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dc.contributor.authorBerrou, Eliane
dc.contributor.authorSoukaseum, Christelle
dc.contributor.authorFavier, Rémi
dc.contributor.authorAdam, Frédéric
dc.contributor.authorElaib, Ziane
dc.contributor.authorKauskot, Alexandre
dc.contributor.authorBordet, Jean-Claude
dc.contributor.authorBallerini, Paola
dc.contributor.authorLoyau, Stephane
dc.contributor.authorFeng, Miao
dc.contributor.authorDias, Karine
dc.contributor.authorMuheidli, Abbas
dc.contributor.authorGirault, Stephane
dc.contributor.authorNurden, Alan T
dc.contributor.authorTurro Bassols, Ernest
dc.contributor.authorOuwehand, Willem
dc.contributor.authorDenis, Cécile V
dc.contributor.authorJandrot-Perrus, Martine
dc.contributor.authorRosa, Jean-Philippe
dc.contributor.authorNurden, Paquita
dc.contributor.authorBryckaert, Marijke
dc.date.accessioned2018-11-23T00:32:37Z
dc.date.available2018-11-23T00:32:37Z
dc.date.issued2018-11-08
dc.identifier.issn0006-4971
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/285826
dc.description.abstractThe ephrin transmembrane receptor family of tyrosine kinases is involved in platelet function. We report the first EPHB2 variant affecting platelets in 2 siblings (P1 and P2) from a consanguineous family with recurrent bleeding and normal platelet counts. Whole-exome sequencing identified a c.2233C>T variant (missense p.R745C) of the EPHB2 gene. P1 and P2 were homozygous for this variant, while their asymptomatic parents were heterozygous. The p.R745C variant within the tyrosine kinase domain was associated with defects in platelet aggregation, αIIbβ3 activation, and granule secretion induced by G-protein-coupled receptor (GPCR) agonists and convulxin, as well as in thrombus formation on collagen under flow. In contrast, clot retraction, flow-dependent platelet adhesion, and spreading on fibrinogen were only mildly affected, indicating limited effects on αIIbβ3 outside-in signaling. Most importantly, Lyn, Syk, and FcRγ phosphorylation, the initial steps in glycoprotein VI (GPVI) platelet signaling were drastically impaired in the absence of platelet-platelet contact, indicating a positive role for EPHB2 in GPVI activation. Likewise platelet activation by PAR4-AP showed defective Src activation, as opposed to normal protein kinase C activity and Ca2+ mobilization. Overexpression of wild-type and R745C EPHB2 variant in RBL-2H3 (rat basophilic leukemia) cells stably expressing human GPVI confirmed that EPHB2 R745C mutation impaired EPHB2 autophosphorylation but had no effect on ephrin ligand-induced EPHB2 clustering, suggesting it did not interfere with EPHB2-ephrin-mediated cell-to-cell contact. In conclusion, this novel inherited platelet disorder affecting EPHB2 demonstrates this tyrosine kinase receptor plays an important role in platelet function through crosstalk with GPVI and GPCR signaling.
dc.format.mediumPrint-Electronic
dc.languageeng
dc.publisherAmerican Society of Hematology
dc.subjectBlood Platelets
dc.subjectHumans
dc.subjectReceptor, EphB2
dc.subjectPlatelet Membrane Glycoproteins
dc.subjectPlatelet Glycoprotein GPIIb-IIIa Complex
dc.subjectPedigree
dc.subjectSignal Transduction
dc.subjectPlatelet Adhesiveness
dc.subjectPlatelet Activation
dc.subjectPlatelet Aggregation
dc.subjectMutation, Missense
dc.subjectAdolescent
dc.subjectChild
dc.subjectFemale
dc.subjectMale
dc.subjectYoung Adult
dc.titleA mutation of the human EPHB2 gene leads to a major platelet functional defect.
dc.typeArticle
prism.endingPage2077
prism.issueIdentifier19
prism.publicationDate2018
prism.publicationNameBlood
prism.startingPage2067
prism.volume132
dc.identifier.doi10.17863/CAM.33170
dcterms.dateAccepted2018-09-08
rioxxterms.versionofrecord10.1182/blood-2018-04-845644
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.licenseref.startdate2018-11
dc.contributor.orcidKauskot, Alexandre [0000-0002-4064-8114]
dc.contributor.orcidTurro Bassols, Ernest [0000-0002-1820-6563]
dc.contributor.orcidOuwehand, Willem [0000-0002-7744-1790]
dc.contributor.orcidRosa, Jean-Philippe [0000-0001-7342-0389]
dc.contributor.orcidBryckaert, Marijke [0000-0003-3398-0976]
dc.identifier.eissn1528-0020
rioxxterms.typeJournal Article/Review
rioxxterms.freetoread.startdate2019-11-30


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