Department of Cardiovascular Science, University of Sheffield Medical School, University of Sheffield, Sheffield, United Kingdom;
Blood. 2013 Dec 12;122(25):4090-3. doi: 10.1182/blood-2013-06-506873. Epub 2013 Oct 7.
We analyzed candidate platelet function disorder genes in 13 index cases with a history of excessive bleeding in association with a significant reduction in dense granule secretion and impaired aggregation to a panel of platelet agonists. Five of the index cases also had mild thrombocytopenia. Heterozygous alterations in FLI1 and RUNX1, encoding Friend leukemia integration 1 and RUNT-related transcription factor 1, respectively, which have a fundamental role in megakaryocytopoeisis, were identified in 6 patients, 4 of whom had mild thrombocytopenia. Two FLI1 alterations predicting p.Arg337Trp and p.Tyr343Cys substitutions in the FLI1 DNA-binding domain abolished transcriptional activity of FLI1. A 4-bp deletion in FLI1, and 2 splicing alterations and a nonsense variation in RUNX1, which were predicted to cause haploinsufficiency of either FLI1 or RUNX1, were also identified. Our findings suggest that alterations in FLI1 and RUNX1 may be common in patients with platelet dense granule secretion defects and mild thrombocytopenia.
我们分析了 13 例有明显致密颗粒分泌缺陷和聚集功能障碍的血小板功能障碍病史的索引病例的候选血小板功能障碍基因。其中 5 例索引病例也有轻度血小板减少症。在 6 名患者中发现了编码 Friend 白血病整合蛋白 1 和 runt 相关转录因子 1 的 FLI1 和 RUNX1 的杂合改变，这两种蛋白在巨核细胞生成中具有重要作用，其中 4 名患者有轻度血小板减少症。两种预测 FLI1 DNA 结合域中 p.Arg337Trp 和 p.Tyr343Cys 取代的 FLI1 改变，使 FLI1 的转录活性丧失。在 FLI1 中发现了 4 个碱基对缺失，在 RUNX1 中发现了 2 个剪接改变和一个无义变异，这些改变预计会导致 FLI1 或 RUNX1 的单倍体不足。我们的研究结果表明，FLI1 和 RUNX1 的改变可能在血小板致密颗粒分泌缺陷和轻度血小板减少症患者中较为常见。
