3.1 Wiskott-Aldrich syndrome

More than 350 mutations in the WAS gene have been found to cause Wiskott-Aldrich syndrome, a condition characterized by abnormal immune system function (immune deficiency) and a reduced ability to form blood clots leading to prolonged bleeding episodes. Most of the mutations lead to the production of an abnormally short, nonfunctional version of WASP or prevent the production of any WASP. As a result, WASP cannot relay signals, which disrupts the function of the actin cytoskeleton in developing blood cells. White blood cells that lack WASP have a decreased ability to respond to their environment and form immune synapses. As a result, white blood cells are less able to respond to foreign invaders, causing many of the immune problems related to Wiskott-Aldrich syndrome. Similarly, when cells that aid blood clot formation (platelets) lack functional WASP, their development is impaired. A reduction in platelet size and early cell death leads to the bleeding problems in affected individuals. The impairments of white blood cells and platelets are largely responsible for the immune deficiency and bleeding problems characteristic of Wiskott-Aldrich syndrome.

3.2 X-linked thrombocytopenia

More than 60 mutations in the WAS gene have been found to cause X-linked thrombocytopenia, a blood disorder characterized by a decrease in the amount and size of platelets, leading to prolonged bleeding episodes. Immune problems such as an increased susceptibility to infections may also occur. Most of these WAS gene mutations change single protein building blocks (amino acids) in WASP. Mutations typically lead to the production of an altered protein that cannot efficiently relay signals from the cell membrane to the actin cytoskeleton. In people with X-linked thrombocytopenia, these signaling problems primarily affect the development of platelets. In some cases, white blood cells are affected. When WASP function is impaired in white blood cells, these cells are less able to respond to foreign invaders and immune disorders are more likely to occur.

Some WAS gene mutations cause X-linked thrombocytopenia in some individuals and a related condition called Wiskott-Aldrich syndrome (described above) in others. These mutations usually prevent the production of any WASP. It is unknown why some people with these mutations have the relatively mild features of X-linked thrombocytopenia and others have the severe symptoms of Wiskott-Aldrich syndrome. Because they have overlapping features and the same genetic cause, Wiskott-Aldrich syndrome, X-linked thrombocytopenia, and severe congenital neutropenia are sometimes collectively referred to as WAS-related disorders.