Novel heterozygous missense mutation in the second leucine rich repeat of GPIbα affects GPIb/IX/V expression and results in macrothrombocytopenia in a patient initially misdiagnosed with idiopathic thrombocytopenic purpura

Recent studies have shown that heterozygous carriers of the bleeding disorder Bernard-Soulier syndrome are occasionally identified as isolated case of giant platelet disorder/macrothrombocytopenia or misdiagnosed with idiopathic thrombocytopenic purpura (ITP). We describe here a patient with congenital macrothrombocytopenia who had been diagnosed with ITP. On peripheral blood smears, platelet diameter was similar to 30% larger than normal controls. In the patient's platelets, the expression level of the GPIbIX complex was slightly decreased (70-80% of normal control). Densitometric analysis of immunoblots showed GPIb alpha to be similar to 52% of normal. DNA sequencing analysis revealed a novel heterozygous missense mutation in the GPIb alpha gene that converts Tyr to Asp at residue 54 (Y54D) in the second leucine-rich repeat. Mutant GPIb alpha protein was not detected in the patient's platelets. Transient transfection studies demonstrated that mutant GPIb alpha affects complex expression. These findings suggest that null expression of the mutant GPIb alpha causes decreased density of the complex and results in macrothrombocytopenia.