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Involvement of GATOR complex genes in familial focal epilepsies and focal cortical dysplasia
Author(s) -
Weckhuysen Sarah,
Marsan Elise,
Lambrecq Virginie,
Marchal Cécile,
MorinBrureau Mélanie,
AnGourfinkel Isabelle,
Baulac Michel,
Fohlen Martine,
Kallay Zetchi Christine,
Seeck Margitta,
Grange Pierre,
Dermaut Bart,
Meurs Alfred,
Thomas Pierre,
Chassoux Francine,
Leguern Eric,
Picard Fabienne,
Baulac Stéphanie
Publication year - 2016
Publication title -
epilepsia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.687
H-Index - 191
eISSN - 1528-1167
pISSN - 0013-9580
DOI - 10.1111/epi.13391
Subject(s) - cortical dysplasia , gene , epilepsy , mutation , phenotype , epileptogenesis , proband , biology , genetics , cancer research , neuroscience
Summary Objective The discovery of mutations in DEPDC 5 in familial focal epilepsies has introduced a novel pathomechanism to a field so far dominated by ion channelopathies. DEPDC 5 is part of a complex named GAP activity toward RAGs (GATOR) complex 1 ( GATOR 1), together with the proteins NPRL 2 and NPRL 3, and acts to inhibit the mechanistic target of rapamycin ( mTOR ) complex 1 ( mTORC 1) pathway. GATOR 1 is in turn inhibited by the GATOR 2 complex. The mTORC 1 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 GATOR 1 ( DEPDC 5, NPRL 2, and NPRL 3) and GATOR 2 ( MIOS , SEC 13, SEH 1L, WDR 24, and WDR 59 ) complex in 93 European probands with focal epilepsy with or without focal cortical dysplasia. Phospho‐S6 immunoreactivity was used as evidence of mTORC 1 pathway activation in resected brain tissue of patients carrying pathogenic variants. Results We identified four pathogenic variants in DEPDC 5, two in NPRL 2 , and one in NPRL 3 . We showed hyperactivation of the mTORC 1 pathway in brain tissue from patients with NPRL 2 and NPRL 3 mutations. Collectively, inactivating mutations in GATOR 1 complex genes explained 11% of cases of focal epilepsy , whereas no pathogenic mutations were found in GATOR 2 complex genes. GATOR 1‐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 GATOR 1 complex gene mutations leading to mTORC 1 pathway upregulation is an important cause of focal epilepsy with cortical malformations and represents a potential target for novel therapeutic approaches.