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Blood. 2015 Feb 5;125(6):1006-13. doi: 10.1182/blood-2013-07-517896. Epub 2014 Nov 26.

Identification of a new dysfunctional platelet P2Y12 receptor variant associated with bleeding diathesis.

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Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Ca' Granda - Ospedale Maggiore Policlinico, Milan, Italy;
Divisione di Medicina 3, Ospedale San Paolo, Dipartimento di Scienze della Salute - Università degli Studi di Milano, Milan, Italy;
Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD;
Unité Mixte de Recherche_S949, Inserm, Université de Strasbourg, Etablissement Français du Sang-Alsace, Strasbourg, France; and.
Department of Pediatrics and Adolescent Medicine, University Medical Center Freiburg, Freiburg, Germany.


Defects of the platelet P2Y12 receptor (P2Y12R) for adenosine diphosphate (ADP) are associated with increased bleeding risk. The study of molecular abnormalities associated with inherited qualitative defects of the P2Y12R protein is useful to unravel structure-function relationships of the receptor. We describe the case of 2 brothers, sons of first cousins, with lifelong history of abnormal bleeding, associated with dysfunctional P2Y12R and a previously undescribed missense mutation in the encoding gene. ADP (4-20 µM)-induced aggregation of patients' platelets was markedly reduced and rapidly reversible. Other agonists induced borderline-normal aggregation. Inhibition of vasodilator-stimulated phosphoprotein phosphorylation and prostaglandin E1-induced increase in cyclic adenosine monophosphate (cAMP) by ADP was impaired, whereas inhibition of cAMP increase by epinephrine was normal. [(3)H]PSB-0413, a selective P2Y12R antagonist, bound to a normal number of binding sites; however, its affinity, and that of the agonists ADP and 2-methylthio-adenosine-5'-diphosphate, was reduced. Patients' DNA showed a homozygous c.847T>A substitution that changed the codon for His-187 to Gln (p.His187Gln). Crystallographic data and molecular modeling studies indicated that His187 in transmembrane 5 is important for agonist and nucleotide antagonist binding and located in a region undergoing conformational changes. These studies delineate a region of P2Y12R required for normal function after ADP binding.

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