NMD逃逸机制及其在疾病治疗中的应用

doi:10.16288/j.yczz.19-335

遗传 ›› 2020, Vol. 42 ›› Issue (4): 354-362.doi: 10.16288/j.yczz.19-335

NMD逃逸机制及其在疾病治疗中的应用

程苗苗, 曹延延()

首都儿科研究所遗传室,北京 100020

收稿日期:2019-12-20 修回日期:2020-02-25 出版日期:2020-04-20 发布日期:2020-03-06
通讯作者: 曹延延 E-mail:caoyanyan@bjmu.deu.cn
作者简介:程苗苗,硕士研究生,专业方向：儿科学。E-mail: 1245156226@qq.com
基金资助:
北京市自然科学基金项目编号(No.5163028);国家自然科学基金项目编号(81500979);国家重点研发计划项目编号(2016YFC0901505);中国医学科学院医学与健康科技创新工程项目资助编号：(2016-I2M-1-008)

The NMD escape mechanism and its application in disease therapy

Miaomiao Cheng, Yanyan Cao()

Department of Medical Genetics, Capital Institute of Pediatrics, Beijing 100020, China

Received:2019-12-20 Revised:2020-02-25 Online:2020-04-20 Published:2020-03-06
Contact: Cao Yanyan E-mail:caoyanyan@bjmu.deu.cn
Supported by:
Supported by Beijing Natural Science Foundation(No.5163028);the National Natural Science Foundation of China No(81500979);CAMS Initiative for Innovative Medicine No(2016YFC0901505);CAMS Initiative for Innovative Medicine No(2016-I2M-1-008)

摘要/Abstract

摘要：

无义介导的mRNA降解(nonsense-mediated mRNA decay, NMD)是指在病理或正常生理情况下mRNA上出现了提前终止密码子(premature termination codon, PTC),从而导致mRNA降解。它是一种广泛存在的mRNA质量监控机制。近年来,在多种疾病中发现某些PTC并未触发NMD,这种现象被称为NMD逃逸(NMD escape),然而其确切机制尚不十分清楚。目前公认的两个学说为：(1) PTC通读,即蛋白的翻译可以顺利通过PTC直至正常的终止密码子,产生全长蛋白;(2)翻译的重新启动,即蛋白翻译在PTC下游的潜在起始点重新开始直至终止密码子,产生N端截短蛋白。目前,通过利用PTC通读,越来越多的药物或小分子已被成功用于无义变异相关疾病的治疗。本文主要综述了NMD逃逸的机制及其在疾病治疗中的应用和进展,以期为进一步了解NMD逃逸及其相关应用概况提供参考。

关键词: NMD逃逸, 无义突变, 提前终止密码子, PTC通读

Abstract:

Nonsense-mediated mRNA decay (NMD) refers to the degradation of mRNA due to the presence of premature stop codon (PTC) on mRNA under pathological or physiological conditions. NMD is widely considered an mRNA-specific quality control process. Recently it was discovered that some PTCs do not trigger NMD in a variety of diseases - a process known as NMD escape; however, its exact mechanism remains unclear. At present, there are two widely accepted mechanistic hypotheses during NMD escape. The first is PTC read-through, in which protein translation undergoes PTC until the normal stop codon is encountered, producing a full-length protein. The second is translation reinitiation, in which protein translation recommences at the potential start codon downstream of PTC and terminates at the stop codon, producing an N-terminal truncated protein. Currently, an increasing number of drugs or small molecules that use PTC read-through have been successfully applied to treat nonsense variation-associated diseases. In this review, we summarize the NMD mechanism and discuss the application and progress in our understanding of NMD escape in disease therapy. This review should provide a useful framework to advance current understanding of the research and application of NMD escape.

Key words: NMD escape, nonsense mutation, premature stop codon (PTC), PTC read-through

程苗苗, 曹延延. NMD逃逸机制及其在疾病治疗中的应用[J]. 遗传, 2020, 42(4): 354-362.

