Identification and characterization of a novel P2Y 12 variant in a patient diagnosed with type 1 von Willebrand disease in the European MCMDM-1VWD study

We investigated whether defects in the P2Y(12) ADP receptor gene (P2RY12) contribute to the bleeding tendency in 92 index cases enrolled in the European MCMDM-1VWD study. A heterozygous mutation, predicting a lysine to glutamate (K174E) substitution in P2Y(12), was identified in one case with mild t...

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Bibliographic Details
Published in:Blood 2009-04, Vol.113 (17), p.4110-4113
Main Authors: Daly, Martina E, Dawood, Ban B, Lester, William A, Peake, Ian R, Rodeghiero, Francesco, Goodeve, Anne C, Makris, Michael, Wilde, Jonathan T, Mumford, Andrew D, Watson, Stephen P, Mundell, Stuart J
Format: Article
Language:English
Subjects:
Adenosine Diphosphate - metabolism
Animals
CHO Cells
Cricetinae
Cricetulus
Europe
Hemorrhage - complications
Hemorrhage - genetics
Hemorrhage - metabolism
Humans
Mutation - genetics
Platelet Activation - drug effects
Protein Binding
Purinergic P2 Receptor Agonists
Receptors, Purinergic P2 - genetics
Receptors, Purinergic P2 - metabolism
Receptors, Purinergic P2Y12
Societies, Medical
von Willebrand Diseases - complications
von Willebrand Diseases - diagnosis
von Willebrand Diseases - genetics
von Willebrand Diseases - metabolism
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Summary:We investigated whether defects in the P2Y(12) ADP receptor gene (P2RY12) contribute to the bleeding tendency in 92 index cases enrolled in the European MCMDM-1VWD study. A heterozygous mutation, predicting a lysine to glutamate (K174E) substitution in P2Y(12), was identified in one case with mild type 1 von Willebrand disease (VWD) and a VWF defect. Platelets from the index case and relatives carrying the K174E defect changed shape in response to ADP, but showed reduced and reversible aggregation in response to 10 muM ADP, unlike the maximal, sustained aggregation observed in controls. The reduced response was associated with an approximate 50% reduction in binding of [(3)H]2MeS-ADP to P2Y(12), whereas binding to the P2Y(1) receptor was normal. A hemagglutinin-tagged K174E P2Y(12) variant showed surface expression in CHO cells, markedly reduced binding to [(3)H]2MeS-ADP, and minimal ADP-mediated inhibition of forskolin-induced adenylyl cyclase activity. Our results provide further evidence for locus heterogeneity in type 1 VWD.
ISSN:1528-0020
DOI:10.1182/blood-2008-11-190850