Inherited dysfunctional platelet P2Y₁₂ receptor mutations associated with bleeding disorders

Area of Science:

• Hematology
• Molecular Biology
• Genetics

Background:

• The P2Y12 receptor (P2Y12R) is crucial for platelet aggregation.
• Dysfunctional P2Y12R mutations can lead to congenital lifelong bleeding disorders.

Purpose of the Study:

• To report a newly identified dysfunctional P2Y12R variant in patients with severe bleeding disorders.
• To characterize the molecular and functional consequences of this mutation.

Main Methods:

• Genetic sequencing to identify mutations in the P2Y12R gene.
• In vitro platelet aggregation studies to assess ADP-promoted aggregation.
• Structure modeling to predict the impact of the mutation on receptor function.

Main Results:

• A homozygous c.561T>A substitution (p.His187Gln) was identified in two brothers with severe bleeding.
• Patient platelets exhibited reduced and rapidly reversible ADP-promoted aggregation.
• The p.His187Gln mutation decreased ligand affinity without altering receptor expression.
• Structure modeling indicated impaired conformational changes in the TM5 domain.

Conclusions:

• The p.His187Gln mutation in P2Y12R causes a severe bleeding disorder.
• Impaired receptor function is due to reduced ligand affinity and altered receptor conformation.
• The TM5 region is essential for P2Y12R agonist/antagonist binding and overall function.