Epilepsy is one of the most frequent neurological diseases, with focal epilepsy accounting for the largest number of cases. The genetic alterations involved in focal epilepsy are far from being fully elucidated. Here, we show that defective lipid signalling caused by heterozygous ultra-rare variants in PIK3C2B, encoding for the class II phosphatidylinositol 3-kinase PI3K-C2β, underlie focal epilepsy in humans. We demonstrate that patients' variants act as loss-of-function alleles, leading to impaired synthesis of the rare signalling lipid phosphatidylinositol 3,4-bisphosphate, resulting in mTORC1 hyperactivation. In vivo, mutant Pik3c2b alleles caused dose-dependent neuronal hyperexcitability and increased seizure susceptibility, indicating haploinsufficiency as a key driver of disease. Moreover, acute mTORC1 inhibition in mutant mice prevented experimentally induced seizures, providing a potential therapeutic option for a selective group of patients with focal epilepsy. Our findings reveal an unexpected role for class II PI3K-mediated lipid signalling in regulating mTORC1-dependent neuronal excitability in mice and humans.

中文翻译：

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由 PIK3C2B 突变引起的脂质信号缺陷是局灶性癫痫的基础。

癫痫是最常见的神经系统疾病之一，其中局灶性癫痫占病例最多。与局灶性癫痫有关的遗传改变远未完全阐明。在这里，我们表明，由编码 II 类磷脂酰肌醇 3-激酶 PI3K-C2β 的 PIK3C2B 中的杂合超罕见变体引起的脂质信号缺陷是人类局灶性癫痫的基础。我们证明患者的变异作为功能丧失的等位基因，导致稀有信号脂质磷脂酰肌醇 3,4-二磷酸的合成受损，导致 mTORC1 过度激活。在体内，突变的 Pik3c2b 等位基因导致剂量依赖性神经元过度兴奋和癫痫易感性增加，表明单倍体不足是疾病的关键驱动因素。而且，突变小鼠中的急性 mTORC1 抑制可防止实验诱导的癫痫发作，为选择性的局灶性癫痫患者群体提供了潜在的治疗选择。我们的研究结果揭示了 II 类 PI3K 介导的脂质信号传导在调节小鼠和人类 mTORC1 依赖性神经元兴奋性中的意外作用。