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<p>Mutations in the cyclin-dependent kinase-like 5 gene (<i>CDKL5</i>) cause a severe neurodevelopmental disorder, yet the impact of truncating mutations remains unclear. Here, we introduce the <i>Cdkl5</i><sup><i>492stop</i></sup> mouse model, mimicking C-terminal truncating mutations in patients. 492stop/Y mice exhibit altered dendritic spine morphology and spontaneous seizure-like behaviors, alongside other behavioral deficits. After creating cell lines with various <i>Cdkl5</i> truncating mutations, we found that these mutations are regulated by the nonsense-mediated RNA decay pathway. Most truncating mutations result in CDKL5 protein loss, leading to multiple disease phenotypes, and offering new insights into the pathogenesis of CDKL5 disorder.</p>

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A Novel Mouse Model Unveils Protein Deficiency in Truncated CDKL5 Mutations

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年3月5日

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  • Xue Feng,
  • Zi-Ai Zhu,
  • Hong-Tao Wang,
  • Hui-Wen Zhou,
  • Ji-Wei Liu,
  • Ya Shen,
  • Yu-Xian Zhang,
  • Zhi-Qi Xiong

摘要

Mutations in the cyclin-dependent kinase-like 5 gene (CDKL5) cause a severe neurodevelopmental disorder, yet the impact of truncating mutations remains unclear. Here, we introduce the Cdkl5492stop mouse model, mimicking C-terminal truncating mutations in patients. 492stop/Y mice exhibit altered dendritic spine morphology and spontaneous seizure-like behaviors, alongside other behavioral deficits. After creating cell lines with various Cdkl5 truncating mutations, we found that these mutations are regulated by the nonsense-mediated RNA decay pathway. Most truncating mutations result in CDKL5 protein loss, leading to multiple disease phenotypes, and offering new insights into the pathogenesis of CDKL5 disorder.