Nonsense-mediated mRNA decay efficiency influences bleeding severity in ITGA2B c.2659C > T (p.Q887X) knock-in mice
Nonsense-mediated mRNA decay efficiency influences bleeding severity in ITGA2B c.2659C > T (p.Q887X) knock-in mice
复制标题
无义介导的 mRNA 衰减效率影响 ITGA2B c.2659C > T (p.Q887X) 敲入小鼠的出血严重程度
DOI：
10.1111/cge.13975
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发表时间：
2021-05-05
影响因子：
3.5
通讯作者：
Zhou, Lu
中科院分区：
文献类型：
--
作者：
Xie, Zhanli;Jiang, Jiang;Zhou, Lu
血小板无力症（GT）是一种严重的出血性疾病。它是由ITGA 2B或ITGB 3突变引起的，ITGA 2B或ITGB 3分别是编码整合素α IIb和β 3的基因。尽管进行了广泛的突变分析，但在受影响个体中观察到的出血严重程度的广泛变异性的机制仍然知之甚少。为了探讨出血异质性的机制，研究了具有不同出血评分的三名ITGA 2B c.2671C > T（p.Q891X）的GT患者。分析表明，无义介导的mRNA衰变（NMD）效率在三个患者之间存在显著差异。这些差异与他们的出血评分呈正相关。接下来，使用CRISPR/Cas9产生具有ITGA 2B c.2659C > T（p.Q887X）的敲入小鼠模型（KI小鼠）。重要的是，该突变与人类中的ITGA 2B c.2671C > T（p.Q891X）同源。KI小鼠的出血时间与野生型小鼠相比有显著性差异。有趣的是，在用咖啡因治疗后出血停止，咖啡因是一种已知的NMD抑制剂。这表明NMD效率潜在地影响ITGA 2B c.2659C > T（p.Q887X）KI小鼠中的出血严重性。
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 alpha IIb and beta 3. 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.