Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2016 Jun;57(6):994-1003.
doi: 10.1111/epi.13391. Epub 2016 May 13.

Involvement of GATOR complex genes in familial focal epilepsies and focal cortical dysplasia

Sarah Weckhuysen  1   2   3   4   5 , Elise Marsan  1   2   3   4 , Virginie Lambrecq  1   2   3   4   5 , Cécile Marchal  6 , Mélanie Morin-Brureau  1   2   3   4 , Isabelle An-Gourfinkel  1   5 , Michel Baulac  1   2   3   4   5 , Martine Fohlen  7 , Christine Kallay Zetchi  8 , Margitta Seeck  8 , Pierre de la Grange  9 , Bart Dermaut  10   11 , Alfred Meurs  12 , Pierre Thomas  13 , Francine Chassoux  14 , Eric Leguern  1   2   3   4   15 , Fabienne Picard  8 , Stéphanie Baulac  1   2   3   4   15
Affiliations
Free article

Involvement of GATOR complex genes in familial focal epilepsies and focal cortical dysplasia

Sarah Weckhuysen et al. Epilepsia. 2016 Jun.
Free article

Abstract

Objective: The discovery of mutations in DEPDC5 in familial focal epilepsies has introduced a novel pathomechanism to a field so far dominated by ion channelopathies. DEPDC5 is part of a complex named GAP activity toward RAGs (GATOR) complex 1 (GATOR1), together with the proteins NPRL2 and NPRL3, and acts to inhibit the mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) pathway. GATOR1 is in turn inhibited by the GATOR2 complex. The mTORC1 pathway is a major signaling cascade regulating cell growth, proliferation, and migration. We aimed to study the contribution of GATOR complex genes to the etiology of focal epilepsies and to describe the associated phenotypical spectrum.

Methods: We performed targeted sequencing of the genes encoding the components of the GATOR1 (DEPDC5, NPRL2, and NPRL3) and GATOR2 (MIOS, SEC13, SEH1L, WDR24, and WDR59) complex in 93 European probands with focal epilepsy with or without focal cortical dysplasia. Phospho-S6 immunoreactivity was used as evidence of mTORC1 pathway activation in resected brain tissue of patients carrying pathogenic variants.

Results: We identified four pathogenic variants in DEPDC5, two in NPRL2, and one in NPRL3. We showed hyperactivation of the mTORC1 pathway in brain tissue from patients with NPRL2 and NPRL3 mutations. Collectively, inactivating mutations in GATOR1 complex genes explained 11% of cases of focal epilepsy, whereas no pathogenic mutations were found in GATOR2 complex genes. GATOR1-related focal epilepsies differ clinically from focal epilepsies due to mutations in ion channel genes by their association with focal cortical dysplasia and seizures emerging from variable foci, and might confer an increased risk of sudden unexplained death in epilepsy (SUDEP).

Significance: GATOR1 complex gene mutations leading to mTORC1 pathway upregulation is an important cause of focal epilepsy with cortical malformations and represents a potential target for novel therapeutic approaches.

Keywords: DEPDC5; Genetics; NPRL2; NPRL3; SUDEP; mTOR.

PubMed Disclaimer

Similar articles

  • mTOR signaling pathway genes in focal epilepsies.
    Baulac S. Baulac S. Prog Brain Res. 2016;226:61-79. doi: 10.1016/bs.pbr.2016.04.013. Epub 2016 Jun 7. Prog Brain Res. 2016. PMID: 27323939 Review.
  • GATORopathies: The role of amino acid regulatory gene mutations in epilepsy and cortical malformations.
    Iffland PH 2nd, Carson V, Bordey A, Crino PB. Iffland PH 2nd, et al. Epilepsia. 2019 Nov;60(11):2163-2173. doi: 10.1111/epi.16370. Epub 2019 Oct 17. Epilepsia. 2019. PMID: 31625153 Free PMC article. Review.
  • Mutations in the mammalian target of rapamycin pathway regulators NPRL2 and NPRL3 cause focal epilepsy.
    Ricos MG, Hodgson BL, Pippucci T, Saidin A, Ong YS, Heron SE, Licchetta L, Bisulli F, Bayly MA, Hughes J, Baldassari S, Palombo F; Epilepsy Electroclinical Study Group; Santucci M, Meletti S, Berkovic SF, Rubboli G, Thomas PQ, Scheffer IE, Tinuper P, Geoghegan J, Schreiber AW, Dibbens LM. Ricos MG, et al. Ann Neurol. 2016 Jan;79(1):120-31. doi: 10.1002/ana.24547. Epub 2015 Dec 12. Ann Neurol. 2016. PMID: 26505888
  • GATOR1 complex: the common genetic actor in focal epilepsies.
    Baldassari S, Licchetta L, Tinuper P, Bisulli F, Pippucci T. Baldassari S, et al. J Med Genet. 2016 Aug;53(8):503-10. doi: 10.1136/jmedgenet-2016-103883. Epub 2016 May 19. J Med Genet. 2016. PMID: 27208208 Review.
  • The landscape of epilepsy-related GATOR1 variants.
    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. Baldassari S, et al. Genet Med. 2019 Feb;21(2):398-408. doi: 10.1038/s41436-018-0060-2. Epub 2018 Aug 10. Genet Med. 2019. PMID: 30093711 Free PMC article.
See all similar articles

Cited by

See all "Cited by" articles

MeSH terms