GFI1B mutation causes a bleeding disorder with abnormal platelet function
GFI1B mutation causes a bleeding disorder with abnormal platelet function
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DOI：
10.1111/jth.12368
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发表时间：
2013-11-01
影响因子：
10.4
通讯作者：
Ward, C. M.
中科院分区：
文献类型：
--
作者：
Stevenson, W. S.;Morel-Kopp, M. -C.;Ward, C. M.
背景GFI1B是一个转录因子，红细胞生成和巨核细胞的发展，但以前未知的是与人类diseases.MethodsA家庭与一种新的出血性疾病的鉴定和特点。遗传连锁分析和大规模平行测序被用来定位9号染色体上引起疾病表型的突变。功能研究，然后在巨核细胞系，以确定突变体transcript.ResultsWe的生物学效应已经确定了一个家庭与常染色体显性遗传性出血性疾病与巨血小板减少症，红细胞各向异性红细胞增多症，血小板功能障碍。出血的严重程度是可变的，一些受影响的个体经历自发性出血，而其他家庭成员仅在手术后表现出异常出血。在GFI1B中发现了一个单核苷酸插入，预测了第五个锌指DNA结合结构域中的移码突变。这种突变改变了蛋白的转录活性，导致血小板颗粒含量减少和关键血小板蛋白的异常表达。结论GFI1B突变代表了一种新的人类出血性疾病，所描述的表型鉴定了GFI1B作为血小板形状、数量和功能的关键调节因子。
Background GFI1B is a transcription factor important for erythropoiesis and megakaryocyte development but previously unknown to be associated with human disease.MethodsA family with a novel bleeding disorder was identified and characterized. Genetic linkage analysis and massively parallel sequencing were used to localize the mutation causing the disease phenotype on chromosome 9. Functional studies were then performed in megakaryocytic cell lines to determine the biological effects of the mutant transcript.ResultsWe have identified a family with an autosomal dominant bleeding disorder associated with macrothrombocytopenia, red cell anisopoikilocytosis, and platelet dysfunction. The severity of bleeding is variable with some affected individuals experiencing spontaneous bleeding while other family members exhibit only abnormal bleeding with surgery. A single nucleotide insertion was identified in GFI1B that predicts a frameshift mutation in the fifth zinc finger DNA-binding domain. This mutation alters the transcriptional activity of the protein, resulting in a reduction in platelet -granule content and aberrant expression of key platelet proteins.ConclusionsGFI1B mutation represents a novel human bleeding disorder, and the described phenotype identifies GFI1B as a critical regulator of platelet shape, number, and function.