Key result
A homozygous p.His187Gln mutation in the P2Y12R gene was identified in two brothers with severe bleeding, which decreases ligand affinity and impairs receptor conformational changes.
The identification of the p.His187Gln mutation in the P2Y12 receptor highlights the critical role of the fifth transmembrane domain in receptor function and ADP-promoted platelet aggregation.
Identifies novel P2Y12 variant impairing aggregation; extends receptor structure-function insights but leaves clinical prevalence and management open.
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.
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Lecchi et al. (2016) conducted a review in Congenital lifelong bleeding problems. Dysfunctional platelet P2Y12R mutations (e.g., p.His187Gln) was evaluated on Platelet aggregation and receptor function. A homozygous p.His187Gln mutation in the P2Y12R gene was identified in two brothers with severe bleeding, which decreases ligand affinity and impairs receptor conformational changes.
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