement as all other DOCK proteins, with a is_associated_with::DHR2 domain which, in other proteins, contains GEF activity and a is_associated_with::DHR1 domain known, in other proteins, to interact with is_associated_with::phospholipids. In the YTH system Dock8 was reported to interact with both is_associated_with::Rac1 and Cdc42. However, no stable interaction between Dock8 and these small G proteins was observed in a GST-pulldown assay. This may be due to the fact many DOCK-G protein interactions require the presence of is_associated_with::adaptor proteins to stabilise the complex and thus facilitate nucleotide exchange.

Somatic mutations
Despite the fact that little is known about the cellular role of Dock8 its importance has been highlighted in several studies which have identified distruption of the DOCK8 gene in disease. Deletion and reduced expression of Dock8 have been reported in a human is_associated_with::lung cancer cell line and Dock8 was also identified as a putative candidate gene associated with progression of is_associated_with::gliomas.

Clinical Significance of Germline Mutations
Autosomal recessive DOCK8 deficiency is associated with a variant of is_associated_with::combined immunodeficiency. This variant of is_associated_with::Hyperimmunoglobulin E syndrome (HIES) was first described in 2004 and this clinical entity is known to be due to having biallelic is_associated_with::germline mutations in the DOCK8 gene. HIES due to DOCK8-deficiency has a distinct clinical presentation compared to other forms of HIES and in inherited in an is_associated_with::autosomal recessive manner.

The clinical manifestations of DOCK8 immunodefiency include recurrent infections, allergies, and malignancies. Nearly all patients have recurrent or chronic upper and lower respiratory tract infections, with many requiring sinus surgery and is_associated_with::myringotomy tube placement. Recurrent lung infections may lead to is_associated_with::bronchiectasis or damage to the airways leaving them widened and scarred. The cutaneous or skin infections are distinctive and include severe and difficult to treat viral infections, such as is_associated_with::herpes simplex virus, is_associated_with::human papilloma virus, and is_associated_with::molluscum contagiosum; bacteria such as is_associated_with::Staphylococcus aureus; as well as fungal infections of the mouth or skin with Candida. is_associated_with::Eczema is common, and can be quite severe and further complicated by bacterial infection. Together, these skin infections can become disfiguring.

DOCK8 immunodefiency patients frequently have allergies to many food and environmental allergens, as well as asthma. is_associated_with::Autoimmunity has been seen in some patients, such as autoimmune hemolytic anemia, as well as vasculitis and vasculopathy. Patients are also at increased risk for developing is_associated_with::squamous cell carcinomas and lymphoid malignancies. Some but not all lymphomas are associated with poor control of the cancer-causing virus, is_associated_with::Epstein-Barr. These cancer risks are significant and patients should be monitored closely for signs of malignancy.

This disorder is considered a is_associated_with::combined immunodeficiency because it includes both decreased is_associated_with::lymphocyte numbers and defective lymphocyte function. It can also be classified as a type of is_associated_with::autosomal recessive hyperimmunoglobulinemia E syndrome. Laboratory manifestations include progressive is_associated_with::lymphopenia that primarily affects CD4 and CD8 is_associated_with::T cell subsets, reduced is_associated_with::B cell and/or is_associated_with::NK cell counts in some patients, eosinophilia, and immunoglobulin abnormalities. Antibody responses to vaccines are frequently poor. Loss of Dock8 protein expression can be demonstrated by diagnostic intracellular is_associated_with::flow cytometry testing.

Once a diagnosis is made, treatment is based on an individual’s clinical condition and may include medication and other strategies for managing infections, allergies, and asthma. Supportive care includes is_associated_with::prophylactic is_associated_with::antimicrobials, and consideration of immune globulin replacement. is_associated_with::Interferon alpha has been used for control of serious viral infections, such as widespread warts or herpes simplex virus. is_associated_with::Hematopoietic stem cell transplant is curative in many primary immunodeficiencies and has successfully been used for patients with DOCK8 immunodefiency.