A new variant of Glanzmann's thrombasthenia (Strasbourg I). Platelets with functionally defective glycoprotein IIb-IIIa complexes and a glycoprotein IIIa 214Arg----214Trp mutation.

Lanza, François; Stierlé, A; Fournier, Dominique; Morales, Martine; André, G.; Nurden, Alan T.; Cazenave, Jean‐Pierre

doi:10.1172/jci115808

Cited by 134 publications

(74 citation statements)

References 72 publications

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“…Two variant type GT mutations in ␤ 3 , Asp119Tyr and Arg214Trp, were examined in parallel as negative controls. 37,38 As expected, Asp119Tyr and Arg214Trp mutations abolished the ligand binding function of both ␤ 3 integrins. Neither His280Pro nor Cys374Tyr mutation impaired the ligand binding to both ␣ IIb ␤ 3 and ␣ v ␤ 3 .…”

supporting

confidence: 76%

Missense mutations in the β3 subunit have a different impact on the expression and function between αIIbβ3 and αvβ3

Tadokoro

Tomiyama

Honda

et al. 2002

Blood

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belong to the ␤ 3 integrin subfamily. Although the ␤ 3 subunit is a key regulator for the biosynthesis of ␤ 3 integrins, it remains obscure whether missense mutations in ␤ 3 may induce the same defects in both ␣ IIb ␤ 3 and ␣ v ␤ 3 . In this study, it is revealed that thrombasthenic platelets with a His280Pro mutation in ␤ 3 , which is prevalent in Japanese patients with Glanzmann thrombasthenia, did contain significant amounts of ␣ v ␤ 3 (about 50% of control) using sensitive enzyme-linked immunosorbent assay. Expression studies showed that the His280Pro␤ 3 mutation impaired ␣ IIb ␤ 3 expression but not ␣ v ␤ 3 expression in 293 cells. To extend these findings, the effects of several ␤ 3 missense mutations leading to an impaired ␣ IIb ␤ 3 expression on ␣ v ␤ 3 function as well as expression was examined: Leu117Trp, Ser162Leu, Arg216Gln, Cys374Tyr, and a newly created Arg216Gln/Leu292Ser mutation. IntroductionIntegrins are a family of cell surface molecules that mediate cellular attachment to the extracellular matrix and cell cohesion and are involved in such diverse biologic processes as thrombus formation, angiogenesis, inflammation, and embryogenesis. 1 Integrins are ␣␤ heterodimers, and ␤ 3 is one of 8 known ␤ subunits. ␣ IIb ␤ 3 and ␣ v ␤ 3 belong to the ␤ 3 integrin subfamily and share the same ␤ subunit (␤ 3 ). 2,3 ␣ IIb ␤ 3 , whose expression is restricted to the megakaryocyte/platelet lineage, is a prototypic integrin that functions as a physiologic receptor for fibrinogen and von Willebrand factor and plays a crucial role in normal hemostasis and platelet aggregation. 4 On the other hand, ␣ v ␤ 3 is expressed in a number of tissues, such as platelets, endothelial cells, smooth muscle cells, and osteoclasts, and plays a key role in cell proliferation, cell migration, angiogenesis, and bone resorption. [5][6][7] Glanzmann thrombasthenia (GT) is a rare autosomal recessive bleeding disorder characterized by a quantitative or qualitative abnormality of ␣ IIb ␤ 3 and caused by a defect in either the ␣IIb or ␤ 3 gene. [8][9][10][11] The quantitative abnormality in GT can be divided into 2 groups: type I has a severe ␣ IIb ␤ 3 deficiency (Ͻ 5% of normal) with no or minimal clot retraction, and type II has a moderate ␣ IIb ␤ 3 deficiency (10%-20% of normal) with normal or only moderately diminished clot retraction. 8 The numbers of ␣ IIb ␤ 3 and ␣ v ␤ 3 expressed on the platelet surface are 40 000 to 80 000 molecules per platelet and about 100 molecules per platelet, respectively. 12 Previous studies have shown that ␣ IIb ␤ 3 and ␣ v ␤ 3 are synthesized by a similar mechanism. 13 The ␣IIb ␣v and ␤ 3 subunits are synthesized from separate messenger RNA transcripts, and the ␤ 3 subunit becomes associated with either pro␣IIb or pro␣v, single-chain precursor forms of ␣ subunits, in the endoplasmic reticulum. The pro␣ IIb ␤ 3 and pro␣ v ␤ 3 complex are then transported to the Golgi apparatus, where pro␣ subunits undergo sugar modification and endoproteolytic cleavage into heavy and light chains. After these process...

