Rectifier of aberrant mRNA splicing recovers tRNA modification in familial dysautonomia.
Rectifier of aberrant mRNA splicing recovers tRNA modification in familial dysautonomia.
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异常 mRNA 剪接的矫正器可恢复家族性自主神经功能障碍中的 tRNA 修饰。
DOI：
10.1073/pnas.1415525112
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发表时间：
2015
期刊：
影响因子：
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通讯作者：
Hagiwara M.
中科院分区：
文献类型：
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作者：
Yoshida M;Kataoka N;Miyauchi K;Ohe K;Iida K;Yoshida S;Nojima T;Okuno Y;Onogi H;Usui T;Takeuchi A;Hosoya T;Suzuki T;Hagiwara M.
家族性自主神经功能障碍（Familial dysautonomia，FD）是由B细胞kappa轻链多肽抑制因子基因增强子（IKK complex associated protein，IKAP）/延长蛋白1（elongator protein 1，ELP 1）基因外显子20的内含子突变引起的一种遗传性感觉和自主神经病。新建立的剪接报告分析使我们能够可视化细胞中的致病性剪接，并筛选小的化学物质的能力，以纠正异常剪接ofIKBKAP。使用这种剪接报告基因，我们筛选了我们的化学文库，并确定了一种化合物，异常剪接的整流器（RECTAS），它纠正了FD患者细胞中的异常IKBKAP剪接。在这里，我们发现在FD患者的细胞中，细胞质tRNA中摆动位置处的修饰尿苷水平降低，并且用RECTAS治疗增加了IKAP的表达并恢复了tRNA修饰。这些结果表明，IKBKP的错误剪接导致FD患者的tRNA修饰减少，RECTAS是一种有前途的FD治疗药物候选者。
Familial dysautonomia (FD), a hereditary sensory and autonomic neuropathy, is caused by missplicing of exon 20, resulting from an intronic mutation in the inhibitor of kappa light polypeptide gene enhancer in B cells, kinase complex-associated protein (IKBKAP) gene encoding IKK complex-associated protein (IKAP)/elongator protein 1 (ELP1). A newly established splicing reporter assay allowed us to visualize pathogenic splicing in cells and to screen small chemicals for the ability to correct the aberrant splicing ofIKBKAP. Using this splicing reporter, we screened our chemical libraries and identified a compound, rectifier of aberrant splicing (RECTAS), that rectifies the aberrantIKBKAPsplicing in cells from patients with FD. Here, we found that the levels of modified uridine at the wobble position in cytoplasmic tRNAs are reduced in cells from patients with FD and that treatment with RECTAS increases the expression of IKAP and recovers the tRNA modifications. These findings suggest that the missplicing ofIKBKAPresults in reduced tRNA modifications in patients with FD and that RECTAS is a promising therapeutic drug candidate for FD.