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αIIbβ3 variants in ten families with autosomal dominant macrothrombocytopenia: Expanding the mutational and clinical spectrum

2020-12-04Journal article Open access
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dc.contributor.authorMorais, Sara
dc.contributor.authorOliveira, Jorge
dc.contributor.authorLau, Catarina
dc.contributor.authorPereira, Mónica
dc.contributor.authorGonçalves, Marta
dc.contributor.authorMonteiro, Catarina
dc.contributor.authorGonçalves, Ana
dc.contributor.authorMatos, Rui
dc.contributor.authorSampaio, Marco
dc.contributor.authorCruz, Eugénia
dc.contributor.authorFreitas, Inês
dc.contributor.authorSantos, Rosário
dc.contributor.authorLima, Margarida
dc.date.accessioned2022-07-11T13:20:17Z
dc.date.available2022-07-11T13:20:17Z
dc.date.issued2020-12-04
dc.description.abstractBackground: Rare pathogenic variants in either the ITGA2B or ITGB3 genes have been linked to autosomal dominant macrothrombocytopenia associated with abnormal platelet production and function, deserving the designation of Glanzmann Thrombasthenia-Like Syndrome (GTLS) or ITGA2B/ITGB3-related thrombocytopenia. Objectives: To describe a series of patients with familial macrothrombocytopenia and decreased expression of αIIbβ3 integrin due to defects in the ITGA2B or ITGB3 genes. Methods: We reviewed the clinical and laboratory records of 10 Portuguese families with GTLS (33 patients and 11 unaffected relatives), including the functional and genetic defects. Results: Patients had absent to moderate bleeding, macrothrombocytopenia, low αIIbβ3 expression, impaired platelet aggregation/ATP release to physiological agonists and low expression of activation-induced binding sites on αIIbβ3 (PAC-1) and receptor-induced binding sites on its ligand (bound fibrinogen), upon stimulation with TRAP-6 and ADP. Evidence for constitutive αIIbβ3 activation, occurred in 2 out of 9 patients from 8 families studied, but also in 2 out of 12 healthy controls. We identified 7 missense variants: 3 in ITGA2B (5 families), and 4 in ITGB3 (5 families). Three variants (αIIb: p.Arg1026Trp and p.Arg1026Gln and β3: p.Asp749His) were previously reported. The remaining (αIIb: p.Gly1007Val and β3: p.Thr746Pro, p.His748Pro and p.Arg760Cys) are new, expanding the αIIbβ3 defects associated with GTLS. The integration of the clinical and laboratory data allowed the identification of two GTLS subgroups, with distinct disease severity. Conclusions: Previously reported ITGA2B and ITGB3 variants related to thrombocytopenia were clustered in a confined region of the membrane-proximal cytoplasmic domains, the inner membrane clasp. For the first time, variants are reported at the outer membrane clasp, at the transmembrane domain of αIIb, and at the membrane distal cytoplasmic domains of β3. This is the largest single-center series of inherited macrothrombocytopenia associated with αIIbβ3 variants published to date.pt_PT
dc.description.sponsorshiphis study was supported by the Centro Hospitalar Universitário do Porto (CHUP)and by the Fórum Hematológico do Norte (FHN).The funders had no role in study design, data collection, and analysis, decision to publish, or preparation of the manuscript.pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationMorais S, Oliveira J, Lau C, et al. αIIbβ3 variants in ten families with autosomal dominant macrothrombocytopenia: Expanding the mutational and clinical spectrum. PLoS One. 2020;15(12):e0235136. doi:10.1371/journal.pone.0235136pt_PT
dc.identifier.doi10.1371/journal.pone.0235136pt_PT
dc.identifier.issn1932-6203
dc.identifier.urihttp://hdl.handle.net/10400.16/2692
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherPublic Library of Sciencept_PT
dc.relation.publisherversionhttps://journals.plos.org/plosone/article?id=10.1371/journal.pone.0235136pt_PT
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/pt_PT
dc.titleαIIbβ3 variants in ten families with autosomal dominant macrothrombocytopenia: Expanding the mutational and clinical spectrumpt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.citation.conferencePlaceUnited States of Americapt_PT
oaire.citation.issue12pt_PT
oaire.citation.startPagee0235136pt_PT
oaire.citation.titlePLOS ONEpt_PT
oaire.citation.volume15pt_PT
person.familyNameMorais
person.familyNameLau
person.familyNameMonteiro
person.familyNameGonçalves
person.familyNameSampaio
person.familyNameCruz
person.familyNameLima
person.givenNameSara
person.givenNameCatarina
person.givenNameCatarina
person.givenNameAna
person.givenNameMarco
person.givenNameEugénia
person.givenNameMargarida
person.identifier.ciencia-idE01B-61E1-B324
person.identifier.ciencia-idB81A-42B4-1433
person.identifier.ciencia-idEF1E-E533-D575
person.identifier.ciencia-id8410-F6C9-183F
person.identifier.orcid0000-0003-4266-4457
person.identifier.orcid0000-0001-8284-0588
person.identifier.orcid0000-0002-6659-4951
person.identifier.orcid0000-0002-3917-2323
person.identifier.orcid0000-0001-9171-003X
person.identifier.orcid0000-0002-4801-5047
person.identifier.orcid0000-0001-9702-5260
person.identifier.ridS-7466-2016
person.identifier.scopus-author-id7007053742
person.identifier.scopus-author-id7202143317
rcaap.rightsopenAccesspt_PT
rcaap.typearticlept_PT
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