Multiexon skipping leading to an artificial DMD protein lacking amino acids from exons 45 through 55 could rescue up to 63 % of patients with Duchenne muscular dystrophy
Multiexon skipping leading to an artificial DMD protein lacking amino acids from exons 45 through 55 could rescue up to 63 % of patients with Duchenne muscular dystrophy
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DOI：
10.1002/humu.20428
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发表时间：
2007-02-01
期刊：
影响因子：
3.9
通讯作者：
Claustres, Mireille
中科院分区：
文献类型：
--
作者：
Beroud, Christophe;Tuffery-Giraud, Sylvie;Claustres, Mireille
大约三分之二的杜氏肌营养不良症（DMD）患者表现出DMD基因的一个到几个外显子的基因内缺失，并导致过早停止密码子。维持该基因翻译阅读框的其他缺失导致较轻的贝克肌营养不良（BMD）形式的疾病。因此，随着反义寡核苷酸技术的发展，将DMD表型转化为BMD表型的机会成为一种新的治疗策略，该技术能够在mrna前水平诱导外显子跳变，以恢复开放阅读框。由于DMD基因包含79个外显子，数以千计的潜在转录本可能通过外显子跳变产生，应该进行研究。传统的方法考虑跳过单个外显子。在这里，我们报告了基于生物信息学分析的单外显子和多外显子跳跃策略的比较。通过使用通用突变数据库(UMD)-DMD，我们预测导致del45-55人工肌营养不良蛋白（c.6439_8217del）的最佳多外显子跳变可以将DMD表型转化为无症状或轻度BMD表型。这种多外显子跳脱理论上可以挽救多达63%的缺失DMD患者，而最佳的51外显子单跳脱只能挽救16%的患者。
Approximately two thirds of Duchenne muscular dystrophy (DMD) patients show intragenic deletions ranging from one to several exons of the DMD gene and leading to a premature stop codon. Other deletions that maintain the translational reading frame of the gene result in the milder Becker muscular dystrophy (BMD) form of the disease. Thus the opportunity to transform a DMD phenotype into a BMD phenotype appeared as a new treatment strategy with the development of antisense oligonucleotides technology, which is able to induce an exon skipping at the pre-mRNA level in order to restore an open reading frame. Because the DMD gene contains 79 exons, thousands of potential transcripts could be produced by exon skipping and should be investigated. The conventional approach considers skipping of a single exon. Here we report the comparison of single- and multiple-exon skipping strategies based on bioinformatic analysis. By using the Universal Mutation Database (UMD)-DMD, we predict that an optimal multiexon skipping leading to the del45-55 artificial dystrophin (c.6439_8217del) could transform the DMD phenotype into the asymptomatic or mild BMD phenotype. This multiple-exon skipping could theoretically rescue up to 63% of DMD patients with a deletion, while the optimal monoskipping of exon 51 would rescue only 16% of patients.