Protective effect of CACNA1A deficiency in oligogenic refractory epilepsy with CACNA1A‐CELSR2 digenic mutations

作者：ChengYan Liu, Mei‐Zhen Sun, Yong‐Miao Lin, Xuefei Zhang, Ruina Huang, Ming‐Feng He, Sheng Luo, Si‐Yuan Luo, Tao Huang, Nan Jiang, Jie Luo, Jiaxin Zhang, P.Y. Chen, Xi Liang Dai, Tian‐Ai Han, Wei‐Ping Liao, Rong‐Chao Peng, Jing‐Da Qiao · 发表于：Epilepsia · 年份：2025 · DOI：10.1111/epi.18390 · 被引用次数：4 · 研究领域：Genomics and Rare Diseases、Epilepsy research and treatment、Neuroscience and Neuropharmacology Research

OBJECTIVE: The vast majority of refractory epilepsy cases have a complex oligogenic/polygenic origin, which presents a challenge to precision medicine in individual patients. Nonetheless, the high workload and lack of effective guidelines have limited the number of in-depth animal studies. METHODS: Whole-exon sequencing identified a case with refractory epilepsy caused by a combination of two rare and de novo heterozygous variants in CACNA1A and CELSR2, respectively. Polygenic mutation flies were established and logistic regression were applied to study the gene-gene interaction and quantify the seizure-risk weight of epilepsy-associated genes in a polygenic background. In addition, calcium imaging, pharmacology, and transgenic rescue experiments were used to explore the mechanism and the precision medicine strategy for this model. RESULTS: Seizure-like activity was mitigated in the Cacna1a-Celsr2 digenic knockdown flies, whereas it was aggravated in the Cacna1a knockin-Celsr2 knockdown flies, and all relevant monogenic mutation flies showed seizures. Logistic regression suggested that the Cacna1a deficiency provided a protective effect against seizures in Celsr2 knockdown flies. The severe seizures from Cacna1a knockin-Celsr2 knockdown, the genotype mimicking that of the patient, can be completely rescued by inhibiting the calcium channel via genetic (Cacna1a knockdown) or pharmacologic (pregabalin) treatment during a limited period of development. Calcium imaging results su...