A large alteration in the human platelet glycoprotein Illa (integrin β<sub>3</sub>) gene associated with Glanzmann's thrombasthenia

Djaffar, Isabelle; Caen, Jacques P.; Rosa, Jean‐Philippe

doi:10.1093/hmg/2.12.2183

Cited by 24 publications

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“…GP IIb and GP IIIa are the products of separate genes and in vitro studies indicate that the heterodimer -structure and assembly are essential to ensure normal GP IIb-IIIa intracellular transport and expression on the platelet surface. Heterogeneity of the molecular basis of GT has recently been shown (Burck et al, 1991;Gu et al, 1993;Simsek et al, 1993;Djaffar et al, 1993;Poncz et al, 1994;Iwamoto et al, 1994). Therefore, it could be of help to have a simple test for detection of the possibly implicated defective gene before any molecular investigation, thus allowing research focusing only on the GP IIb or IIIa gene.…”

Section: Discussionmentioning

confidence: 99%

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Platelet phenotyping in carriers for Glanzmann's thrombasthenia: a simple screening test for assessment of the molecular defect

Clemenceau¹,

Schlegel

Lecompte

et al. 1995

Transfusion Medicine

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Glanzmann's thrombasthenia (GT) is a recessive autosomal bleeding disorder characterized by the abnormality of aggregation due to a platelet glycoprotein (GP) IIb-IIIa deficiency or a dysfunctional complex. Molecular abnormalities have been localized on the gene coding for GP IIb or IIIa. The aim of our work was an attempt to obtain indirectly information on the putative localization of the molecular defect in patients with GT type I or II by the determination of the HPA-1 (GP IIIa) and HPA-3 (GP IIb) alloantigenic systems' expression in GT carriers. If GT results from a defective GP IIb gene, a GT carrier would appear homozygous for HPA-3 by serology, because the normal gene product will be expressed while the abnormal GP IIb gene product will not be present. Conversely, if the abnormality is in the GP IIIa gene, such an individual would appear homozygous for HPA-1. Therefore, the heterozygous status for HPA would result from the normal expression of the two genes for the considered alloantigenic system. Among the four families studied with informative members, our presumptions were strengthened by the preliminary genetic results in one family showing a mutation in the GP IIb gene. Thus, serology could be a simple screening test for the possible defective gene responsible for GT allowing molecular investigation focusing only on GP IIb or IIIa gene.

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Section: Discussionmentioning

confidence: 99%

“…Gu et af., 1993;Poncz et al, 1994;Iwamoto et al, 1994), deletions (e.g. Burck et al, 1991;Newman et af., 1991;Simsek et al, 1993) and gene insertions (Djaffar et al, 1993).…”

Section: Introductionmentioning

confidence: 99%

Platelet phenotyping in carriers for Glanzmann's thrombasthenia: a simple screening test for assessment of the molecular defect

Clemenceau¹,

Schlegel

Lecompte

et al. 1995

Transfusion Medicine

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“…Patients and Normal Donors-The two patients with Glanzmann's thrombasthenia studied herein have been described previously (20,21). They are characterized by an absence of platelet aggregation and total absence of fibrinogen binding.…”

Section: Methodsmentioning

confidence: 99%

Negative Regulation of Mitogen-activated Protein Kinase Activation by Integrin αIIbβ3 in Platelets

Nadal

Lévy-Toledano

Grelac

et al. 1997

Journal of Biological Chemistry

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Activation of the mitogen-activated protein (MAP) kinase pathway in nucleated cells is dependent on both growth factor receptors and integrins engaged in cell adhesion. Human platelets are an interesting model for studying cell adhesion and the involvement of integrin engagement on extracellular signal-regulated kinase (ERK) activation, independently from the nuclear-DNA signal pathway. Maximal phosphorylation and activity of ERK2 occurred late during thrombin-induced platelet aggregation (90 s and later), an ␣ IIb ␤ 3 integrin-dependent event. Surprisingly, ␣ IIb ␤ 3 inhibition by the RGDS ligand peptide, or (Fab) 2 fragments of the AP-2 monoclonal antibody, resulted in a 2-fold enhancement in ERK2 phosphorylation and activity. A similar 2-fold enhancement of ERK2 activation was observed in thrombasthenic platelets which are defective in ␣ IIb ␤ 3 and do not aggregate. This suggests that ERK2 activation in thrombin-induced platelet aggregation is dependent on thrombin rather than on ␣ IIb ␤ 3 and is down-regulated by ␣ IIb ␤ 3 engaged in ligand (fibrinogen) binding and/or aggregation. Finally, in the absence of stirring which allows fibrinogen binding to ␣ IIb ␤ 3 but prevents aggregation, ERK2 was again overactivated. This overactivation appears to be consecutive to inhibition of aggregation itself and to ␣ IIb ␤ 3 ligand binding. We conclude that in platelets, ␣ IIb ␤ 3 engaged in aggregation down-regulates thrombin-induced ERK2 activation. To our knowledge, this is the first report of a down-regulation of the MAP kinase pathway by integrin engagement.

