Xue Feng1,2,3 · Zi‑Ai Zhu1,3 · Hong‑Tao Wang1 · Hui‑Wen Zhou1,2,3 · Ji‑Wei Liu4 · Ya Shen1 · Yu‑Xian Zhang1 · Zhi‑Qi Xiong1,2,3,5,61 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 Shanghai Center for Brain Science and Brain-Inspired Intelligence Technology, Shanghai 201210, China
6 School of Future Technology, University of Chinese Academy of Sciences, Beijing 100049, China
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; Truncating mutations; CDKL5 defciency disorder; Nonsense-mediated RNA decay
