Defective lipid signalling caused by mutations in PIK3C2B underlies focal epilepsy.

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.

• Authors: Luca Gozzelino, Gaga Kochlamazashvili, Sara Baldassari, Albert Ian Mackintosh, Laura Licchetta, Emanuela Iovino, Yu Chi Liu, Caitlin A Bennett, Mark F Bennett, John A Damiano, Gábor Zsurka, Caterina Marconi, Tania Giangregorio, Pamela Magini, Marijn Kuijpers, Tanja Maritzen, Giuseppe Danilo Norata, Stéphanie Baulac, Laura Canafoglia, Marco Seri, Paolo Tinuper, Ingrid E Scheffer, Melanie Bahlo, Samuel F Berkovic, Michael S Hildebrand, Wolfram S Kunz, Lucio Giordano, Francesca Bisulli, Miriam Martini, Volker Haucke, Emilio Hirsch, Tommaso Pippucci
• Journal: Brain : a journal of neurology (Brain) Vol. 145 Issue 7 Pg. 2313-2331 (07 29 2022) ISSN: 1460-2156 [Electronic] England
• PMID: 35786744 (Publication Type: Journal Article)
• Copyright: © The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.

Chemical References

• Lipids
• Class II Phosphatidylinositol 3-Kinases
• PIK3C2B protein, human
• Mechanistic Target of Rapamycin Complex 1

Topics

• Animals
• Class II Phosphatidylinositol 3-Kinases (genetics)
• Epilepsies, Partial (genetics)
• Humans
• Lipids
• Mechanistic Target of Rapamycin Complex 1
• Mice
• Mutation (genetics)
• Phosphatidylinositol 3-Kinases (genetics)
• Seizures