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Title: Defective lipid signalling caused by mutations in PIK3C2B underlies focal epilepsy.
Austin Authors: Gozzelino, Luca;Kochlamazashvili, Gaga;Baldassari, Sara;Mackintosh, Albert Ian;Licchetta, Laura;Iovino, Emanuela;Liu, Yu Chi;Bennett, Caitlin A;Bennett, Mark F ;Damiano, John A;Zsurka, Gábor;Marconi, Caterina;Giangregorio, Tania;Magini, Pamela;Kuijpers, Marijn;Maritzen, Tanja;Norata, Giuseppe Danilo;Baulac, Stéphanie;Canafoglia, Laura;Seri, Marco;Tinuper, Paolo;Scheffer, Ingrid E ;Bahlo, Melanie;Berkovic, Samuel F ;Hildebrand, Michael S ;Kunz, Wolfram S;Giordano, Lucio;Bisulli, Francesca;Martini, Miriam;Haucke, Volker;Hirsch, Emilio;Pippucci, Tommaso
Affiliation: Department of Pediatrics, University of Melbourne, Royal Children's Hospital, Melbourne, Victoria, Australia..
Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy..
Department of Molecular Pharmacology and Cell Biology, Leibniz Forschungsinstitut für Molekulare Pharmakologie (FMP), Robert-Roessle-Strasse 10, 13125 Berlin, Germany..
Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna, Italy..
Sorbonne Université, Institut du Cerveau-Paris Brain Institute-ICM, Inserm, CNRS, F-75013 Paris, France..
IRCCS Istituto delle Scienze Neurologiche di Bologna, Epilepsy Center (Reference Center for Rare and Complex Epilepsies-EpiCARE), Bologna, Italy..
Epilepsy Research Centre
Population Health and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia..
Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia..
Department of Experimental Epileptology and Cognition Research and Department of Epileptology, University Bonn Medical Center, Venusberg Campus 1, D-53105 Bonn, Germany..
U.O. Genetica Medica, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy..
Department of Nanophysiology, Technische Universität Kaiserslautern, 67663 Kaiserslautern, Germany..
Department of Excellence in Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan and Center for the Study of Atherosclerosis, SISA Bassini Hospital Cinisello B, Italy..
Unit of Integrated Diagnostics for Epilepsy, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy..
Department of Biomedical and NeuroMotor Sciences (DIBINEM), University of Bologna, Bologna, Italy..
Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, Melbourne, Victoria, Australia..
The Florey Institute of Neuroscience and Mental Health
Spedali Civili, Neuropsychiatric Department, Brescia, Italy..
Faculty of Biology, Chemistry, Pharmacy, Freie Universität Berlin, 14195 Berlin, Germany..
Issue Date: 29-Jul-2022 2022
Publication information: Brain : a Journal of Neurology 2022; 145(7): 2313-2331
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.
DOI: 10.1093/brain/awac082
ORCID: 0000-0001-9578-647X
PubMed URL: 35786744
PubMed URL:
Type: Journal Article
Subjects: PI3K-C2B
class II PI3K
Appears in Collections:Journal articles

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