title: Novel heterozygous missense mutation in the second leucine rich repeat of GPIbalpha affects GPIb/IX/V expression and results in macrothrombocytopenia in a patient initially misdiagnosed with idiopathic thrombocytopenic purpura.
abstract: 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 approximately 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 GPIbalpha to be approximately 52% of normal. DNA sequencing analysis revealed a novel heterozygous missense mutation in the GPIbalpha gene that converts Tyr to Asp at residue 54 (Y54D) in the second leucine-rich repeat. Mutant GPIbalpha protein was not detected in the patient's platelets. Transient transfection studies demonstrated that mutant GPIbalpha affects complex expression. These findings suggest that null expression of the mutant GPIbalpha causes decreased density of the complex and results in macrothrombocytopenia.
authors.affiliation: Department of Hemostasis and Thrombosis, Clinical Research Center, National Hospital Organization Nagoya Medical Center, Nagoya, Japan. kunishis@nnh.hosp.go.jp
authors.forename: Shinji
authors.initials: S
authors.lastname: Kunishima
authors.forename: Toshi
authors.initials: T
authors.lastname: Imai
authors.forename: Motohiro
authors.initials: M
authors.lastname: Hamaguchi
authors.forename: Hidehiko
authors.initials: H
authors.lastname: Saito
mesh_terms: D000328:Adult; D019943:Amino Acid Substitution; D001606:Bernard-Soulier Syndrome / Q000175:diagnosis* / Q000235:genetics* / Q000473:pathology; D004252:DNA Mutational Analysis / Q000379:methods; D003951:Diagnostic Errors; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D020125:Mutation, Missense; D019038:Platelet Glycoprotein GPIb-IX Complex / Q000235:genetics*; D017433:Protein Structure, Secondary / Q000235:genetics; D017434:Protein Structure, Tertiary / Q000235:genetics; D016553:Purpura, Thrombocytopenic, Idiopathic / Q000175:diagnosis* / Q000473:pathology; D013921:Thrombocytopenia / Q000175:diagnosis / Q000235:genetics / Q000473:pathology
chemical_list: D019038:Platelet Glycoprotein GPIb-IX Complex; C023592:glycocalicin