Miaomiao Cheng, Yanyan Cao. The NMD escape mechanism and its application in disease therapy[J]. Hereditas(Beijing), 2020, 42(4): 354-362.

图/表 3

图1

图2

表1

基于促通读机制的药物研究应用现况"

通读药物	实验模型	临床试验	相关疾病	特点与问题
氨基糖苷类
庆大霉素^[27]	动物和患者	有	囊性纤维化(CF)、杜氏肌营养不良(DMD)、瑞特综合征(RTT)、共济失调性毛细血管扩张症(AT)、法布里病(Fabry)、尼曼匹克症A/B型(NPA/NPB)、全身性神经节苷脂贮积(Gangliosidosis I )、粘多糖累积症II型(MPS II) 、MPS I-H,MPS IIIB,MPS VI、血友病A和B(HA和HB)、无脉络膜症(Choroideremia)、先天性黑朦(LCA type 2)、眼缺损(Ocular coloboma )和Usher综合征I型(USH1)	副作用如耳毒性、肾毒性和视网膜毒性
阿米卡星^[28]	动物和细胞	无	囊性纤维化(CF)、瑞特综合征(RTT)、粘多糖累积症I-H(MPS I-H)和脊髓型肌萎缩症I型 (SMA I)
妥布霉素^[29]	动物	无	囊性纤维化和脊髓型肌萎缩症I型(SMA I)
巴龙霉素^[30]	细胞	无	囊性纤维化(CF)、杜氏肌营养不良(DMD)、瑞特综合征(RTT)、无脉络膜症(Choroideremia)、粘多糖累积症I-H(MPS I-H)、眼缺损(Ocular coloboma )和Usher综合征I型(USH1)
G418^[28]	动物和细胞	无	囊性纤维化(CF)、瑞特综合征(RTT)、共济失调性毛细血管扩张症(AT)、粘多糖累积症I-H(MPS I-H)、脊髓型肌萎缩症I型(SMA I)、先天性黑朦(LCA type 2)、色素性视网膜炎(RP)和Usher综合征I型(USH1)
氨基糖苷类衍生物
新霉素衍生物 (TC003和TC007)^[29]	动物和细胞	无	脊髓型肌萎缩症I型(SMA I)	生物相容性更好
卡那霉素衍生物 (JL023)^[29]			脊髓型肌萎缩症I型(SMA I)	无明显副作用
巴龙霉素衍生物 (NB30、NB54、 NB84和NB124)^[31]	动物和细胞	无	囊性纤维化(CF)、瑞特综合征(RTT) Usher综合征I型(USH1)和粘多糖累积症I-H(MPS I-H)	较高的生物相容性、剂量依赖性,可通过血脑屏障,无明显副作用
非氨基糖苷类^[32]
PTC124	动物和患者	有	囊性纤维化(CF)、杜氏肌营养不良(DMD)、粘多糖累积症VI型(MPS VI)、神经元蜡样脂褐质沉积症(NCLs)、贝敦氏病(Batten disease)、色素性视网膜炎(RP)、Usher综合征I型(USH1)和先天性无虹膜(Congenital aniridia)	耐受性良好,无严重副作用
RTC13、RTC14和 RTC229	细胞	无	杜氏肌营养不良(DMD)和共济失调性毛细血管扩张症(AT)	对3种提前终止密码子均有效

表1

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The NMD escape mechanism and its application in disease therapy

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[1]	付洋, 舒在悦, 顾鸣敏. 促通读药物的作用机制与临床应用[J]. 遗传, 2016, 38(7): 623-633.
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[3]	郭文婷，徐汪洋，顾鸣敏. 无义介导的mRNA降解机制及其在单基因遗传病中的作用[J]. 遗传, 2012, 34(8): 935-942.
[4]	黄颖浩，杨琴波，邓云华，余念文，王擎，刘木根. 一个Ⅰ型神经纤维瘤家系的基因突变分析[J]. 遗传, 2008, 30(3): 309-312.