Identification and characterization of novel variations in platelet G-protein coupled receptor (GPCR) genes in patients historically diagnosed with type 1 von Willebrand disease: GPCR variations in type 1 von Willebrand disease

Jacqueline Stockley, Shaista P. Nisar, Vincenzo C. Leo, Essa Sabi, Margaret R. Cunningham, Jeroen C. Eikenboom, Stefan Lethagen, Reinhard Schneppenheim, Anne C. Goodeve, Steve P. Watson, Stuart J. Mundell, Martina E. Daly, on behalf of the GAPP study in collaboration with the MCMDM-1VWD study group

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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.
Original languageEnglish
Article numbere0143913
Number of pages15
JournalPLoS ONE
Issue number12
Publication statusPublished - 2 Dec 2015


  • platelets
  • G-protein coupled receptors
  • von Willebrand disease
  • platelet activation

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