dedicator of cytokinesis 8
The DOCK8 gene provides instructions for making a member of the DOCK family of proteins. The proteins in this family act as guanine nucleotide exchange factors (GEFs). GEFs turn on (activate) proteins called GTPases, which play an important role in chemical signaling within cells. Signaling stimulated by DOCK family proteins are typically involved in the arrangement of the structural framework inside cells (the cytoskeleton). By controlling the shape of the cytoskeleton, DOCK family proteins play a role in cell structure and movement (migration).
The DOCK8 protein is found most abundantly in cells of the immune system. DOCK8 plays a critical role in the survival and function of several types of immune system cells, including T cells, NK cells, and B cells. T cells and NK cells recognize and attack foreign invaders, such as viruses, to prevent infection. B cells produce proteins called antibodies, which attach to foreign particles and germs and mark them for destruction.
Through its function as a GEF, the DOCK8 protein helps maintain the structure and integrity of T cells and NK cells. It also aids in the migration of these immune system cells to sites of infection, particularly the skin. DOCK8 is also involved in chemical signaling pathways that stimulate B cells to mature and produce antibodies. DOCK8 is also involved in the normal development and survival of other types of immune system cells.
At least 110 mutations in the DOCK8 gene have been found to cause autosomal recessive hyper-IgE syndrome (AR-HIES), an immune system disorder that causes recurrent severe infections of the skin and respiratory tract. Most of the mutations involved in this disorder delete regions of DNA from the DOCK8 gene. These deletions and other DOCK8 gene mutations lead to an abnormally short protein, if any protein is produced. As a result, affected individuals have little or no functional DOCK8 protein.
A shortage of DOCK8 protein impairs normal immune cell development and function. It is thought that T cells lacking DOCK8 cannot maintain their shape as they move through dense spaces, such as those found within the skin. The abnormal cells die, resulting in reduced numbers of these cells. A shortage of T cells impairs the immune response to foreign invaders, accounting for the severe skin infections common in AR-HIES. A lack of DOCK8 also impairs B cell maturation and the production of antibodies. Impairment of this type of immune response leads to recurrent respiratory tract infections in people with this disorder.
Mutations affecting the DOCK8 gene have been found in two individuals with a rare form of intellectual disability described in the medical literature as autosomal dominant mental retardation 2. These individuals have developmental delays, including delayed or absent speech. The mutations involved in this condition result in production of an abnormally short DOCK8 protein. Unlike in AR-HIES (described above), the mutations associated with autosomal dominant mental retardation 2 affect only one copy of the DOCK8 gene. Researchers are unsure how these genetic changes lead to intellectual disability.
- dedicator of cytokinesis protein 8 isoform 1
- dedicator of cytokinesis protein 8 isoform 2
- dedicator of cytokinesis protein 8 isoform 3
- epididymis luminal protein 205