Scholarlink

<p>Aberrant inclusion of pseudoexons (PE) in mature mRNA is a rare splicing defect contributing to Duchenne muscular dystrophy (DMD) pathogenesis. In this study, we described two affected males from a Chinese family who presented with progressive muscle weakness, elevated creatine kinase (CK) levels, and dystrophic changes on muscle pathology. Whole-genome sequencing followed by linkage-based filtering identified a shared deep intronic variant in intron 47 of <i>DMD</i> gene (c.6913-4037T&gt;G), which activated a cryptic splice site and resulted in the inclusion of a 72 bp PE between exons 47 and 48. Patient induced pluripotent stem cells (iPSCs)-derived myotubes from the patient confirmed the presence of this PE, with a significant reduction in dystrophin expression compared to controls. Quantitative PCR revealed that aberrant transcripts comprised ~89% of total <i>DMD</i> transcripts in myotubes and ~97% in muscle, correlating with near-complete loss of dystrophin. Functional assays further showed impaired myotube fusion and altered calcium signaling. This study underscores the diagnostic complexity of intronic <i>DMD</i> variants and provides evidence supporting the pathogenicity of c.6913-4037T&gt;G.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Pseudoexon activating by a deep intronic variant and phenotype variation in a Chinese family with dystrophinopathy

  • 期刊论文

  • 发表日期：

    2025年6月30日

查看全文
  • Xingyu Xia,
  • Kexin Jiao,
  • Chaoping Hu,
  • Nachuan Cheng,
  • Mingshi Gao,
  • Shiyi Xiong,
  • Ningning Wang,
  • Bochen Zhu,
  • Meining Diao,
  • Dongyue Yue,
  • Jianying Xi,
  • Chongbo Zhao,
  • Chengwen Chen,
  • Wenhua Zhu

摘要

Aberrant inclusion of pseudoexons (PE) in mature mRNA is a rare splicing defect contributing to Duchenne muscular dystrophy (DMD) pathogenesis. In this study, we described two affected males from a Chinese family who presented with progressive muscle weakness, elevated creatine kinase (CK) levels, and dystrophic changes on muscle pathology. Whole-genome sequencing followed by linkage-based filtering identified a shared deep intronic variant in intron 47 of DMD gene (c.6913-4037T>G), which activated a cryptic splice site and resulted in the inclusion of a 72 bp PE between exons 47 and 48. Patient induced pluripotent stem cells (iPSCs)-derived myotubes from the patient confirmed the presence of this PE, with a significant reduction in dystrophin expression compared to controls. Quantitative PCR revealed that aberrant transcripts comprised ~89% of total DMD transcripts in myotubes and ~97% in muscle, correlating with near-complete loss of dystrophin. Functional assays further showed impaired myotube fusion and altered calcium signaling. This study underscores the diagnostic complexity of intronic DMD variants and provides evidence supporting the pathogenicity of c.6913-4037T>G.