Journal
BLOOD
Volume 113, Issue 2, Pages 458-461Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2008-06-162610
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Funding
- Japan Society for the Promotion of Science [18591094, 20591161]
- Ministry of Health, Labor and Welfare (Grant for Child Health and Development 19C-2)
- Charitable Trust Laboratory Medicine Foundation of Japan
- National Hospital Organization
- Grants-in-Aid for Scientific Research [18591094, 20591161] Funding Source: KAKEN
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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 beta 1-tubulin localization/marginal band organization was observed, the level of beta 1-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 beta 1-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 beta 1-tubulin may not be transported from the megakaryocytes into platelets. W318 beta 1-tubulin may interfere with normal platelet production, resulting in macrothrombocytopenia. (Blood. 2009;113:458-461)
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