title: TUBB1 mutation disrupting microtubule assembly impairs proplatelet formation and results in congenital macrothrombocytopenia.
abstract: 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.
authors.affiliation: Department of Advanced Diagnosis, Clinical Research Center, National Hospital Organization Nagoya Medical Center, Nagoya, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Kunishima
authors.forename: Satoshi
authors.initials: S
authors.lastname: Nishimura
authors.forename: Hidenori
authors.initials: H
authors.lastname: Suzuki
authors.forename: Masue
authors.initials: M
authors.lastname: Imaizumi
authors.forename: Hidehiko
authors.initials: H
authors.lastname: Saito
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D000818:Animals; D001792:Blood Platelets / Q000378:metabolism* / Q000473:pathology* / Q000648:ultrastructure; D016466:CHO Cells; D002648:Child; D003412:Cricetulus; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D008297:Male; D008533:Megakaryocytes / Q000378:metabolism; D051379:Mice; D008870:Microtubules / Q000378:metabolism* / Q000648:ultrastructure; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D011487:Protein Conformation; D016415:Sequence Alignment; D013921:Thrombocytopenia / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism*; D014404:Tubulin / Q000737:chemistry / Q000235:genetics*; D014429:Twins, Dizygotic
chemical_list: C578986:TUBB1 protein, human; D014404:Tubulin
keywords: TUBB1; macrothrombocytopenia; microtubules; proplatelet formation; β1-tubulin