Identification of the integrin ß3 L718P mutation in a pedigree with autosomal dominant thrombocytopenia with anisocytosis.

ABSTRACT

αIIbß3 integrin mutations that result in the complete loss of expression of this molecule on the platelet surface cause Glanzmann thrombasthenia. This is usually autosomal recessive, while other mutations are known to cause dominantly inherited macrothrombocytopenia (although such cases are rare). Here, we report a 4-generation pedigree including 10 individuals affected by dominantly inherited thrombocytopenia with anisocytosis. Six individuals, whose detailed clinical and laboratory data were available, carried a non-synonymous ITGB3 gene alteration resulting in mutated integrin ß3 (ITGB3)-L718P. This mutation causes partial activation of the αIIbß3 complex, which promotes the generation of abnormal pro-platelet-like protrusions through downregulating RhoA (RHOA) activity in transfected Chinese Hamster Ovary cells. These findings suggest a model whereby the integrin ß3-L718P mutation contributes to thrombocytopenia through gain-of-function mechanisms.