ArticleBrain : a journal of neurology2022
Defective lipid signalling caused by mutations in PIK3C2B underlies focal epilepsy.
Article in Brain : a journal of neurology, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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10 citing papers in PubMed, 23 citations in OpenAlex.
- Metabolic changes in mTOR pathway-associated cortical malformation.Frontiers in neuroscience · 2026Review
- PIK3C2B drives lung cancer progression through coordinating metabolic reprogramming and EMT-mediated metastasis.Biochemistry and biophysics reports · 2025Article
- Tcf4 Deficiency causes recurrent seizures in mice.Progress in neurobiology · 2025Article
- Neuronal autophagy controls excitability via ryanodine receptor-mediated regulation of calcium-activated potassium channel function.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Serum HDL-C levels in children with epilepsy: a single-center retrospective study.Frontiers in nutrition · 2025Article
- Schisandrin B, a dual positive allosteric modulator of GABAActa pharmacologica Sinica · 2024Article
- Integrating metabolomics and lipidomics revealed a decrease in plasma fatty acids but an increase in triglycerides in children with drug-refractory epilepsy.Epilepsia open · 2023Article
- Beyond PI3Ks: targeting phosphoinositide kinases in disease.Nature reviews. Drug discovery · 2023Review
- Article
- Antagonistic control of active surface integrins by myotubularin and phosphatidylinositol 3-kinase C2β in a myotubular myopathy model.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
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Authors and funding
32 authors at 13 institutions in 4 countries.
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Abstract
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.
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