Abstract
The platelet adenosine 5'-diphosphate (ADP) receptor P2Y(12) (P2Y(12)R) plays a critical role in platelet aggregation. The present report illustrates an update of dysfunctional platelet P2Y(12)R mutations diagnosed with congenital lifelong bleeding problems. Described patients with heterozygous or homozygous substitution in the P2Y(12)R gene and qualitative abnormalities of the platelet P2Y(12)R are summarized. Recently, a further dysfunctional variant of P2Y(12)R has been identified in two brothers who presented with a lifelong severe bleeding disorder. During in vitro aggregation studies, the patient´s platelets show a markedly reduced and rapid reversible ADP-promoted aggregation. A homozygous c.561T>A substitution that changes the codon for His187 to Gln (p.His187Gln) in the P2Y(12)R gene has been identified. This mutation causes no change in receptor expression but decreases the affinity of the ligand for the receptor, even at high concentrations. Structure modelling studies indicated that the p.His187Gln mutation, located in the fifth transmembrane spanning domain (TM5), impairs conformational changes of the receptor. Structural integrity of the TM5 region is necessary for agonist and antagonist binding and for correct receptor function.