Document Detail

Platelet dysfunction associated with the novel Trp29Cys thromboxane A₂ receptor variant.
MedLine Citation:
PMID:  23279270     Owner:  NLM     Status:  MEDLINE    
BACKGROUND: Genetic variations that affect the structure of the thromboxane A2 receptor (TP receptor) provide insights into the function of this key platelet and vascular receptor, but are very rare in unselected populations.
OBJECTIVES: To determine the functional consequences of the TP receptor Trp29Cys (W29C) substitution.
PATIENTS/METHODS: We performed a detailed phenotypic analysis of an index case (P1) with reduced platelet aggregation and secretion responses to TP receptor pathway activators, and a heterozygous TP receptor W29C substitution. An analysis of the variant W29C TP receptor expressed in heterologous cells was performed.
RESULTS: Total TP receptor expression in platelets from P1 was similar to that of controls, but there was reduced maximum binding and reduced affinity of binding to the TP receptor antagonist [(3) H]SQ29548. HEK293 cells transfected with W29C TP receptor cDNA showed similar total TP receptor expression to wild-type (WT) controls. However, the TP receptor agonist U46619 was less potent at inducing rises in cytosolic free Ca(2+) in HEK293 cells expressing the W29C TP receptor than in WT controls, indicating reduced receptor function. Immunofluorescence microscopy and cell surface ELISA showed intracellular retention and reduced cell surface expression of the W29C TP receptor in HEK293 cells. Consistent with the platelet phenotype, both maximum binding and the affinity of binding of [(3) H]SQ29548 to the W29C TP receptor were reduced compared to WT controls.
CONCLUSION: These findings extend the phenotypic description of the very rare disorder TP receptor deficiency, and show that the W29C substitution reduces TP receptor function by reducing surface receptor expression and by disrupting ligand binding.
A D Mumford; S Nisar; L Darnige; M L Jones; C Bachelot-Loza; S Gandrille; F Zinzindohoue; A-M Fischer; S J Mundell; P Gaussem;
Publication Detail:
Type:  Case Reports; Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Journal of thrombosis and haemostasis : JTH     Volume:  11     ISSN:  1538-7836     ISO Abbreviation:  J. Thromb. Haemost.     Publication Date:  2013 Mar 
Date Detail:
Created Date:  2013-03-15     Completed Date:  2013-08-30     Revised Date:  2014-02-20    
Medline Journal Info:
Nlm Unique ID:  101170508     Medline TA:  J Thromb Haemost     Country:  England    
Other Details:
Languages:  eng     Pagination:  547-54     Citation Subset:  IM    
Copyright Information:
© 2012 International Society on Thrombosis and Haemostasis.
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MeSH Terms
15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / pharmacology
Blood Coagulation Disorders / blood*,  genetics
Blood Platelets / drug effects,  metabolism*
Calcium / blood
Enzyme-Linked Immunosorbent Assay
Genetic Predisposition to Disease
Genetic Variation*
HEK293 Cells
Hydrazines / metabolism
Microscopy, Fluorescence
Middle Aged
Platelet Aggregation* / drug effects,  genetics
Radioligand Assay
Receptors, Thromboxane A2, Prostaglandin H2 / agonists,  blood*,  deficiency,  genetics
Grant Support
FS/11/49/28751//British Heart Foundation; PG/06/038//British Heart Foundation; RG/09/007//British Heart Foundation
Reg. No./Substance:
0/Hydrazines; 0/Ligands; 0/Receptors, Thromboxane A2, Prostaglandin H2; 76898-47-0/15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; 98299-61-7/SQ 29548; SY7Q814VUP/Calcium

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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