Abstract
The clinical expression of type 1 von Willebrand disease may be modified by co-inheritance of other mild bleeding diatheses. We previously showed that mutations in the platelet P2Y12 ADP receptor gene (P2RY12) could contribute to the bleeding phenotype in patients with type 1 von Willebrand disease. Here we investigated whether variations in platelet G protein-coupled receptor genes other than P2RY12 also contributed to the bleeding phenotype. Platelet G protein-coupled receptor genes P2RY1, F2R, F2RL3, TBXA2R and PTGIR were sequenced in 146 index cases with type 1 von Willebrand disease and the potential effects of identified single nucleotide variations were assessed using in silico methods and heterologous expression analysis. Seven heterozygous single nucleotide variations were identified in 8 index cases. Two single nucleotide variations were detected in F2R; a novel c.-67G>C transversion which reduced F2R transcriptional activity and a rare c.1063C>T transition predicting a p.L355F substitution which did not interfere with PAR1 expression or signalling. Two synonymous single nucleotide variations were identified in F2RL3 (c.402C>G, p.A134 =; c.1029 G>C p.V343 =), both of which introduced less commonly used codons and were predicted to be deleterious, though neither of them affected PAR4 receptor expression. A third single nucleotide variation in F2RL3 (c.65 C>A; p.T22N) was co-inherited with a synonymous single nucleotide variation in TBXA2R (c.6680 C>T, p.S218 =). Expression and signalling of the p.T22N PAR4 variant was similar to wild-type, while the TBXA2R variation introduced a cryptic splice site that was predicted to cause premature termination of protein translation. The enrichment of single nucleotide variations in G protein-coupled receptor genes among type 1 von Willebrand disease patients supports the view of type 1 von Willebrand disease as a polygenic disorder.
Highlights
Type 1 von Willebrand disease is a highly heterogeneous bleeding disorder that is characterised by a partial quantitative deficiency of functionally normal von Willebrand factor (VWF) [1]
We have previously identified two mutations in the platelet P2Y12 ADP receptor gene (P2RY12) in patients with type 1 VWD who were recruited through the European Molecular and Clinical Markers for the Diagnosis and Management of type 1 von Willebrand Disease (MCMDM1VWD) study and showed that they could contribute to the bleeding phenotype in these patients [7,8]
We have investigated the possible contribution of variations in the genes encoding these five GPCRs, to the bleeding tendency of patients diagnosed with type 1 VWD and recruited to the MCMDM-1VWD study
Summary
Type 1 von Willebrand disease is a highly heterogeneous bleeding disorder that is characterised by a partial quantitative deficiency of functionally normal von Willebrand factor (VWF) [1]. The search for genetic factors that may explain the bleeding tendency in the 35% of patients with no recognisable VWF mutations has focused mainly on the identification of modifier genes that have a role in influencing plasma VWF levels. Given the role of VWF in primary haemostasis, and the clinical similarities of patients with type 1 VWD and platelet bleeding disorders, the bleeding tendency in patients with type 1 VWD may be influenced by variation in the genes encoding the receptors and signalling proteins that mediate platelet adhesion and aggregation. We have previously identified two mutations in the platelet P2Y12 ADP receptor gene (P2RY12) in patients with type 1 VWD who were recruited through the European Molecular and Clinical Markers for the Diagnosis and Management of type 1 von Willebrand Disease (MCMDM1VWD) study and showed that they could contribute to the bleeding phenotype in these patients [7,8]
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