WAS

The WAS protein (WASP) is found in cells made from hematopoietic stem cells, including blood cells and certain immune cells. This protein is involved in relaying signals from the cell surface to the actin cytoskeleton, which is a network of fibers that make up the cell's structural framework. The actin cytoskeleton has several critical functions, including determining cell shape and allowing cells to move. In immune cells, the actin cytoskeleton is involved in establishing the interaction between immune cells and the foreign invaders that they target.

Wiskott-Aldrich syndrome - caused by mutations in the WAS gene

More than 250 mutations in the WAS gene have been found to cause Wiskott-Aldrich syndrome. Most of these mutations lead to the production of an abnormally short, nonfunctional version of WASP or prevent cells from producing any WASP at all. Mutations that entirely prevent the production of WASP tend to be associated with more severe symptoms and a greater risk of developing cancer. Mutations in the WAS gene impair WASP's ability to relay signals from the cell surface to the actin cytoskeleton and disrupt its developmental role in bone marrow cells. These impairments cause immune cells to malfunction, leading to eczema and an increased risk of infection, autoimmune disorders, and lymphoma associated with this condition. Impaired WASP function also interferes with normal platelet development, causing microthrombocytopenia, the characteristic sign of Wiskott-Aldrich syndrome.

other disorders - caused by mutations in the WAS gene

At least seven mutations in the WAS gene have been found to cause a blood disorder called X-linked thrombocytopenia. People with this condition have microthrombocytopenia, which is a decrease in the amount and size of blood cells involved in clotting (platelets), but they have no other signs or symptoms of Wiskott-Aldrich syndrome. This platelet abnormality can cause individuals to bruise easily or have episodes of prolonged bleeding following minor trauma. Some affected individuals may develop immune disorders or cancers, but it is unclear whether these people have a mild version of Wiskott-Aldrich syndrome or a severe version of X-linked thrombocytopenia. The mutations that cause X-linked thrombocytopenia change single protein building blocks (amino acids) in WASP. Mutations that result in the production of some functional WASP tend to result in this milder condition rather than the more severe Wiskott-Aldrich syndrome.

Mutations in the WAS gene can also cause a disorder of the immune system called X-linked neutropenia. This condition is characterized by low levels of white blood cells (neutropenia) and decreased survival of bone marrow cells. People with this condition tend to have immune system problems resulting in recurrent infections. WAS mutations that cause this condition affect a region of WASP known as the Cdc42 binding site. The Cdc42 binding site has to be attached (bound) to the Cdc42 protein complex in order for WASP to be turned on (active). At least three mutations in the WAS gene have been found to cause X-linked neutropenia. These mutations lead to a protein that is always active. It is not fully understood how a constantly active WASP leads to the signs and symptoms of X-linked neutropenia.