title: Glanzmann thrombasthenia-like syndromes associated with Macrothrombocytopenias and mutations in the genes encoding the αIIbβ3 integrin.
abstract: Glanzmann thrombasthenia (GT) is the most widely studied inherited disorder of platelets; it is caused by the absence of platelet aggregation due to quantitative and/or qualitative deficiencies of the αIIbβ3 integrin coded by the  ITGA2B and  ITGB3 genes located at 17q21-23. Although platelet count and platelet volume (and morphology) are normal in classic GT, some reports have inferred a role for αIIbβ3 in megakaryocytopoiesis and some novel but rare point mutations in either of the  ITGA2B and  ITGB3 genes have been associated with an altered platelet production and selective deficiencies in platelet function. This was brought to light by the discovery of mutations at Arg995 in αIIb and Asp723 in β3 that lead to platelet anisotropy (increased size variation) and thrombocytopenia. Significantly, Arg995 and Asp723 form a salt linkage binding the cytoplasmic tails of αIIbβ3 together keeping the integrin in a bent resting state. Mutations weakening this link (if not abolishing it) increase the activation state of αIIbβ3 and interfere with megakaryocytopoiesis. Other mutations affecting platelet production involve extracellular but membrane proximal domains of β3. Our purpose is to review the mutations in the  ITGA2B and  ITGB3 genes that lead to anisotropy and to discuss mechanisms by which this can be brought about.
authors.affiliation: Centre de Référence des Pathologies Plaquettaires, Plateforme Technologique et d'Innovation Biomédicale, Hôpital Xavier Arnozan, Pessac, France. Alan.Nurden@cnrshl.u-bordeaux2.fr
authors.forename: Alan T
authors.initials: AT
authors.lastname: Nurden
authors.forename: Xavier
authors.initials: X
authors.lastname: Pillois
authors.forename: Mathieu
authors.initials: M
authors.lastname: Fiore
authors.forename: Roland
authors.initials: R
authors.lastname: Heilig
authors.forename: Paquita
authors.initials: P
authors.lastname: Nurden
mesh_terms: D001483:Base Sequence; D001792:Blood Platelets / Q000378:metabolism / Q000473:pathology; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D009154:Mutation; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000235:genetics*; D013577:Syndrome; D013915:Thrombasthenia / Q000235:genetics*; D013921:Thrombocytopenia / Q000235:genetics*; D034061:Thrombopoiesis / Q000235:genetics
chemical_list: D019039:Platelet Glycoprotein GPIIb-IIIa Complex