A variant thrombasthenic phenotype associated with compound heterozygosity of integrin β3-subunit: (Met124Val)β3 alters the subunit dimerization rendering a decreased number of constitutive active αIIbβ3 receptors

 

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Summary

We report the analysis of a variant case of thrombasthenic phenotype that is a compound heterozygote for two mutations located within the metal ion dependent adhesion site (MIDAS) of the β3 subunit.The patient inherited a maternal allele carrying the Met124Val substitution and a paternal allele that changes Asp119 to Tyr. Phenotyping of the human platelet antigen 1 (HPA-1) showed that the platelet αIIbβ3 complex in the patient was mostly accounted for by the Asp 119Tyr allele that does not bind to fibrinogen (Fg). The patient showed agonistinduced binding of platelets to Fg but neither binding to PAC-1 nor cell aggregation could be detected, most likely due to the minute expression (≤5%) of αIIb(124Val)β3 receptors. CHO cells expressing (124Val)β3 showed a diminished surface expression of αIIbβ3, enhanced adhesion to immobilized Fg, and spontaneous aggregation in the presence of soluble Fg, suggesting that (124Val)β3 may confer constitutive activity to the αIIb(124Val)β3 receptors. A distinct feature of these cells is the failure of DTT to enhance the binding to soluble Fg and the formation of cell aggregates. The substitution of (124Met)β3 by either a polar or a positively charged amino acid restored the surface exposure and function of the αIIbβ3 receptors whereas a negatively charged residue did not.

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