Hemophilia B Leyden: substitution of thymine for guanine at position -21 results in a disruption of a hepatocyte nuclear factor 4 binding site in the factor IX promoter.
Hemophilia B Leyden: substitution of thymine for guanine at position -21 results in a disruption of a hepatocyte nuclear factor 4 binding site in the factor IX promoter.
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B 型血友病 Leyden：在 -21 位用胸腺嘧啶取代鸟嘌呤会导致因子 IX 启动子中肝细胞核因子 4 结合位点的破坏。
DOI：
10.1182/blood.v82.1.151.bloodjournal821151
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发表时间：
1993
期刊：
影响因子：
20.3
通讯作者：
Pieter H. Reitsma
中科院分区：
文献类型：
--
作者：
Marlene J. Reijnen;K. Peerlinck;Diedka Maasdam;R. Bertina;Pieter H. Reitsma
血友病B Leyden是一种X染色体相关的出血性疾病，其特征是血液凝固因子IX的发育表达改变。这种形式的B型血友病已被发现与因子IX启动子区域的多种单点突变有关。我们现在描述了一个新的点突变，T- >g在位置-21，在两个相关的血友病B莱顿表型患者。该突变位于因子IX启动子区域（-40至-9），该区域包含肝细胞核因子4 （HNF-4）和雄激素受体的重叠结合位点。HepG2细胞的瞬时转染实验表明-21突变导致因子IX启动子活性显著降低。凝胶迁移转移试验和瞬时共转染实验显示，-21突变破坏了hnf -4结合位点，但没有破坏雄激素反应元件。将-21突变与先前描述的-20 T- >A突变（与血友病B Leyden表型相关）和-26 G- >C突变（终生与严重血友病B相关）进行了比较。结果表明，-21突变将HNF-4的结合和反活化降低到与-20突变相似的水平，而-26突变则完全消除了HNF-4的结合和反活化。迁移迁移实验表明，重组雄激素受体蛋白对含有野生型和-21或-20突变DNA的寡核苷酸的结合亲和力无显著差异。对含有-26突变的寡核苷酸的结合亲和力降低了两倍。结果表明，-21 T- >G突变破坏hnf -4结合位点是这两例患者出血性疾病的原因。这项研究进一步支持了这样一种观点，即青春期血友病的恢复可能不仅与完整的雄激素反应元件有关，而且与hnf -4结合位点的破坏程度有关。
Hemophilia B Leyden is an X chromosome-linked bleeding disorder characterized by an altered developmental expression of blood coagulation factor IX. This form of hemophilia B has been found to be associated with a variety of single point mutations in the factor IX promoter region. We now describe a novel point mutation, T-->G at position -21, in two related patients with the hemophilia B Leyden phenotype. This mutation lies within the factor IX promoter region (-40 to -9) that contains overlapping binding sites for hepatocyte nuclear factor 4 (HNF-4) and androgen receptor. Transient transfection assays in HepG2 cells show that the -21 mutation causes a significant reduction in factor IX promoter activity. Gel mobility shift assays and transient cotransfection experiments revealed that the HNF-4-binding site but not the androgen-responsive element is disrupted by the -21 mutation. A comparison of the -21 mutation with the previously described -20 T-->A mutation (associated with the hemophilia B Leyden phenotype) and -26 G-->C mutation (associated with severe hemophilia B throughout life) was made. It shows that the -21 mutation reduced HNF-4 binding and transactivation to a similar level as the -20 mutation, whereas the -26 mutation completely abolished HNF-4 binding and transactivation. Mobility shift experiments indicate that there was no significant difference in binding affinity of recombinant androgen receptor protein for oligonucleotides containing wild-type and -21 or -20 mutated DNA. The binding affinity for the oligonucleotide containing the -26 mutation was twofold lower. The results indicate that the disruption of the HNF-4-binding site by the -21 T-->G mutation is the cause of the bleeding disorder in these two patients. This study adds further support for the notion that the recovery from hemophilia at puberty may not only be related to an intact androgen-responsive element but also to the degree of disruption of the HNF-4-binding site.
纠正：与新世界猴子殖民地中的暴发性肺炎爆发相关的新型腺病毒的跨物种传播
影响因子：
6.7
作者：
Chen EC;Yagi S;Kelly KR;Mendoza SP;Maninger N;Rosenthal A;Spinner A;Bales KL;Schnurr DP;Lerche NW;Chiu CY
通讯作者：
Chiu CY
人类凝血因子 IX 基因发育调节的结构和功能基础：因子 IX Leyden。
DOI：
10.1073/pnas.87.12.4421
发表时间：
1990
影响因子：
11.1
作者：
Hirosawa,S;Fahner,JB;Salier,JP;Wu,CT;Lovrien,EW;Kurachi,K
通讯作者：
Kurachi,K