Defective lipid signalling caused by mutations in PIK3C2B underlies focal epilepsy.
Luca GozzelinoGaga KochlamazashviliSara BaldassariAlbert Ian MackintoshLaura LicchettaEmanuela IovinoYu Chi LiuCaitlin A BennettMark F BennettJohn A DamianoGábor ZsurkaCaterina MarconiTania GiangregorioPamela MaginiMarijn KuijpersTanja MaritzenGiuseppe Danilo NorataStéphanie BaulacLaura CanafogliaMarco SeriPaolo TinuperIngrid E SchefferMelanie BahloSamuel Frank BerkovicMichael S HildebrandWolfram S KunzLucio GiordanoFrancesca BisulliMiriam MartiniVolker HauckeEmilio HirschTommaso PippucciPublished in: Brain : a journal of neurology (2022)
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.
Keyphrases
- temporal lobe epilepsy
- fatty acid
- copy number
- wild type
- liver failure
- ejection fraction
- end stage renal disease
- high fat diet induced
- cerebral ischemia
- type diabetes
- single cell
- early onset
- oxidative stress
- diabetic rats
- blood brain barrier
- adipose tissue
- metabolic syndrome
- tyrosine kinase
- transcranial direct current stimulation
- insulin resistance
- dna methylation
- extracorporeal membrane oxygenation
- brain injury