TY - JOUR
T1 - 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
AU - Daly, ME
AU - Dawood, Ban
AU - Lester, WA
AU - Peake, IR
AU - Rodeghiero, F
AU - Goodeve, AC
AU - Makris, M
AU - Wilde, Johnathan
AU - Mumford, AD
AU - Watson, Steve
AU - Mundell, SJ
PY - 2009/4/1
Y1 - 2009/4/1
N2 - We investigated whether defects in the P2Y(12) ADP receptor gene (P2RY(12)) 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 mu M ADP, unlike the maximal, sustained aggregation observed in controls. The reduced response was associated with an approximate 50% reduction in binding of [H-3]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 [H-3]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. (Blood. 2009; 113: 4110-4113)
AB - We investigated whether defects in the P2Y(12) ADP receptor gene (P2RY(12)) 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 mu M ADP, unlike the maximal, sustained aggregation observed in controls. The reduced response was associated with an approximate 50% reduction in binding of [H-3]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 [H-3]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. (Blood. 2009; 113: 4110-4113)
U2 - 10.1182/blood-2008-11-190850
DO - 10.1182/blood-2008-11-190850
M3 - Article
C2 - 19237732
SN - 1528-0020
VL - 113
SP - 4110
EP - 4113
JO - Blood
JF - Blood
IS - 17
ER -