The regulation of platelet-dense granules by Rab27a in the ashen mouse, a model of Hermansky-Pudlak and Griscelli syndromes, is granule-specific and dependent on genetic background
The regulation of platelet-dense granules by Rab27a in the ashen mouse, a model of Hermansky-Pudlak and Griscelli syndromes, is granule-specific and dependent on genetic background
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DOI：
10.1182/blood.v100.1.128
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发表时间：
2002-07-01
期刊：
影响因子：
20.3
通讯作者：
Swank, RT
中科院分区：
文献类型：
--
作者：
Novak, EK;Gautam, R;Swank, RT
ashen (ash) 小鼠是 Hermansky-Pudlak 综合征 (HPS) 和一部分 Griscelli 综合征患者的模型，由于 Rab27a 蛋白表达的突变而导致色素沉着不足、出血时间延长和血小板储存池缺乏。 C3H/HeSnJ 近交系背景上具有 ashen 突变的小鼠血小板中，致密颗粒成分（如血清素和腺嘌呤核苷酸）的量大大减少，尽管致密颗粒特异性荧光染料 mepacrine 所计数的致密颗粒数量接近正常。因此，产生基本上正常数量的血小板致密颗粒，但颗粒内部是异常的。胶原介导的突变血小板聚集明显受到抑制。其他两种主要血小板颗粒（溶酶体和α颗粒）的浓度或分泌率没有明显异常。同样，除了涉及致密颗粒的改变外，没有检测到血小板超微结构的改变。因此，Rab27a 仅调节一种主要血小板细胞器，即致密颗粒的合成和分泌。同样，对其他几种组织的溶酶体酶的水平或分泌也没有突变影响。结合最近对 ashen 小鼠的其他分析，这些结果表明血小板致密颗粒、黑素细胞的黑素体和细胞毒性 T 淋巴细胞的分泌溶酶体之间存在密切关系，所有这些均由 Rab27a 介导。令人惊讶的是，ashen 突变对血小板致密颗粒成分、血小板聚集和出血时间的影响高度依赖于遗传背景。这表明，患有 Griscelli 综合征和具有 Rab27a 突变的 HPS 患者的出血倾向可能同样有所不同。
The ashen (ash) mouse, a model for Hermansky-Pudlak syndrome (HPS) and for a subset of patients with Griscelli syndrome, presents with hypopigmentation, prolonged bleeding times, and platelet storage pool deficiency due to a mutation which abrogates expression of the Rab27a protein. Platelets of mice with the ashen mutation on the C3H/HeSnJ inbred strain background have greatly reduced amounts of dense granule components such as serotonin and adenine nucleotides though near-normal numbers of dense granules as enumerated by the dense granule-specific fluorescent dye mepacrine. Thus, essentially normal numbers of platelet dense granules are produced but the granule interiors are abnormal. Collagen-mediated aggregation of mutant platelets is significantly depressed. No abnormalities in the concentrations or secretory rates of 2 other major platelet granules, lysosomes and alpha granules, were apparent. Similarly, no platelet ultrastructural alterations other than those involving dense granules were detected. Therefore, Rab27a regulates the synthesis and secretion of only one major platelet organelle, the dense granule. There were likewise no mutant effects on levels or secretion of lysosomal enzymes of several other tissues. Together with other recent analyses of the ashen mouse, these results suggest a close relationship between platelet dense granules, melanosomes of melanocytes and secretory lysosomes of cytotoxic T lymphocytes, all mediated by Rab27a. Surprisingly, the effects of the ashen mutation on platelet-dense granule components, platelet aggregation, and bleeding times were highly dependent on genetic background. This suggests that bleeding tendencies may likewise vary among patients with Griscelli syndrome and HPS with Rab27a mutations.