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TUBB 1 mutation disrupting microtubule assembly impairs proplatelet formation and results in congenital macrothrombocytopenia
Author(s) -
Kunishima Shinji,
Nishimura Satoshi,
Suzuki Hidenori,
Imaizumi Masue,
Saito Hidehiko
Publication year - 2014
Publication title -
european journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.904
H-Index - 84
eISSN - 1600-0609
pISSN - 0902-4441
DOI - 10.1111/ejh.12252
Subject(s) - tubulin , microtubule , microbiology and biotechnology , biology , mutant , thrombopoiesis , chinese hamster ovary cell , cell culture , megakaryocyte , biochemistry , genetics , stem cell , gene , haematopoiesis
This report describes a family with TUBB 1 ‐associated macrothrombocytopenia diagnosed based on abnormal platelet β1‐tubulin distribution. A circumferential marginal microtubule band was undetectable, whereas microtubules were frayed and disorganized in every platelet from the affected individuals. Patients were heterozygous for novel TUBB 1 p.F260S that locates at the α‐ and β‐tubulin intradimer interface. Mutant β1‐tubulin was not incorporated into microtubules with endogenous α‐tubulin, and α‐tubulin expression was decreased in transfected Chinese hamster ovary cells. Transduction of mutant β1‐tubulin into mouse fetal liver‐derived megakaryocytes demonstrated no incorporation of mutant β1‐tubulin into microtubules with endogenous α‐tubulin and diminished proplatelet formation, leading to the production of fewer, but larger, proplatelet tips. Furthermore, mutant β1‐tubulin was not associated with endogenous α‐tubulin in the proplatelets. Deficient functional microtubules might lead to defective proplatelet formation and abnormal protrusion‐like platelet release, resulting in congenital macrothrombocytopenia.