Differential stabilities of alternative exon-skipped rod motifs of dystrophin.
Differential stabilities of alternative exon-skipped rod motifs of dystrophin.
复制标题
肌营养不良蛋白的替代外显子跳跃杆基序的差异稳定性。
DOI：
10.1016/j.bbapap.2009.02.016
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发表时间：
2009
期刊：
影响因子：
--
通讯作者：
Menhart,Nick
中科院分区：
文献类型：
--
作者：
Ruszczak,Chris;Mirza,Ahmed;Menhart,Nick
外显子跳跃修复是一种正在早期临床试验中研究的治疗杜氏肌营养不良症的策略。这最适用于当遗传缺陷导致移码突变时出现的大多数情况，并且异相外显子的诱导外显子跳跃恢复阅读框。然而，尚未考虑如此产生的编辑蛋白质的后果。在许多情况下，恢复阅读框的替代途径是可能的，我们在涉及外显子 44 的测试案例中表明，所得到的不同编辑的蛋白质在稳定性上有很大差异，其中一种与正常的未跳过的肌营养不良蛋白非常相似，而另一种根据折叠热力学和蛋白水解抗性评估的稳定性要差得多。这对于最佳治疗性外显子跳跃策略的设计具有影响，该策略可能希望以尽可能忠实于正常肌营养不良蛋白的方式进行修复。
Exon skipping repair is a strategy being investigated in early stage clinical trials to treat Duchenne muscular dystrophy. This is most applicable to the majority of cases which arise when genetic defects cause frame shift mutations, and induced exon skipping of out-of-phase exons restores the reading frame. However, the consequences to the edited protein so produced have not been considered. In many cases alternative routes to restoring the reading frame are possible, and we show in a test case involving exon 44 that the resulting differently edited proteins greatly vary in stability, with one of them very similar to normal unskipped dystrophin, and the other much less stable as assessed by the thermodynamics of folding as well as resistance to proteolysis. This has implications for the design of optimal therapeutic exon skipping strategies, which presumably wish to result repairs with as much fidelity to normal dystrophin as possible.