A variant of Glanzmann's thrombasthenia with abnormal glycoprotein IIb-IIIa complexes in the platelet membrane.

Nurden, Alan T.; Rosa, Jean‐Philippe; Fournier, Dominique; Legrand, Chantal; Didry, Dominique; Parquet, A.; Pidard, Dominique

doi:10.1172/jci112907

Cited by 76 publications

(47 citation statements)

References 38 publications

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“…In contrast, only the C177A mutation affected AP2, 7E3, and LM609 binding, while the C273A mutation had no inhibitory effect. (45,46), D119Y (47,48), and S162L (49). Our results suggest that the structural integrity of the two insertions of the I-like domain, in close contact with the ␣ subunit ␤ propeller domain, is important for stable ␣␤ heterodimerization of ␣ IIb ␤ 3 .…”

Section: Discussionmentioning

confidence: 99%

Probing Conformational Changes in the I-like Domain and the Cysteine-rich Repeat of Human β3 Integrins following Disulfide Bond Disruption by Cysteine Mutations

Chen

Melchior

Brons

et al. 2001

Journal of Biological Chemistry

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Section: Discussionmentioning

confidence: 99%

Probing Conformational Changes in the I-like Domain and the Cysteine-rich Repeat of Human β3 Integrins following Disulfide Bond Disruption by Cysteine Mutations

Chen

Melchior

Brons

et al. 2001

Journal of Biological Chemistry

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“…by guest www.bloodjournal.org From and 1 from Australia; all with moderate to severe bleeding, Table 1) possessed homozygous substitutions of Arg214 (Arg214Gln or Trp) in the ADMIDAS (adjacent to MIDAS) Ca 2ϩ -binding domain of ␤3 (Figure 2). [32][33][34][35][36][37] These substitutions made ␣IIb␤3 unstable, sensitive to divalent-cation chelation, and unable to bind Fg; they not only prevent aggregation, they also stop clot retraction and platelet Fg capture, reinforcing the idea that ␣IIb␤3 is required for each task. Although 3-dimensional structures of the unactivated and activated (Fg-binding) forms of ␣IIb␤3 have been defined and key residues essential for Fg binding located on both the ␤3 MIDAS and ADMIDAS domains, 3,4,36,37 different structural requirements may be required for clot retraction and Fg trafficking.…”

Section: Mutations Affecting Extracellular Domains Of ␤3mentioning

confidence: 99%

Glanzmann thrombasthenia: a review of ITGA2B and ITGB3 defects with emphasis on variants, phenotypic variability, and mouse models

Nurden

Fiore

Pillois

2011

Blood

205

269

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Characterized by mucocutaneous bleeding arising from a lack of platelet aggregation to physiologic stimuli, Glanzmann thrombasthenia (GT) is the archetypeinherited disorder of platelets. Transmitted by autosomal recessive inheritance, platelets in GT have quantitative or qualitative deficiencies of the fibrinogen receptor, ␣IIb␤3, an integrin coded by the ITGA2B and ITGB3 genes. Despite advances in our understanding of the disease, extensive phenotypic variability with respect to severity and intensity of bleeding remains poorly understood. Importantly, genetic defects of ITGB3 also potentially affect other tissues, for ␤3 has a wide tissue distribution when present as ␣v␤3 (the vitronectin receptor). We now look at the repertoire of ITGA2B and ITGB3 gene defects, reexamine the relationship between phenotype and genotype, and review integrin structure in the many variant forms. Evidence for modifications in platelet production is assessed, as is the multifactorial etiology of the clinical expression of the disease. Reports of cardiovascular disease and deep vein thrombosis, cancer, brain disease, bone disorders, and pregnancy defects in GT are discussed in the context of the results obtained for mouse models where nonhemostatic defects of ␤3-deficiency or nonfunction are being increasingly described. (Blood. 2011;118(23):5996-6005) IntroductionGlanzmann thrombasthenia (GT) is the most frequently encountered inherited disorder of platelet function. [1][2][3] Patients have a lifelong hemorrhagic syndrome typically characterized by episodes of spontaneous mucocutaneous bleeding. Platelets fail to aggregate in response to stimuli because they lack or have nonfunctional ␣IIb␤3 integrin (formerly known as GPIIb-IIIa). Resting normal platelets are suspected to have ␣IIb␤3 in a bent conformation; when platelets are stimulated, the integrin straightens in parallel to the exposure of determinants essential for the binding of fibrinogen (Fg) or other soluble adhesive proteins. 3,4 The latter assure aggregation by cross-linking adjacent platelets, a process that cannot occur in GT. Elucidation of this pathway led to the development of integrin-blocking drugs that are strong inhibitors of arterial thrombosis, thereby increasing interest in the clinical manifestations of GT. 3,4 Platelet ␣IIb␤3 also transmits the forces generated by intracellular cytoskeletal proteins during clot contraction and platelet spreading, processes that also fail in patients lacking adequate amounts of functional integrin.Although the GT phenotype is well defined, bleeding severity differs considerably between affected persons, even within the same family or ethnic group. 1,2 In this review, we discuss phenotypic variability, present variant types, and identify possible additional effects associated with ␤3 deletion, for although ␣IIb is largely restricted to the megakaryocyte (MK) lineage, ␤3 is much more widespread in its tissue distribution occurring as ␣v␤3, the vitronectin receptor. 5,6 Data for patients will be compared with those obtained for...

