Multiple exon skipping strategies to by-pass dystrophin mutations

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• 作者：Carl F. Adkin^a ; Penelope L. Meloni^a ; Susan Fletcher^a ; Abbie M. Adams^a ; Francesco Muntoni^b ; Brenda Wong^c ; ^d ; Steve D. Wilton^a ; ^{swilton@meddent.uwa.edu.au}
• 关键词：Dystrophin ; Duchenne muscular dystrophy ; Exon skipping ; Antisense oligomers ; Splice-switching ; Personalised genetic therapy
• 刊名：Neuromuscular Disorders
• 出版年：2012
• 期刊代码：203_09608966
• 类别：med
• 出版时间：April, 2012
• 卷：22
• 期：4
• 页码：297-305
• 文件大小：775 K

摘要

Manipulation of dystrophin pre-mRNA processing offers the potential to overcome mutations in the dystrophin gene that would otherwise lead to Duchenne muscular dystrophy. Dystrophin mutations will require the removal of one or more exons to restore the reading frame and in some cases, multiple exon skipping strategies exist to restore dystrophin expression. However, for some small intra-exonic mutations, a third strategy, not applicable to whole exon deletions, may be possible. The removal of only one frame-shifting exon flanking the mutation-carrying exon may restore the reading frame and allow synthesis of a functional dystrophin isoform, providing that no premature termination codons are encountered. For these mutations, the removal of only one exon offers a simpler, cheaper and more feasible alternative approach to the dual exon skipping that would otherwise be considered. We present strategies to by-pass intra-exonic dystrophin mutations that clearly demonstrate the importance of tailoring exon skipping strategies to specific patient mutations.