β1-tubulin in human platelets: not simply a structural cell frame

Comment on Freson et al, page 2356

Freson and colleagues present a novel polymorphism of platelet β1-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 α- and β-tubulin, the basic building block of the microtubule.¹ 

Among the β-tubulin isoforms, β1-tubulin is specifically expressed in platelets and mature megakaryocytes,²  and accounts for about 90% of the β-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.

β1-tubulin is also required for optimal platelet assembly as it localizes in proplatelets, the megakaryocyte cytoplasmic extensions that branch and fragment into platelets.²  β1-tubulin-deficient mice, generated by the targeted disruption of the β1-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 β1-tubulin in platelet function.

To date, no human β1-tubulin-associated disorder has been described. In this issue of Blood, Freson and colleagues describe the first human β1-tubulin functional substitution (AG>CC) inducing both structural and functional platelet alterations. The Q43P β1-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 β1-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 β1-tubulin in platelet function, probably independent from the maintenance of platelet shape.⁴ 

Given the mild platelet function impairment associated with the Q43P β1-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 β1-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 β1-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 β1-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 β1-tubulin functional variant protects only men is interesting but unclear.

But the identification of a genetic polymorphism of β1-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 β1-tubulin alteration. The Q43P β1-tubulin variant described by Freson et al reconciles the dicotomic view of the platelet often seen either as an hemostatic or a thrombotic effector. ▪