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
  • 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. [email protected].
  • 6. School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China. [email protected].
  • 7. University of Chinese Academy of Sciences, Beijing, 100049, China. [email protected].
  • 8. Shanghai Center for Brain Science and Brain-Inspired Intelligence Technology, Shanghai, 201210, China. [email protected].
  • 9. School of Future Technology, University of Chinese Academy of Sciences, Beijing, 100049, China. [email protected].
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.
Products