Mutation of the beta1-tubulin gene associated with congenital macrothrombocytopenia affecting microtubule assembly.
Blood
; 113(2): 458-61, 2009 Jan 08.
Article
in En
| MEDLINE
| ID: mdl-18849486
ABSTRACT
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Tubulin
/
Purpura, Thrombocytopenic, Idiopathic
/
Mutation, Missense
/
Genetic Diseases, Inborn
/
Microtubules
Type of study:
Prognostic_studies
/
Risk_factors_studies
Limits:
Animals
/
Child
/
Humans
/
Male
Language:
En
Journal:
Blood
Year:
2009
Document type:
Article
Affiliation country:
Japan