Inherited dysfunctional platelet P2Y₁₂ receptor mutations associated with bleeding disorders

Summary

The platelet adenosine 5’-diphosphate (ADP) receptor P2Y₁₂ (P2Y₁₂R) plays a critical role in platelet aggregation. The present report illustrates an update of dysfunctional platelet P2Y₁₂R mutations diagnosed with congenital lifelong bleeding problems. Described patients with heterozygous or homozygous substitution in the P2Y₁₂R gene and qualitative abnormalities of the platelet P2Y₁₂R are summarized. Recently, a further dysfunctional variant of P2Y₁₂R 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 P2Y₁₂R 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.

Zusammenfassung

Der thrombozytäre Adenosin-5‘-diphosphat(ADP)-Rezeptor P2Y₁₂ (P2Y₁₂R) spielt eine entscheidende Rolle bei der Thrombozytenaggregation. Im Folgenden soll ein kurzes Update über dysfunktionale thrombozytäre P2Y₁₂R-Mutationen, welche im Zusammenhang mit angeborenen, lebenslang bestehenden Blutungsproblemen diagnostiziert wurden, gegeben werden. Patienten mit bereits beschriebenen homo- und heterozygoten Substitutionen im P2Y₁₂ -Gen sowie die daraus folgenden qualitativen Abnormitäten des thrombozytären P2Y₁₂R werden hier zusammengefasst. Zudem wurde kürzlich bei einem Brüderpaar mit einer langjährigen schweren Blutungsstörung eine weitere dysfunktionale Variante des P2Y₁₂R identifiziert. In in vitro- Aggregationsstudien zeigen die Thrombozyten dieser beiden Patienten eine erheblich reduzierte und schnell reversible ADP-induzierte Aggregation. Hierbei wurde eine homozygote c.561T>A Substitution, die das Kodon für His187 zu Gln (p.His187Gln) im P2Y₁₂R-Gen verändert, nachgewiesen. Die Mutation verursacht dabei keine Änderung der Rezeptorexpression, erhöht aber selbst bei einer hohen Ligandenkonzentration die Affinität des Liganden zum Rezeptor. „Strukturmodelling“-Studien zeigen, dass die in der fünften Transmembrandomäne (TM5) lokalisierte p.His187Gln Mutation die Konformationsänderung des Rezeptors beeinträchtigt, was darauf hindeutet, dass die strukturelle Integrität der TM5 Region für die Bin-dung von Agonisten als auch von Antagonisten notwendig ist und damit zu einer normalen Rezeptorfunktion beiträgt.

Keywords

Platelets - mutation - P2Y₁₂ receptor

Schlüsselwörter

Thrombozyten - Mutation - P2Y₁₂-Rezeptor

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