Mutation of the 1-tubulin gene associated with congenital macrothrombocytopenia affecting microtubule assembly

Department of Hemostasis and Thrombosis, Clinical Research Center, National Hospital Organization Nagoya Medical Center, Nagoya, Japan.
Blood (Impact Factor: 10.45). 11/2008; 113(2):458-61. DOI: 10.1182/blood-2008-06-162610
Source: PubMed


Congenital macrothrombocytopenia is a genetically heterogeneous group of rare disorders. We identified the first TUBB1 mutation, R318W, in a patient with congenital macrothrombocytopenia. The patient was heterozygous for Q43P, but this single-nucleotide polymorphism (SNP) did not relate to macrothrombocytopenia. Although no abnormal platelet beta1-tubulin localization/marginal band organization was observed, the level of beta1-tubulin was decreased by approximately 50% compared with healthy controls. Large and irregular bleb protrusions observed in megakaryocytes derived from the patient's peripheral blood CD34(+) cells suggested impaired megakaryocyte fragmentation and release of large platelets. In vitro transfection experiments in Chinese hamster ovary (CHO) cells demonstrated no incorporation of mutant beta1-tubulin into microtubules, but the formation of punctuated insoluble aggregates. These results suggested that mutant protein is prone to aggregation but is unstable within megakaryocytes/platelets. Alternatively, mutant beta1-tubulin may not be transported from the megakaryocytes into platelets. W318 beta1-tubulin may interfere with normal platelet production, resulting in macrothrombocytopenia.

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Available from: Ryoji Kobayashi
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    • "␤1- tubulin is the major isoform of tubulin in MKs and is necessary for PPF (Wang et al., 1986; Schwer et al., 2001). Mutations in ␤1- tubulin (Tubb1) cause autosomal dominant thrombocytopenia in humans (Kunishima et al., 2009). Although pharmacological disruption of the actin cytoskeleton does not prevent PP extension, actin is involved in the bifurcation of PPs which increases PP tip number (Italiano et al., 1999). "
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