Severe factor VII deficiency due to a mutation disrupting a hepatocyte nuclear factor 4 binding site in the factor VII promoter
Severe factor VII deficiency due to a mutation disrupting a hepatocyte nuclear factor 4 binding site in the factor VII promoter
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DOI：
10.1182/blood.v89.1.176.176_176_182
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发表时间：
1997-01-01
期刊：
影响因子：
20.3
通讯作者：
Bauer, KA
中科院分区：
文献类型：
--
作者：
Arbini, AA;Pollak, ES;Bauer, KA
尽管在凝血因子VII缺乏症患者中发现了微小的缺失、剪接位点异常、错义和无义突变，但还没有关于凝血因子VII启动子突变的报道。我们调查了一名女孩，其凝血因子VII水平低于正常水平的1%，与严重出血素质有关。患者是纯合子，T到G的颠换发生在翻译起始点之前61BP。该核苷酸位于第VII因子启动子(ACTTTG AE-->；ACGTTG)内的肝细胞核因子4(HNF-4)结合部位。凝胶迁移率改变分析表明，突变破坏了HNF-4与其同源结合位点的结合，在生长激素报告基因检测中，含有突变启动子的质粒的活性是野生型启动子的6.7%。虽然HNF-4能够在Hela细胞中反式激活野生型因子VII启动子5.4倍，但突变的启动子没有显示出反式激活。这些发现表明，HNF-4对第VII因子的表达起着重要的正向调节作用，并在体内提供了证据，表明该转录因子的结合对第VII因子的正常表达至关重要。(C)1997年由美国血液病学会主办。
Although small deletions, splice site abnormalities, missense, and nonsense mutations have been identified in patients with factor VII deficiency, there have been no reports of mutations in the factor VII promoter. We investigated a girl with factor VII levels that were less than 1% of normal in association with a severe bleeding diathesis. The patient is homozygous for a T to G transversion that occurs 61 bp before the translation start site. This nucleotide is in a sequence that is an hepatocyte nuclear factor 4 (HNF-4) binding site within the factor VII promoter (ACTTTG AE --> ACGTTG). Using gel mobility shift assays, we show that the mutation disrupts the binding of HNF-4 to its cognate binding sits, In growth hormone reporter gene assays, the activity of a plasmid containing the mutant promoter was 6.7% of the wild-type promoter plasmid. Although HNF-4 was able to transactivate the wild-type factor VII promoter 5.4-fold in Hela cells, no transactivation could be shown with the mutant promoter. These findings indicate that HNF-4 exerts a major positive regulatory effect on factor VII expression and provides in vivo evidence that binding of this transcription factor is critical for normal factor VII expression. (C) 1997 by The American Society of Hematology.