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Blood, 1 October 2005, Vol. 106, No. 7, pp. 2229-2230. This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Gresele, P. Articles by Falcinelli, E. Search for Related Content PubMed Articles by Gresele, P. Articles by Falcinelli, E. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMOSTASIS Comment on Freson et al, page 2356 1-tubulin in human platelets: not simply a structural cell frame Paolo Gresele, and Emanuela Falcinelli UNIVERSITY OF PERUGIA, ITALY Freson and colleagues present a novel polymorphism of platelet 1-tubulin that is frequent in the healthy population and may protect men against arterial thrombosis. Microtubules represent one of the major components of the cytoskeletons of eukaryotic cells and play an essential function in the maintainance of cell shape, but participate also in cell division, ciliar and flagellar motility, and intracellular transport.1 Eukaryotic organisms express multiple isotypes of - and -tubulin, the basic building block of the microtubule.1 Among the -tubulin isoforms, 1-tubulin is specifically expressed in platelets and mature megakaryocytes,2 and accounts for about 90% of the -tubulin present in the platelet marginal band, a single peripheral microtubule strand that maintains the discoid shape. Platelets play a critical role in hemostasis, but also in arterial thrombosis. At rest, they circulate in blood as small anucleated discs which, following blood-vessel injury, interact with exposed elements of the underlying connective tissue, rapidly changing their shape to spheres, the latter a phenomenon the functional significance of which is not yet fully understood. View larger version (97K): [in this window] [in a new window]   Electron microscopy of platelets of a healthy individual and a 1-tubulin Q43P variant carrier. Distrupted marginal band, cytoplasmatic clusters composed of abnormal membrane complexes, and organelle-free zones are present.   1-tubulin is also required for optimal platelet assembly as it localizes in proplatelets, the megakaryocyte cytoplasmic extensions that branch and fragment into platelets.2 1-tubulin-deficient mice, generated by the targeted disruption of the 1-tubulin gene, are mildly thrombocytopenic and their platelets are spherical, but interestingly and in part unexpectedly, they have a disproportionately prolonged bleeding time and an attenuated platelet response to thrombin.3 These results established for the first time a role for 1-tubulin in platelet function. To date, no human 1-tubulin-associated disorder has been described. In this issue of Blood, Freson and colleagues describe the first human 1-tubulin functional substitution (AG>CC) inducing both structural and functional platelet alterations. The Q43P 1-tubulin variant was found in 10.6% of the general population and in 24.2% of 33 unrelated patients with undefined congenital macrothrombocytopenia. Electron microscopy revealed enlarged spherocytic platelets with a disrupted marginal band and structural alterations (see figure), generated by a disturbed tubulin organization. Interestingly, platelets with the Q43P 1-tubulin variant showed a mild platelet dysfunction, with reduced adenosine triphosphate (ATP) secretion, thrombin-receptor-activating peptide (TRAP)-induced aggregation, and impaired adhesion to collagen under flow conditions, thus confirming a role of 1-tubulin in platelet function, probably independent from the maintenance of platelet shape.4 Given the mild platelet function impairment associated with the Q43P 1-tubulin variant, the authors looked comparatively at the prevalence of this mutation in apparently healthy subjects and in age- and sex-matched patients with a cardiovascular history and found a significant imbalance, with a more than doubled prevalence of the 1-tubulin variant among subjects not undergoing ischemic events. This is the first genetic polymorphysm involving an intraplatelet protein to be associated with ischemic cardiovascular disorders. The Q43P 1-tubulin variant results from a double-nucleotide substitution and is probably a very ancient mutation, this suggesting that it could confer an evolutionary advantage, reducing ischemic cardiovascular risk. Much more needs to be done in order to fully characterize the possible cardiovascular protective role of the Q43P 1-tubulin variant, such as a larger cohort study, an adjustment for other risk factors, subgroup analysis by severity of coronary heart disease, etc. Moreover, the observation that the 1-tubulin functional variant protects only men is interesting but unclear. But the identification of a genetic polymorphism of 1-tubulin modulating arterial thrombosis may represent one further step in a patient's tailored approach to cardiovascular risk management.5,6 In addition, the high prevalence of the Q43P variant in undefined congenital macrothrombocytopenias suggests that a number of inherited thrombocytopenias that are so far unclassified7 may indeed be reconducted to a 1-tubulin alteration. The Q43P 1-tubulin variant described by Freson et al reconciles the dicotomic view of the platelet often seen either as an hemostatic or a thrombotic effector. References McKean PG, Vaughan S, Gull K. The extended tubulin superfamily. J Cell Science. 2001;114: 2723-2733.[Abstract/Free Full Text] Barkalow KL, Falet H, Hartwig J. Dynamics of platelet cytoskeleton. In: Gresele P, Page C, Fuster V, Vermylen J, Eds. Platelets in Thrombotic and Non-Thrombotic Disorders. Cambridge, United Kingdom: Cambridge University Press; 2002: 93-100. Schwer HD, Lecine P, Tiwari S, Italiano JE Jr, Hartwig J, Shivdasani RA. A lineage-restricted and divergent beta-tubulin isoform is essential for the biogenesis, structure and function of blood platelets. Curr Biol. 2001;11: 579-586.[CrossRef][Medline] [Order article via Infotrieve] Italiano JE Jr, Bergmeier W, Tiwari S, et al. Mechanisms and implications of platelet discoid shape. Blood. 2003;101: 4789-4796.[Abstract/Free Full Text] Franco RF, Reitsma PH. Gene polymorphisms of the haemostatic system and the risk of arterial thrombotic disease. Br J Haematol. 2001;115: 491-506.[CrossRef][Medline] [Order article via Infotrieve] O'Donnell CJ, Larson MG, Feng D, et al. Genetic and environmental contributions to platelet aggregation: the Framingham heart study. Circulation. 2001;103: 3051-3056.[Abstract/Free Full Text] Balduini CL, Cattaneo M, Fabris F, et al. Inherited thrombocytopenias: a proposed diagnostic algorithm from the Italian Gruppo di Studio delle Piastrine. Haematologica. 2003;88: 582-592.[Abstract/Free Full Text] CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: The TUBB1 Q43P functional polymorphism reduces the risk of cardiovascular disease in men by modulating platelet function and structure Kathleen Freson, Rita De Vos, Christine Wittevrongel, Chantal Thys, Johan Defoor, Luc Vanhees, Jos Vermylen, Kathelijne Peerlinck, and Chris Van Geet Blood 2005 106: 2356-2362. [Abstract] [Full Text] [PDF] This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Gresele, P. Articles by Falcinelli, E. Search for Related Content PubMed Articles by Gresele, P. Articles by Falcinelli, E. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?

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