Epilepsy and autism spectrum disorders (ASD) frequently show comorbidity, suggesting shared or overlapping neurobiological basis underlying these conditions. R104Q is the first mutation in the PRICKLE 1(PK1) gene that was discovered in human patients with progressive myoclonus epilepsy (PME). Subsequently, a number of mutations in the PK1 gene were shown to be associated with either epilepsy, autism, or both, as well as other developmental disorders. Using CRISPR-Cas9-mediated gene editing, we generated a PK1^R104Q mouse line. The mutant mice showed reduced density of excitatory synapses in hippocampus and impaired interaction between PK1 and the repressor element 1(RE-1) silencing transcription factor (REST). They also displayed reduced seizure threshold, impaired social interaction, and cognitive functions. Taken together, the PK1^R104Q mice display characteristic behavioral features similar to the key symptoms of epilepsy and ASD, providing a useful model for studying the molecular and neural circuit mechanisms underlying the comorbidity of epilepsy and ASD.

癫痫和自闭症谱系障碍 (ASD) 经常表现出合并症，表明这些疾病背后存在共同或重叠的神经生物学基础。 R104Q是在患有进行性肌阵挛癫痫 (PME) 的人类患者中发现的PRICKLE 1 (PK1)基因的第一个突变。随后， PK1基因中的许多突变被证明与癫痫、自闭症或两者以及其他发育障碍有关。使用 CRISPR-Cas9 介导的基因编辑，我们生成了 PK1 ^R104Q小鼠品系。突变小鼠的海马兴奋性突触密度降低，PK1 与阻遏元件 1 (RE-1) 沉默转录因子 (REST) 之间的相互作用受损。他们还表现出癫痫阈值降低、社交互动和认知功能受损。综上所述，PK1 ^R104Q小鼠表现出与癫痫和 ASD 关键症状相似的特有行为特征，为研究癫痫和 ASD 共病的分子和神经回路机制提供了有用的模型。