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

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.