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Related Collections Hemostasis, Thrombosis, and Vascular Biology Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 15 October 2001, Vol. 98, No. 8, pp. 2432-2441 HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY A point mutation in the cysteine-rich domain of glycoprotein (GP) IIIa results in the expression of a GPIIb-IIIa (IIb3) integrin receptor locked in a high-affinity state and a Glanzmann thrombasthenia-like phenotype Catherine Ruiz, Chao-Yan Liu, Qi-Hong Sun, Marianne Sigaud-Fiks, Edith Fressinaud, Jean-Yves Muller, Paquita Nurden, Alan T. Nurden, Peter J. Newman, and Nathalie Valentin From the Laboratoire d'Immunologie and Laboratoire d'Hématologie, Institut de Biologie, Centre Hospitalier Universitaire, Nantes, France; Blood Research Institute, The Blood Center of Southeastern Wisconsin, Milwaukee; Departments of Cellular Biology and Pharmacology, The Medical College of Wisconsin, Milwaukee; and Centre National de la Recherche Scientifique Unité Mixte de Recherche 5533, Hôpital Cardiologique, Pessac, France. 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 ligand-induced 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 GPIIb-Arg560IIIa. 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. © 2001 by The American Society of Hematology.   CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: K. Vanhoorelbeke, S. F. De Meyer, I. Pareyn, C. Melchior, S. Plancon, C. Margue, O. Pradier, P. Fondu, N. Kieffer, T. A. Springer, et al. The Novel S527F Mutation in the Integrin {beta}3 Chain Induces a High Affinity {alpha}IIb{beta}3 Receptor by Hindering Adoption of the Bent Conformation J. Biol. Chem., May 29, 2009; 284(22): 14914 - 14920. 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	Copyright © 2001 by American Society of Hematology         Online ISSN: 1528-0020