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.

Defective lipid signalling caused by mutations in PIK3C2B underlies focal epilepsy

Iovino E.;Marconi C.;Magini P.;Seri M.;Tinuper P.;Bisulli F.;Hirsch E.
;
Pippucci T.
2022

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.
Gozzelino L.; Kochlamazashvili G.; Baldassari S.; Mackintosh A.I.; Licchetta L.; Iovino E.; Liu Y.-C.; Bennett C.A.; Bennett M.F.; Damiano J.A.; Zsurka G.; Marconi C.; Giangregorio T.; Magini P.; Kuijpers M.; Maritzen T.; Norata G.D.; Baulac S.; Canafoglia L.; Seri M.; Tinuper P.; Scheffer I.E.; Bahlo M.; Berkovic S.F.; Hildebrand M.S.; Kunz W.S.; Giordano L.; Bisulli F.; Martini M.; Haucke V.; Hirsch E.; Pippucci T.
File in questo prodotto:
File Dimensione Formato  
awac082.pdf

accesso aperto

Tipo: Versione (PDF) editoriale
Licenza: Licenza per Accesso Aperto. Creative Commons Attribuzione - Non commerciale (CCBYNC)
Dimensione 1.62 MB
Formato Adobe PDF
1.62 MB Adobe PDF Visualizza/Apri
awac082_supplementary_data.zip

accesso aperto

Tipo: File Supplementare
Licenza: Licenza per accesso libero gratuito
Dimensione 20.63 MB
Formato Zip File
20.63 MB Zip File 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/11585/901431
Citazioni
  • ???jsp.display-item.citation.pmc??? 2
  • Scopus 2
  • ???jsp.display-item.citation.isi??? 2
social impact