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“…Mutations include splice defects and stop codons that interfere with or abrogate mRNA synthesis, whereas small deletions (del) and insertions (ins) with frameshifts are common. Large gene deletions are rare [Burk et al, 1991;Djaffar et al, 1993;Rosenberg et al, 1997]. Mostly, they affect αIIbβ3 synthesis or maturation; however, missense mutations allowing partial or normal αIIbβ3 expression have helped identify functional domains [Loftus et al, 1990;Bajt et al, 1992;Chen et al, 1992].…”

Section: Introductionmentioning

confidence: 99%

Expanding the Mutation Spectrum Affecting αIIbβ3 Integrin in Glanzmann Thrombasthenia: Screening of theITGA2BandITGB3Genes in a Large International Cohort

et al. 2015

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We report the largest international study on Glanzmann thrombasthenia (GT), an inherited bleeding disorder where defects of the ITGA2B and ITGB3 genes cause quantitative or qualitative defects of the αIIbβ3 integrin, a key mediator of platelet aggregation. Sequencing of the coding regions and splice sites of both genes in members of 76 affected families identified 78 genetic variants (55 novel) suspected to cause GT. Four large deletions or duplications were found by quantitative real-time PCR. Families with mutations in either gene were indistinguishable in terms of bleeding severity that varied even among siblings. Families were grouped into type I and the rarer type II or variant forms with residual αIIbβ3 expression. Variant forms helped identify genes encoding proteins mediating integrin activation. Splicing defects and stop codons were common for both ITGA2B and ITGB3 and essentially led to a reduced or absent αIIbβ3 expression; included was a heterozygous c.1440-13_c.1440-1del in intron 14 of ITGA2B causing exon skipping in seven unrelated families. Molecular modeling revealed how many missense mutations induced subtle changes in αIIb and β3 domain structure across both subunits, thereby interfering with integrin maturation and/or function. Our study extends knowledge of GT and the pathophysiology of an integrin.

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A large alteration in the human platelet glycoprotein Illa (integrin β₃) gene associated with Glanzmann's thrombasthenia

Cited by 24 publications

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Platelet phenotyping in carriers for Glanzmann's thrombasthenia: a simple screening test for assessment of the molecular defect

Platelet phenotyping in carriers for Glanzmann's thrombasthenia: a simple screening test for assessment of the molecular defect

Negative Regulation of Mitogen-activated Protein Kinase Activation by Integrin αIIbβ3 in Platelets

Expanding the Mutation Spectrum Affecting αIIbβ3 Integrin in Glanzmann Thrombasthenia: Screening of theITGA2BandITGB3Genes in a Large International Cohort

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A large alteration in the human platelet glycoprotein Illa (integrin β3) gene associated with Glanzmann's thrombasthenia

Cited by 24 publications

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Platelet phenotyping in carriers for Glanzmann's thrombasthenia: a simple screening test for assessment of the molecular defect

Platelet phenotyping in carriers for Glanzmann's thrombasthenia: a simple screening test for assessment of the molecular defect

Negative Regulation of Mitogen-activated Protein Kinase Activation by Integrin αIIbβ3 in Platelets

Expanding the Mutation Spectrum Affecting αIIbβ3 Integrin in Glanzmann Thrombasthenia: Screening of theITGA2BandITGB3Genes in a Large International Cohort

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A large alteration in the human platelet glycoprotein Illa (integrin β₃) gene associated with Glanzmann's thrombasthenia