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-C2 beta, 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.Gozzelino et al. show that defective lipid signalling caused by heterozygous ultra-rare variants in PIK3C2B gives rise to focal epilepsy via mTOR hyperactivation. In vivo, mutant Pik3c2b alleles cause dose-dependent neuronal hyperexcitability and increased seizure susceptibility, identifying haploinsufficiency as a key driver of disease.

Defective lipid signalling caused by mutations in PIK3C2B underlies focal epilepsy

Gozzelino, Luca;Martini, Miriam
Co-last
;
Hirsch, Emilio;
2022-01-01

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-C2 beta, 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.Gozzelino et al. show that defective lipid signalling caused by heterozygous ultra-rare variants in PIK3C2B gives rise to focal epilepsy via mTOR hyperactivation. In vivo, mutant Pik3c2b alleles cause dose-dependent neuronal hyperexcitability and increased seizure susceptibility, identifying haploinsufficiency as a key driver of disease.
2022
145
7
2313
2331
PI3K-C2B; class II PI3K; epilepsy; mTOR; variants
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
File in questo prodotto:
File Dimensione Formato  
Gozzelino_Brain_2022.pdf

Accesso aperto

Tipo di file: PDF EDITORIALE
Dimensione 1.58 MB
Formato Adobe PDF
1.58 MB Adobe PDF Visualizza/Apri

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2318/1889681
Citazioni
  • ???jsp.display-item.citation.pmc??? 2
  • Scopus 8
  • ???jsp.display-item.citation.isi??? 9
social impact