| Autor: |
Stockley J; Department of Cardiovascular Science, University of Sheffield, Sheffield, United Kingdom., Nisar SP; School of Physiology and Pharmacology, University of Bristol, Bristol, United Kingdom., Leo VC; Department of Cardiovascular Science, University of Sheffield, Sheffield, United Kingdom., Sabi E; Department of Cardiovascular Science, University of Sheffield, Sheffield, United Kingdom., Cunningham MR; School of Physiology and Pharmacology, University of Bristol, Bristol, United Kingdom., Eikenboom JC; Department of Thrombosis and Hemostasis, Leiden University Medical Center, Leiden, The Netherlands., Lethagen S; National Haemophilia Center, University Hospital, Rigshospitalet, Copenhagen, Denmark., Schneppenheim R; Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany., Goodeve AC; Department of Cardiovascular Science, University of Sheffield, Sheffield, United Kingdom., Watson SP; Centre for Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom., Mundell SJ; School of Physiology and Pharmacology, University of Bristol, Bristol, United Kingdom., Daly ME; Department of Cardiovascular Science, University of Sheffield, Sheffield, United Kingdom. |
| Abstrakt: |
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. |
