Nonsense Mutation in Exon-19 of GPIIb Associated with Thrombasthenic Phenotype. Failure of GPIIb(Δ597-1008) to Form Stable Complexes with GPIIIa

Summary We report the molecular genetic analysis of a patient with thrombasthenic phenotype. The lack of surface platelet GPIIb-IIIa complexes and the presence of GPIIIa suggested it was a case of type I Glanzmann’s thrombasthenia due to a mutation in GPIIb. Single stranded conformational polymorphism analysis (SSCP) of exon-19 of GPIIb showed polymorphic DNA bands. The DNA sequence of exon-19 revealed the presence of a homozygous C1882T transition that changes residue R597 to STOP codon. Since no other mutations were found in either GPIIb or GPIIIa it is concluded that the C1882T substitution in GPIIb is responsible for the thrombasthenic phenotype of the patient. The lack of platelet GPIIb-mRNA in the proband indicates instability of the [C1882T]GPIIb-mRNA. Coexpression of normal GPIIIa and GPIIb(Δ597-1008) in CHO cells failed to show surface expression of GPIIb(Δ597-1008)-IIIa complexes. Immunoprecipitation analysis demonstrated that GPIIb(Δ597-1008) may indeed complex GPIIIa; however, the association is either unstable or incapable of progressing along the secretory pathway.