2. Academic Validation
  3. A Novel Mouse Model Unveils Protein Deficiency in Truncated CDKL5 Mutations

A Novel Mouse Model Unveils Protein Deficiency in Truncated CDKL5 Mutations

  • Neurosci Bull. 2025 Mar 5. doi: 10.1007/s12264-024-01346-4.
Xue Feng 1 2 3,  Zi-Ai Zhu 1 3,  Hong-Tao Wang 1,  Hui-Wen Zhou 1 2 3,  Ji-Wei Liu 4,  Ya Shen 1,  Yu-Xian Zhang 1,  Zhi-Qi Xiong 5 6 7 8 9
Affiliations

Affiliations

  • 1 Institute of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, 200031, China.
  • 2 School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China.
  • 3 University of Chinese Academy of Sciences, Beijing, 100049, China.
  • 4 Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, China.
  • 5 Institute of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, 200031, China. xiongzhiqi@ion.ac.cn.
  • 6 School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China. xiongzhiqi@ion.ac.cn.
  • 7 University of Chinese Academy of Sciences, Beijing, 100049, China. xiongzhiqi@ion.ac.cn.
  • 8 Shanghai Center for Brain Science and Brain-Inspired Intelligence Technology, Shanghai, 201210, China. xiongzhiqi@ion.ac.cn.
  • 9 School of Future Technology, University of Chinese Academy of Sciences, Beijing, 100049, China. xiongzhiqi@ion.ac.cn.
PMID: 40042769 DOI: 10.1007/s12264-024-01346-4
Abstract

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.

Keywords

Cdkl5; CDKL5 deficiency disorder; Nonsense-mediated RNA decay; Truncating mutations.

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