Defective lipid signalling caused by mutations in PIK3C2B underlies focal epilepsy.
Defective lipid signalling caused by mutations in PIK3C2B underlies focal epilepsy.
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DOI：
10.1093/brain/awac082
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发表时间：
2022-07-29
期刊：
影响因子：
--
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中科院分区：
文献类型：
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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 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.
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影响因子：
9.8
作者：
通讯作者：
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DOI：
10.1083/jcb.201611073
发表时间：
2017-12-04
期刊：
The Journal of cell biology
影响因子：
--
作者：
Hong Z;Pedersen NM;Wang L;Torgersen ML;Stenmark H;Raiborg C
通讯作者：
Raiborg C
影响因子：
64.8
作者：
Iossifov, Ivan;O'Roak, Brian J.;Sanders, Stephan J.;Ronemus, Michael;Krumm, Niklas;Levy, Dan;Stessman, Holly A.;Witherspoon, Kali T.;Vives, Laura;Patterson, Karynne E.;Smith, Joshua D.;Paeper, Bryan;Nickerson, Deborah A.;Dea, Jeanselle;Dong, Shan;Gonzalez, Luis E.;Mandell, Jeffrey D.;Mane, Shrikant M.;Murtha, Michael T.;Sullivan, Catherine A.;Walker, Michael F.;Waqar, Zainulabedin;Wei, Liping;Willsey, A. Jeremy;Yamrom, Boris;Lee, Yoon-ha;Grabowska, Ewa;Dalkic, Ertugrul;Wang, Zihua;Marks, Steven;Andrews, Peter;Leotta, Anthony;Kendall, Jude;Hakker, Inessa;Rosenbaum, Julie;Ma, Beicong;Rodgers, Linda;Troge, Jennifer;Narzisi, Giuseppe;Yoon, Seungtai;Schatz, Michael C.;Ye, Kenny;McCombie, W. Richard;Shendure, Jay;Eichler, Evan E.;State, Matthew W.;Wigler, Michael
通讯作者：
Wigler, Michael
DOI：
10.1038/s41436-018-0060-2
发表时间：
2019-03
期刊：
Genetics in medicine : official journal of the American College of Medical Genetics
影响因子：
--
作者：
Baldassari S;Picard F;Verbeek NE;van Kempen M;Brilstra EH;Lesca G;Conti V;Guerrini R;Bisulli F;Licchetta L;Pippucci T;Tinuper P;Hirsch E;de Saint Martin A;Chelly J;Rudolf G;Chipaux M;Ferrand-Sorbets S;Dorfmüller G;Sisodiya S;Balestrini S;Schoeler N;Hernandez-Hernandez L;Krithika S;Oegema R;Hagebeuk E;Gunning B;Deckers C;Berghuis B;Wegner I;Niks E;Jansen FE;Braun K;de Jong D;Rubboli G;Talvik I;Sander V;Uldall P;Jacquemont ML;Nava C;Leguern E;Julia S;Gambardella A;d'Orsi G;Crichiutti G;Faivre L;Darmency V;Benova B;Krsek P;Biraben A;Lebre AS;Jennesson M;Sattar S;Marchal C;Nordli DR Jr;Lindstrom K;Striano P;Lomax LB;Kiss C;Bartolomei F;Lepine AF;Schoonjans AS;Stouffs K;Jansen A;Panagiotakaki E;Ricard-Mousnier B;Thevenon J;de Bellescize J;Catenoix H;Dorn T;Zenker M;Müller-Schlüter K;Brandt C;Krey I;Polster T;Wolff M;Balci M;Rostasy K;Achaz G;Zacher P;Becher T;Cloppenborg T;Yuskaitis CJ;Weckhuysen S;Poduri A;Lemke JR;Møller RS;Baulac S
通讯作者：
Baulac S
影响因子：
6.1
作者：
Chevere-Torres, Itzamarie;Kaphzan, Hanoch;Bhattacharya, Aditi;Kang, Areum;Maki, Jordan M.;Gambello, Michael J.;Arbiser, Jack L.;Santini, Emanuela;Klann, Eric
通讯作者：
Klann, Eric