2.1. Glanzmann Thrombasthenia

At least 200 mutations in the ITGA2B gene have been found to cause Glanzmann thrombasthenia, which is a rare bleeding disorder. The mutations that cause this disorder occur in both copies of the gene in each cell and impair the production or activity of the alphaIIb subunit, which disrupts the formation of functional integrin αIIbβ3. A shortage (deficiency) of functional integrin αIIbβ3 prevents sufficient binding of fibrinogen or other proteins, impairing the formation of blood clots. A lack of platelet cohesion leads to prolonged or spontaneous bleeding episodes experienced by people with Glanzmann thrombasthenia.

2.2. Other Disorders

Mutations in the ITGA2B gene can also cause another rare bleeding disorder called platelet-type bleeding disorder 16. People with this disorder have signs and symptoms similar to Glanzmann thrombasthenia (described above), including frequent nosebleeds (epistaxis), bleeding from the gums, or red or purple spots on the skin caused by bleeding underneath the skin (petechiae), but the episodes are typically milder.

Unlike Glanzmann thrombasthenia, this disorder results from a mutation in only one copy of the ITGA2B gene in each cell, and the mutations result in the formation of some integrin αIIbβ3 that is abnormally turned on (active), even when no clot is being formed. This abnormally active protein is unable to reach the surface of the platelet where it is needed to bind to other platelets during clot formation. The overactive integrin αIIbβ3 binds inappropriately to clotting proteins within the cell during the formation of platelets, causing the platelets to become misshapen and large. The abnormally shaped platelets have a shortened lifespan, so platelet numbers are often reduced, which impairs clot formation. (The combination of reduced numbers of enlarged platelets is referred to as macrothrombocytopenia.)

Because the mutation that causes this disorder affects only one copy of the ITGA2B gene, some normal integrin is formed and normal platelets produced, which accounts for the mild signs and symptoms in affected individuals.