Defective lipid signalling caused by mutations in<i>PIK3C2B</i>underlies focal epilepsy-Reference-Cited by-同舟云学术

Defective lipid signalling caused by mutations inPIK3C2Bunderlies focal epilepsy

Published:2022-07-01 Issue:7 Volume:145 Page:2313-2331
ISSN:0006-8950
Container-title:Brain
language:en
Short-container-title:

Author:

Gozzelino Luca¹^ORCID,Kochlamazashvili Gaga²,Baldassari Sara³⁴^ORCID,Mackintosh Albert Ian²,Licchetta Laura⁵,Iovino Emanuela³,Liu Yu Chi⁶⁷⁸,Bennett Caitlin A⁶,Bennett Mark F⁶⁷⁸^ORCID,Damiano John A⁶,Zsurka Gábor⁹,Marconi Caterina³,Giangregorio Tania³,Magini Pamela¹⁰,Kuijpers Marijn²,Maritzen Tanja²¹¹,Norata Giuseppe Danilo¹²,Baulac Stéphanie⁴,Canafoglia Laura¹³,Seri Marco³¹⁰,Tinuper Paolo⁵¹⁴,Scheffer Ingrid E⁶¹⁵¹⁶¹⁷,Bahlo Melanie¹⁸¹⁹,Berkovic Samuel F⁶^ORCID,Hildebrand Michael S⁶¹⁵,Kunz Wolfram S⁹,Giordano Lucio¹⁸,Bisulli Francesca⁵¹⁴^ORCID,Martini Miriam¹^ORCID,Haucke Volker²¹⁹^ORCID,Hirsch Emilio¹^ORCID,Pippucci Tommaso¹⁰

Affiliation:

1. Department of Molecular Biotechnology and Health Sciences, University of Torino , Torino , Italy

2. Department of Molecular Pharmacology and Cell Biology, Leibniz Forschungsinstitut für Molekulare Pharmakologie (FMP) , Robert-Roessle-Strasse 10, 13125 Berlin , Germany

3. Department of Medical and Surgical Sciences (DIMEC), University of Bologna , Bologna , Italy

4. Sorbonne Université, Institut du Cerveau—Paris Brain Institute—ICM, Inserm, CNRS , F-75013 Paris , France

5. IRCCS Istituto delle Scienze Neurologiche di Bologna, Epilepsy Center (Reference Center for Rare and Complex Epilepsies—EpiCARE) , Bologna , Italy

6. Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health , Melbourne, Victoria , Australia

7. Population Health and Immunity Division, The Walter and Eliza Hall Institute of Medical Research , Melbourne, Victoria , Australia

8. Department of Medical Biology, University of Melbourne , Melbourne, Victoria Australia

9. Department of Experimental Epileptology and Cognition Research and Department of Epileptology, University Bonn Medical Center , Venusberg Campus 1, D-53105 Bonn , Germany

10. U.O. Genetica Medica, IRCCS Azienda Ospedaliero-Universitaria di Bologna , Bologna , Italy

11. Department of Nanophysiology, Technische Universität Kaiserslautern , 67663 Kaiserslautern , Germany

12. 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

13. Unit of Integrated Diagnostics for Epilepsy, Fondazione IRCCS Istituto Neurologico Carlo Besta , Milan , Italy

14. Department of Biomedical and NeuroMotor Sciences (DIBINEM), University of Bologna , Bologna , Italy

15. Murdoch Children’s Research Institute, Royal Children’s Hospital , Parkville, Melbourne, Victoria , Australia

16. Florey Institute for Neuroscience and Mental Health, University of Melbourne , Melbourne, Victoria , Australia

17. Department of Pediatrics, University of Melbourne, Royal Children's Hospital , Melbourne, Victoria , Australia

18. Spedali Civili, Neuropsychiatric Department , Brescia , Italy

19. Faculty of Biology, Chemistry, Pharmacy, Freie Universität Berlin , 14195 Berlin , Germany

Abstract

AbstractEpilepsy 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.

Funder

National Human Genome Research Institute

NHGRI

National Heart, Lung, and Blood Institute

National Institutes of Health

Fondazione Telethon

Progetti di Rilevante Interesse Nazionale

Ministry of Health

Deutsche Forschungsgemeinschaft

Publisher

Oxford University Press (OUP)

Subject