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“…20 Among point mutations occurring in the GPIIIa gene, some alter the function of the GPIIb-IIIa complex by disrupting ligand binding sites (Cam or Asp119Tyr, ET or Arg214Gln, and Stras I and CM or Arg214Trp variants). [21][22][23][24][25] Others in the cytoplasmic tail result in the integrin's being locked in a low-affinity state (Ser752Pro and Arg724Ter mutations). 26,27 In contrast to naturally occurring mutations, GPIIIa mutations leading to gain of function have been experimentally induced and studied in recombinant GPIIb-IIIa-transfected cells.…”

Section: Introductionmentioning

confidence: 99%

A point mutation in the cysteine-rich domain of glycoprotein (GP) IIIa results in the expression of a GPIIb-IIIa (αIIbβ3) integrin receptor locked in a high-affinity state and a Glanzmann thrombasthenia–like phenotype

Ruiz

Liu

Sun

et al. 2001

Blood

105

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This article reports a Glanzmann thrombasthenia (GT) patient, N.M., with a point mutation in the third cysteine-rich repeat of ␤3-integrin or platelet glycoprotein (GP) IIIa, leading to the expression of a constitutively activated fibrinogen receptor. The diagnosis of GT was based on a severely reduced platelet-aggregation response to a series of agonists and approximately 20% of surface-expressed GPIIb-IIIa. The patient's GPIIb-IIIa constitutively expressed epitopes recognized by antibodies to ligandinduced binding sites (LIBS) and also spontaneously bound the fibrinogen-mimetic antibody, PAC-1. Furthermore, significant amounts of bound fibrinogen were detected on his platelets ex vivo. No signs of platelet activation were observed on sections of unstimulated platelets from N.M. by electron microscopy. Immunogold labeling highlighted the presence of surface-bound fibrinogen but revealed platelet heterogeneity with regard to the surface density. When the patient's platelets were stimulated by thrombin-receptor activating peptide, amounts of surface-expressed GPIIb-IIIa increased and the aggregation response improved, although it failed to normalize. Platelets from N.M. were able to adhere and spread on immobilized fibrinogen. Sequence analysis of genomic DNA from N.M. revealed a homozygous g1776T>C mutation in GPIIIa, leading to a Cys560Arg amino acid substitution. A stable Chinese hamster ovary (CHO) cell line was prepared expressing surface GPIIbArg560IIIa. Like platelets from the patient, GPIIb-Arg560IIIa-transfected CHO cells constitutively bound LIBS antibodies and PAC-1. They also showed an enhanced ability to adhere on surface-bound fibrinogen. Overall, these data demonstrate that a gain-of-function mutation can still be associated with a thrombasthenic phenotype even though platelets show spontaneous fibrinogen binding. IntroductionIntegrins are heterodimeric transmembrane proteins that mediate cell adhesion and cell migration. [1][2][3] They are involved in numerous fundamental biologic processes, including development, homing, inflammation, angiogenesis, and wound healing, all processes in which integrin function is subjected to a highly sophisticated regulation. [4][5][6][7][8] The platelet fibrinogen receptor, the ␣ IIb ␤ 3 integrin (glycoprotein [GP] IIb-IIIa), has constituted an ideal model for the study of an integrin's role in cell contact interactions. [9][10][11][12][13] This receptor has the capacity to shift through conformational changes from a low-affinity state unable to bind macromolecular ligands to a ligand-competent state on activated platelets. This process of affinity modulation is an essential part of integrin function. Furthermore, ligand binding to GPIIb-IIIa itself modifies the conformation of this integrin, exposing neoepitopes known as ligand-induced binding sites (LIBS) and leading to postreceptor occupancy events such as clustering of GPIIb-IIIa complexes, generation of secondary signals, and cytoskeletal rearrangement, all of which contribute to maximal platelet aggregatio...

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A variant of Glanzmann's thrombasthenia with abnormal glycoprotein IIb-IIIa complexes in the platelet membrane.

Cited by 76 publications

References 38 publications

Probing Conformational Changes in the I-like Domain and the Cysteine-rich Repeat of Human β3 Integrins following Disulfide Bond Disruption by Cysteine Mutations

Probing Conformational Changes in the I-like Domain and the Cysteine-rich Repeat of Human β3 Integrins following Disulfide Bond Disruption by Cysteine Mutations

Glanzmann thrombasthenia: a review of ITGA2B and ITGB3 defects with emphasis on variants, phenotypic variability, and mouse models

A point mutation in the cysteine-rich domain of glycoprotein (GP) IIIa results in the expression of a GPIIb-IIIa (αIIbβ3) integrin receptor locked in a high-affinity state and a Glanzmann thrombasthenia–like phenotype

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