Inherited dysfunctional platelet P2Y12 receptor mutations associated with bleeding disorders

Anna Lecchi; Eti A. Femia; Silvia Paoletta; Arnaud Dupuis; Philippe Ohlmann; Christian Gachet; Kenneth A. Jacobson; Katharina Machura; Gian M. Podda; Barbara Zieger; Marco Cattaneo

doi:10.5482/HAMO-16-03-0010

Hämostaseologie, Table of Contents

Hamostaseologie 2016; 36(04): 279-283
DOI: 10.5482/HAMO-16-03-0010

Original article

Schattauer GmbH

Inherited dysfunctional platelet P2Y₁₂ receptor mutations associated with bleeding disorders

Angeborene dysfunktionale thrombozytäre P2Y₁₂-Rezeptormutationen mit assoziierten Blutungs symptomen

Anna Lecchi

¹Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Ca’ Granda – Ospedale Maggiore Policlinico, Milan, Italy

,

Eti A. Femia

²Divisione di Medicina 3, ASST Santi Paolo e Carlo, Dipartimento di Scienze della Salute - Università degli Studi di Milano, Milan, Italy

,

Silvia Paoletta

³Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD

,

Arnaud Dupuis

⁴Unite Mixte de Recherche_S949, Inserm, Université de Strasbourg, Etablissement Français du Sang-Alsace-Lorraine-Champagne-Ardennes, Strasbourg, France

,

Philippe Ohlmann

⁴Unite Mixte de Recherche_S949, Inserm, Université de Strasbourg, Etablissement Français du Sang-Alsace-Lorraine-Champagne-Ardennes, Strasbourg, France

,

Christian Gachet

⁴Unite Mixte de Recherche_S949, Inserm, Université de Strasbourg, Etablissement Français du Sang-Alsace-Lorraine-Champagne-Ardennes, Strasbourg, France

,

Kenneth A. Jacobson

³Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD

,

Katharina Machura

⁵Department of Pediatrics and Adolescent Medicine, Division of Pediatric Hematology and Oncology, Medical Center – University of Freiburg, Faculty of Medicine, Germany

,

Gian M. Podda

²Divisione di Medicina 3, ASST Santi Paolo e Carlo, Dipartimento di Scienze della Salute - Università degli Studi di Milano, Milan, Italy

,

Barbara Zieger

⁵Department of Pediatrics and Adolescent Medicine, Division of Pediatric Hematology and Oncology, Medical Center – University of Freiburg, Faculty of Medicine, Germany

,

Marco Cattaneo

¹Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Ca’ Granda – Ospedale Maggiore Policlinico, Milan, Italy

› Author Affiliations

Abstract

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

Full Text

References

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