TUBB1 mutation disrupting microtubule assembly impairs proplatelet formation and results in congenital macrothrombocytopenia

• Published in: European journal of haematology Vol. 92; no. 4; pp. 276 - 282
• Main Authors: Kunishima, Shinji, Nishimura, Satoshi, Suzuki, Hidenori, Imaizumi, Masue, Saito, Hidehiko
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01.04.2014
• Subjects: Adult; Amino Acid Sequence; Animals; Blood Platelets - metabolism; Blood Platelets - pathology; Blood Platelets - ultrastructure; Child; CHO Cells; Cricetulus; DNA Mutational Analysis; Female; Humans; macrothrombocytopenia; Male; Megakaryocytes - metabolism; Mice; microtubules; Microtubules - metabolism; Microtubules - ultrastructure; Models, Molecular; Molecular Sequence Data; Mutation; proplatelet formation; Protein Conformation; Sequence Alignment; Thrombocytopenia - diagnosis; Thrombocytopenia - genetics; Thrombocytopenia - metabolism; TUBB1; Tubulin - chemistry; Tubulin - genetics; Twins, Dizygotic; β1-tubulin; β1-tubulin; proplatelet formation; microtubules; macrothrombocytopenia; TUBB1
• ISSN: 0902-4441; 1600-0609; 1600-0609
• DOI: 10.1111/ejh.12252

This report describes a family with TUBB1‐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 TUBB1 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.