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Abstract：
Glanzmann\'s thrombasthenia (GT) is a severe hemorrhagic disease. It is caused by mutations in ITGA2B or ITGB3, which are the respective genes encoding integrin αIIb and β3. Despite widespread mutational analysis, the mechanisms underlying the extensive variability in bleeding severity observed among affected individuals remains poorly understood. In order to explore the mechanisms conferring for bleeding heterogeneity, three GT patients with ITGA2B c.2671C > T (p.Q891X) who possessed different bleeding scores were studied. Analysis showed that there was significant difference in nonsense-mediated mRNA decay (NMD) efficiency among the three patients. These differences positively correlated with their bleeding score. Next, a knock-in mouse model (KI mice) with the ITGA2B c.2659C > T (p.Q887X) was generated using CRISPR/Cas9. Importantly, this mutation is homologous to ITGA2B c.2671C > T (p.Q891X) in humans. The bleeding time of KI mice was significantly in comparison to the wide-type mice. Interestingly, bleeding was stopped after treatment with caffeine, which is a known NMD inhibitor. This suggests that NMD efficiency potentially influences bleeding severity in ITGA2B c.2659C > T (p.Q887X) KI mice.
摘要：
Glanzmann血栓性(GT)是一种严重的出血性疾病。它是由ITGA2B或ITGB3中的突变引起的，ITGA2B或ITGB3是编码整合素αIIb和β3的相应基因。尽管有广泛的突变分析,在受影响的个体中观察到的出血严重程度的广泛差异的潜在机制仍然知之甚少.为了探讨出血异质性的机制，三名ITGA2Bc.2671C>T的GT患者（p。研究了具有不同出血评分的Q891X）。分析表明，三名患者的无义介导的mRNA衰减（NMD）效率存在显着差异。这些差异与他们的出血评分呈正相关。接下来,敲入小鼠模型（KI小鼠），ITGA2Bc.2659C>T（p。Q887X）使用CRISPR/Cas9生成。重要的是,此突变与ITGA2Bc.2671C>T同源（p。Q891X）在人类中。与宽型小鼠相比，KI小鼠的出血时间显着。有趣的是,用咖啡因治疗后出血停止，这是一种已知的NMD抑制剂。这表明NMD效率可能会影响ITGA2Bc.2659C>T的出血严重程度（p。Q887X)KI小鼠。
