Kunishima Shinji, Nishimura Satoshi, Suzuki Hidenori, Imaizumi Masue, Saito Hidehiko
Department of Advanced Diagnosis, Clinical Research Center, National Hospital Organization Nagoya Medical Center, Nagoya, Japan.
Eur J Haematol. 2014 Apr;92(4):276-82. doi: 10.1111/ejh.12252. Epub 2014 Jan 11.
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.
本报告描述了一个基于异常血小板β1-微管蛋白分布诊断为TUBB1相关巨血小板减少症的家系。未检测到周缘边缘微管带，而来自受影响个体的每个血小板中的微管都有磨损且排列紊乱。患者为位于α-和β-微管蛋白二聚体内界面的新型TUBB1 p.F260S杂合子。突变的β1-微管蛋白未与内源性α-微管蛋白一起整合到微管中，并且在转染的中国仓鼠卵巢细胞中α-微管蛋白表达降低。将突变的β1-微管蛋白转导到小鼠胎儿肝脏来源的巨核细胞中，结果显示突变的β1-微管蛋白未与内源性α-微管蛋白一起整合到微管中，并且血小板生成减少，导致产生的前血小板尖端数量减少但体积增大。此外，在血小板中突变的β1-微管蛋白未与内源性α-微管蛋白相关联。功能性微管缺陷可能导致前血小板形成缺陷和异常的突起样血小板释放，从而导致先天性巨血小板减少症。
