Holmes-Hampton Gregory P, Crooks Daniel R, Haller Ronald G, Guo Shuling, Freier Susan M, Monia Brett P, Rouault Tracey A
Molecular Medicine Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD, USA.
Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
Hum Mol Genet. 2016 Dec 1;25(23):5178-5187. doi: 10.1093/hmg/ddw338.
ISCU myopathy is an inherited disease that primarily affects individuals of northern Swedish descent who share a single point mutation in the fourth intron of the ISCU gene. The current study shows correction of specific phenotypes associated with disease following treatment with an antisense oligonucleotide (ASO) targeted to the site of the mutation. We have shown that ASO treatment diminished aberrant splicing and increased ISCU protein levels in both patient fibroblasts and patient myotubes in a concentration dependent fashion. Upon ASO treatment, levels of SDHB in patient myotubular cell lines increased to levels observed in control myotubular cell lines. Additionally, we have shown that both patient fibroblast and myotubular cell lines displayed an increase in complex II activity with a concomitant decrease in succinate levels in patient myotubular cell lines after ASO treatment. Mitochondrial and cytosolic aconitase activities increased significantly following ASO treatment in patient myotubes. The current study suggests that ASO treatment may serve as a viable approach to correcting ISCU myopathy in patients.
铁硫簇组装蛋白（ISCU）肌病是一种遗传性疾病，主要影响有瑞典北部血统的个体，这些个体在ISCU基因的第四内含子中有一个单点突变。当前研究表明，用靶向该突变位点的反义寡核苷酸（ASO）治疗后，与该疾病相关的特定表型得到了纠正。我们已经表明，ASO治疗以浓度依赖的方式减少了异常剪接，并增加了患者成纤维细胞和患者肌管中的ISCU蛋白水平。经ASO治疗后，患者肌管细胞系中琥珀酸脱氢酶（SDHB）的水平增加到了对照肌管细胞系中观察到的水平。此外，我们已经表明，在ASO治疗后，患者成纤维细胞和肌管细胞系中复合物II的活性均有所增加，同时患者肌管细胞系中的琥珀酸水平有所下降。在患者肌管中，经ASO治疗后，线粒体和胞质乌头酸酶的活性显著增加。当前研究表明，ASO治疗可能是纠正患者ISCU肌病的一种可行方法。
