Cryptic exon activation causes dystrophinopathy in two Chinese families
Cryptic exon activation causes dystrophinopathy in two Chinese families
复制标题
隐秘外显子激活导致两个中国家庭肌营养不良症
DOI：
10.1038/s41431-020-0578-z
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发表时间：
2020-02-11
影响因子：
5.2
通讯作者：
Wang, Zhi-Qiang
中科院分区：
文献类型：
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作者：
Jin, Ming;Li, Jin-Jing;Wang, Zhi-Qiang
x连锁隐性退行性疾病营养不良症是由dmd基因变异引起的。鉴于dmd基因的大尺寸和复杂性，所有肌营养不良病的分子诊断仍然具有挑战性。在这里，我们使用基于RNA和dna的联合方法鉴定了营养不良症患者中由内含子单核苷酸变异引起的两个隐外显子保留变异。由于一种变异以前未被报道，我们通过生物信息学预测对剪接进行计算机验证，探索了其可能的致病机制。然后，我们构建了一个包含该变异的minigene系统，并使用morpholino修饰的反义寡核苷酸（ASOs）诱导隐外显子跳变。ASOs处理纠正了突变体minigene系统中的错误剪接。我们的研究定义了一种新的内含子变异，可以引起肌营养不良症，并阐明了克服异常剪接的策略。
The X-linked recessive degenerative disease dystrophinopathy results from variants in theDMDgene. Given the large size and complexity of theDMDgene, molecular diagnosis for all dystrophinopathies remains challenging. Here we identified two cryptic exon retention variants caused by intronic single nucleotide variants in dystrophinopathy patients using combined RNA- and DNA-based methods. As one variant was previously unreported, we explored its likely pathogenic mechanism, via bioinformatic prediction for in silico verification of splicing. Then we constructed a minigene system harboring the variant and used morpholino modified antisense oligonucleotides (ASOs) to induce cryptic exon skipping. ASOs treatment corrected the mis-splicing in the mutant minigene system. Our study defines a novel intronic variant that can cause dystrophinopathy, and illustrates a strategy to overcome the aberrant splicing.