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Human CalDAG-GEFI gene (RASGRP2) mutation affects platelet function and causes severe bleeding.

Authors: Matthias M. Canault, Dorsaf D. Ghalloussi, Charlotte C. Grosdidier, Marie M. Guinier, Claire C. Perret, Nadjim N. Chelghoum, Marine M. Germain, Hana H. Raslova, Franck F. Peiretti, Pierre E PE. Morange, Noemie N. Saut, Xavier X. Pillois, Alan T AT. Nurden, François F. Cambien, Anne A. Pierres, Timo K TK. van den Berg, Taco W TW. Kuijpers, Marie-Christine MC. Alessi, David-Alexandre DA. Tregouet
Published: 06/23/2014, The Journal of experimental medicine


The nature of an inherited platelet disorder was investigated in three siblings affected by severe bleeding. Using whole-exome sequencing, we identified the culprit mutation (cG742T) in the RAS guanyl-releasing protein-2 (RASGRP2) gene coding for calcium- and DAG-regulated guanine exchange factor-1 (CalDAG-GEFI). Platelets from individuals carrying the mutation present a reduced ability to activate Rap1 and to perform proper αIIbβ3 integrin inside-out signaling. Expression of CalDAG-GEFI mutant in HEK293T cells abolished Rap1 activation upon stimulation. Nevertheless, the PKC- and ADP-dependent pathways allow residual platelet activation in the absence of functional CalDAG-GEFI. The mutation impairs the platelet's ability to form thrombi under flow and spread normally as a consequence of reduced Rac1 GTP-binding. Functional deficiencies were confined to platelets and megakaryocytes with no leukocyte alteration. This contrasts with the phenotype seen in type III leukocyte adhesion deficiency caused by the absence of kindlin-3. Heterozygous did not suffer from bleeding and have normal platelet aggregation; however, their platelets mimicked homozygous ones by failing to undergo normal adhesion under flow and spreading. Rescue experiments on cultured patient megakaryocytes corrected the functional deficiency after transfection with wild-type RASGRP2. Remarkably, the presence of a single normal allele is sufficient to prevent bleeding, making CalDAG-GEFI a novel and potentially safe therapeutic target to prevent thrombosis.

© 2014 Canault et al.
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