Dystrophin quantification and clinical correlations in Becker muscular dystrophy: implications for clinical trials
Dystrophin quantification and clinical correlations in Becker muscular dystrophy: implications for clinical trials
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DOI：
10.1093/brain/awr291
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发表时间：
2011-12-01
期刊：
影响因子：
14.5
通讯作者：
Muntoni, Francesco
中科院分区：
文献类型：
--
作者：
Anthony, Karen;Cirak, Sebahattin;Muntoni, Francesco
杜氏肌营养不良症是由DMD基因突变引起的，该突变破坏了开放阅读框架并阻止其蛋白产物肌营养不良蛋白的完全翻译。开放阅读框的恢复和肌营养不良蛋白的产生可以通过使用靶向剪接元件的反义寡核苷酸的外显子跳跃来实现。这种方法旨在将杜氏肌营养不良症表型转化为较温和的疾病，贝克尔肌营养不良症，通常由框内肌营养不良蛋白缺失引起，其允许产生内部缺失但部分功能性肌营养不良蛋白。关于不同突变的外显子跳跃产生的不同内部缺失的肌营养不良蛋白的功能特性正在进行辩论;更多的见解对于改善和更好地预测外显子跳跃临床试验的结果是有价值的。为此，我们已经表征了17例贝克肌营养不良症患者的临床表型，这些患者携带与正在进行或计划进行的杜氏肌营养不良症外显子跳跃临床试验相关的框内缺失，并将其与肌营养不良蛋白和肌营养不良蛋白相关蛋白表达水平相关。17名患者的队列，完全根据他们的基因型选择，包括4名无症状，12名轻度和1名重度患者。所有患者的肌营养不良蛋白水平均>对照组的40%，并且在无症状个体中观察到肌营养不良蛋白（P = 0.013）、β-肌营养不良聚糖（P = 0.025）和神经元型一氧化氮合酶（P = 0.034）表达显著高于有症状的贝克肌营养不良患者。此外，通过缺失对患者进行分组，具有以外显子51为终点的缺失的贝克尔肌营养不良症患者（其跳跃可以挽救最大组的杜氏肌营养不良症缺失）显示出比具有以外显子53为终点的缺失的患者显著更高的肌营养不良蛋白水平（P = 0.034）。这是第一个定量研究与正在进行的外显子跳跃试验在杜氏肌营养不良症相关缺失的贝克肌营养不良症患者的肌营养不良蛋白和肌营养不良蛋白相关蛋白的表达。总之，我们的结果表明，在这项研究中评估的所有品种的内部缺失的肌营养不良蛋白的功能能力，提供了一个实质性的临床受益杜氏肌营养不良症患者。
Duchenne muscular dystrophy is caused by mutations in the DMD gene that disrupt the open reading frame and prevent the full translation of its protein product, dystrophin. Restoration of the open reading frame and dystrophin production can be achieved by exon skipping using antisense oligonucleotides targeted to splicing elements. This approach aims to transform the Duchenne muscular dystrophy phenotype to that of the milder disorder, Becker muscular dystrophy, typically caused by in-frame dystrophin deletions that allow the production of an internally deleted but partially functional dystrophin. There is ongoing debate regarding the functional properties of the different internally deleted dystrophins produced by exon skipping for different mutations; more insight would be valuable to improve and better predict the outcome of exon skipping clinical trials. To this end, we have characterized the clinical phenotype of 17 patients with Becker muscular dystrophy harbouring in-frame deletions relevant to on-going or planned exon skipping clinical trials for Duchenne muscular dystrophy and correlated it to the levels of dystrophin, and dystrophin-associated protein expression. The cohort of 17 patients, selected exclusively on the basis of their genotype, included 4 asymptomatic, 12 mild and 1 severe patient. All patients had dystrophin levels of > 40% of control and significantly higher dystrophin (P = 0.013), beta-dystroglycan (P = 0.025) and neuronal nitric oxide synthase (P = 0.034) expression was observed in asymptomatic individuals versus symptomatic patients with Becker muscular dystrophy. Furthermore, grouping the patients by deletion, patients with Becker muscular dystrophy with deletions with an end-point of exon 51 (the skipping of which could rescue the largest group of Duchenne muscular dystrophy deletions) showed significantly higher dystrophin levels (P = 0.034) than those with deletions ending with exon 53. This is the first quantitative study on both dystrophin and dystrophin-associated protein expression in patients with Becker muscular dystrophy with deletions relevant for on-going exon skipping trials in Duchenne muscular dystrophy. Taken together, our results indicate that all varieties of internally deleted dystrophin assessed in this study have the functional capability to provide a substantial clinical benefit to patients with Duchenne muscular dystrophy.