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supporting

confidence: 76%

Missense mutations in the β3 subunit have a different impact on the expression and function between αIIbβ3 and αvβ3

Tadokoro

Tomiyama

Honda

et al. 2002

Blood

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“…Both naturally occurring and induced mutations (24,27,28,60,61) in this segment can abolish Fg binding to ␣ IIb ␤ 3 ; RGD ligand peptides are cross-linked to this region of the receptor (9,62), and peptides from this segment can bind ligands (26,36). Alemany et al (56) have previously expressed ␤ 3 -(274 -368) and reported that it bound Fg but in a divalent ion-independent manner.…”

Section: Discussionmentioning

confidence: 99%

Identification and Characterization of Two Cation Binding Sites in the Integrin β3 Subunit

Cierniewska-Cieslak

Cierniewski

Błędzka

et al. 2002

Journal of Biological Chemistry

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The midsegment of the ␤ 3 subunit has been implicated in the ligand and cation binding functions of the ␤ 3 integrins. This region may contain a metal ion-dependent adhesion site (MIDAS) and fold into an I domain-like structure. Two recombinant fragments, ␤ 3 -(95-373) and ␤ 3 -(95-301), were expressed and found to bind fibrinogen. ␣ IIb ␤ 3 is a typical member of the integrin family of cell adhesion receptors (1), being composed of an ␣ (␣ IIb ) and a ␤ (␤ 3 ) subunit, which associate to form a noncovalent heterodimer. This integrin is the most abundant membrane protein on the platelet surface and serves as a receptor for multiple adhesive proteins including fibrinogen (Fg).1 Two sets of peptides (HHLGGAKQAGDV, corresponding to the sequence at the C terminus of the Fg ␥-chain (2) and RGDX, corresponding to a sequence present in many protein ligands of ␣ IIb ␤ 3 and recognized by many other integrins as well) define the recognition specificity of ␣ IIb ␤ 3 for its macromolecular ligands (reviewed in Ref.3). ␣ V ␤ 3 , which shares the same ␤ 3 subunit as ␣ IIb ␤ 3 , is broadly distributed and binds many but not all of the same ligands as ␣ IIb ␤ 3 , including Fg, von Willebrand factor, and fibronectin (reviewed in Refs. 4 and 5). This integrin also exhibits an RGD recognition specificity but shows a much weaker recognition of Fg ␥-chain peptides (6). Numerous studies have suggested that binding of macromolecular ligands to ␣ IIb ␤ 3 as well as ␣ V ␤ 3 involves multiple contacts in each subunit (7-13). Essential residues for ligand binding to ␣ IIb ␤ 3 reside in two major regions: a midsegment of ␤ 3 , ␤ 3 -(95-400), and the amino-terminal aspect of ␣ IIb , ␣ IIb -(1-334) (11), which contains seven structural repeats (14). The midsegment of the ␤ 3 subunit is highly conserved among integrin ␤ subunits and exhibits some structural and functional features of an I domain. I domains are present in nine integrin ␣ subunits and play major roles in the ligand binding functions of their integrin heterodimers (15)(16)(17)(18)(19)(20). The relationship between the conserved ␤ midsegments and ␣ I domains was proposed based upon similarities in their hydropathy profiles, secondary structural predictions, and mutational analyses (18, 20 -22). A central feature of I domains is a metal ion-dependent adhesion site, a MIDAS motif (15,18,19,23). In MIDAS motifs, three of the five cation coordination sites are provided by a DXSXS sequence and two other coordination sites are provided by oxygenated residues distant in the primary sequence. Mutations of the cation-coordinating residues in a MIDAS motif often cause loss of ligand binding functions of an integrin, and ligand binding sites map in close proximity to MIDAS motifs (18,24,25). The ␤ 3 midsegment does contain a 119 DXSXS sequence, and these residues also have been implicated in the ligand binding functions of ␣ IIb ␤ 3 (24, 26 -28). While there is broad consensus that the midsegment of integrin ␤ subunit contains a functional MIDAS, other structural algorithms have predicted ...

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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

207

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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A new variant of Glanzmann's thrombasthenia (Strasbourg I). Platelets with functionally defective glycoprotein IIb-IIIa complexes and a glycoprotein IIIa 214Arg----214Trp mutation.

Cited by 134 publications

References 72 publications

Missense mutations in the β3 subunit have a different impact on the expression and function between αIIbβ3 and αvβ3

Missense mutations in the β3 subunit have a different impact on the expression and function between αIIbβ3 and αvβ3

Identification and Characterization of Two Cation Binding Sites in the Integrin β3 Subunit

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

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