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A gain of function variant in RGS18 candidate for a familial mild bleeding syndrome

dc.rights.licenseopenen_US
dc.contributor.authorVAYNE, Caroline
dc.contributor.authorROUX, Maguelonne
dc.contributor.authorGRUEL, Yves
dc.contributor.authorPOGGI, Marjorie
dc.contributor.authorPOUPLARD, Claire
dc.contributor.authorPEIRETTI, Franck
hal.structure.identifierBordeaux population health [BPH]
dc.contributor.authorTREGOUET, David-Alexandre
dc.contributor.authorNURDEN, Paquita
dc.contributor.authorALESSI, Marie-Christine
dc.date.accessioned2024-11-26T08:56:32Z
dc.date.available2024-11-26T08:56:32Z
dc.date.issued2024-10-23
dc.identifier.issn1538-7836en_US
dc.identifier.urihttps://oskar-bordeaux.fr/handle/20.500.12278/203481
dc.description.abstractEnInherited platelet diseases are bleeding disorders characterized by either defects in platelet count or platelet function, the latter being less common and very heterogeneous. Numerous gene variants associated with abnormal receptors, granules, and signaling pathways have been reported. Despite significant advancements in our understanding, many patients still lack a precise diagnosis. To identify the genetic basis of a novel mild bleeding syndrome in a family exhibiting a selective defect of platelet aggregation. Our study included 6 family members across 3 generations who displayed reduced platelet aggregation in response to adenosine diphosphate, protease-activated receptor 1-activating peptide, arachidonic acid, and epinephrine but not collagen. Platelet morphology, granule content, and expression of major surface glycoproteins were all found to be normal. Whole exome sequencing was performed for affected and nonaffected family members. We identified RGS18, which encodes the regulator of G protein signaling (RGS) 18, as a candidate gene for the platelet function defect observed in this family. The RGS18 protein serves as a crucial negative regulator of G protein-coupled receptor signaling and coordinates the signaling pathways of natural platelet inhibitors. The heterozygous RGS18 c.643C>T, p.Arg215∗ variant was found to cosegregate among all 6 affected subjects. Truncation at Arg215 removes the S216 and S218 phosphorylation sites, which are crucial regulatory domains for RGS18 activation. The impaired platelet function is thought to arise from excessive platelet downregulation due to constitutive activation of RGS18, resulting from a loss of association of the truncated form with the 14-3-3 protein.
dc.language.isoENen_US
dc.subject.enGTP-Binding Proteins
dc.subject.enBlood Platelets
dc.subject.enExome Sequencing
dc.subject.enHemorrhage
dc.subject.enPlatelet Function Tests
dc.title.enA gain of function variant in RGS18 candidate for a familial mild bleeding syndrome
dc.title.alternativeJ Thromb Haemosten_US
dc.typeArticle de revueen_US
dc.identifier.doi10.1016/j.jtha.2024.10.016en_US
dc.subject.halSciences du Vivant [q-bio]/Santé publique et épidémiologieen_US
dc.identifier.pubmed39454878en_US
bordeaux.journalJournal of Thrombosis and Haemostasisen_US
bordeaux.hal.laboratoriesBordeaux Population Health Research Center (BPH) - UMR 1219en_US
bordeaux.institutionUniversité de Bordeauxen_US
bordeaux.institutionINSERMen_US
bordeaux.teamELEANOR_BPHen_US
bordeaux.peerReviewedouien_US
bordeaux.inpressnonen_US
bordeaux.import.sourcepubmed
hal.identifierhal-04804033
hal.version1
hal.date.transferred2024-11-26T08:56:35Z
hal.popularnonen_US
hal.audienceInternationaleen_US
hal.exporttrue
workflow.import.sourcepubmed
dc.rights.ccPas de Licence CCen_US
bordeaux.COinSctx_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.jtitle=Journal%20of%20Thrombosis%20and%20Haemostasis&rft.date=2024-10-23&rft.eissn=1538-7836&rft.issn=1538-7836&rft.au=VAYNE,%20Caroline&ROUX,%20Maguelonne&GRUEL,%20Yves&POGGI,%20Marjorie&POUPLARD,%20Claire&rft.genre=article


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