title: Inherited dysfunctional platelet P2Y12receptor mutations associated with bleeding disorders.
abstract: 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.
authors.forename: Anna
authors.initials: A
authors.lastname: Lecchi
authors.forename: Eti A
authors.initials: EA
authors.lastname: Femia
authors.forename: Silvia
authors.initials: S
authors.lastname: Paoletta
authors.forename: Arnaud
authors.initials: A
authors.lastname: Dupuis
authors.forename: Philippe
authors.initials: P
authors.lastname: Ohlmann
authors.forename: Christian
authors.initials: C
authors.lastname: Gachet
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Jacobson
authors.affiliation: Katharina Machura, University Medical Center, Freiburg - Department of Pediatrics and Adolescent Medicine, Breisacher-Str. 66, 79106 Freiburg, Germany, Tel. +49/(0)761/27 06 37 10, E-mail: katharina.machura@uniklinik-freiburg.de.
authors.forename: Katharina
authors.initials: K
authors.lastname: Machura
authors.forename: Gian M
authors.initials: GM
authors.lastname: Podda
authors.forename: Barbara
authors.initials: B
authors.lastname: Zieger
authors.forename: Marco
authors.initials: M
authors.lastname: Cattaneo
mesh_terms: D001791:Blood Platelet Disorders / Q000235:genetics / Q000276:immunology*; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006470:Hemorrhage / Q000235:genetics* / Q000276:immunology*; D006801:Humans; D008957:Models, Genetic; D018448:Models, Immunological; D009154:Mutation / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D058925:Receptors, Purinergic P2Y12 / Q000235:genetics*
chemical_list: D058925:Receptors, Purinergic P2Y12
keywords: P2Y12 receptor; Platelets; mutation