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Pathological mechanism and antisense oligonucleotide-mediated rescue of a non-coding variant suppressing factor 9 RNA biogenesis leading to hemophilia B.

导致血友病B的非编码变体抑制因子9 RNA生物发生的病理机制和反义寡核苷酸介导的拯救。

  • 影响因子:5.00
  • DOI:10.1371/journal.pgen.1008690
  • 作者列表:"Krooss S","Werwitzke S","Kopp J","Rovai A","Varnholt D","Wachs AS","Goyenvalle A","Aarstma-Rus A","Ott M","Tiede A","Langemeier J","Bohne J
  • 发表时间:2020-04-08
Abstract

:Loss-of-function mutations in the human coagulation factor 9 (F9) gene lead to hemophilia B. Here, we dissected the consequences and the pathomechanism of a non-coding mutation (c.2545A>G) in the F9 3' untranslated region. Using wild type and mutant factor IX (FIX) minigenes we revealed that the mutation leads to reduced F9 mRNA and FIX protein levels and to lower coagulation activity of cell culture supernatants. The phenotype could not be compensated by increased transcription. The pathomechanism comprises the de novo creation of a binding site for the spliceosomal component U1snRNP, which is able to suppress the nearby F9 poly(A) site. This second, splicing-independent function of U1snRNP was discovered previously and blockade of U1snRNP restored mutant F9 mRNA expression. In addition, we explored the vice versa approach and masked the mutation by antisense oligonucleotides resulting in significantly increased F9 mRNA expression and coagulation activity. This treatment may transform the moderate/severe hemophilia B into a mild or subclinical form in the patients. This antisense based strategy is applicable to other mutations in untranslated regions creating deleterious binding sites for cellular proteins.

摘要

: 人凝血因子9 (F9) 基因的功能丧失突变导致血友病B。在这里,我们剖析了F9 3' 非翻译区非编码突变 (c.2545A>G) 的后果和病理机制。使用野生型和突变因子IX (FIX) 小基因,我们揭示了突变导致f9mrna和FIX蛋白水平降低,并降低细胞培养上清液的凝血活性。表型不能通过增加的转录来补偿。病理机制包括重新创建剪接体组分U1snRNP的结合位点,其能够抑制附近的F9 poly (a) 位点。第二,先前发现了U1snRNP的非剪接依赖性功能,并且U1snRNP的阻断恢复了突变体f9mrna的表达。此外,我们探索了反之亦然的方法,并通过反义寡核苷酸掩蔽突变,导致f9mrna表达和凝血活性显著增加。这种治疗可以在患者中将中度/重度血友病B转化为轻度或亚临床形式。这种基于反义的策略适用于在非翻译区中产生细胞蛋白的有害结合位点的其他突变。

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影响因子:3.70
发表时间:2020-01-01
DOI:10.1093/ndt/gfy373
作者列表:["Caluwé R","Verbeke F","De Vriese AS"]

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翻译标题与摘要 下载文献
影响因子:2.36
发表时间:2020-01-01
来源期刊:Platelets
DOI:10.1080/09537104.2019.1572875
作者列表:["Wang L","Xu L","Hao H","Jansen AJG","Liu G","Li H","Liu X","Zhao Y","Peng J","Hou M"]

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