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

Abstract

SummaryObjective: 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.

Germline and somatic mutations in the MTOR gene in focal cortical dysplasia and epilepsy

“…1 Most mutations in GATOR1-encoding genes are loss of function (nonsense, frameshift, splice variants), while all mutations in the MTOR gene are missense mutations predicted to be activating. Both GATOR1 8,13,14 and MTOR mutations 17 have been shown to lead to hyperactivation of the mTORC1 pathway in resected epileptogenic brain tissue. How an increased activity of the intracellular signaling cascade alters network function and ultimately leads to seizures is one of the next challenging questions to be elucidated.…”

“…8 In this cohort, 7 individuals were previously shown to have a mutation in one of the GATOR1-encoding genes. 8 We also screened a third Danish cohort of 245 unrelated patients with various forms of childhood-onset epilepsies referred for diagnostic gene panel testing.…”

“…8 In this cohort, 7 individuals were previously shown to have a mutation in one of the GATOR1-encoding genes. 8 We also screened a third Danish cohort of 245 unrelated patients with various forms of childhood-onset epilepsies referred for diagnostic gene panel testing. The phenotypic spectrum within this cohort was broad and ranged from benign familial neonatal/infantile epilepsy to generalized epilepsies, focal epilepsies, and severe epileptic encephalopathies.…”

Somatic Mutations Activating the mTOR Pathway in Dorsal Telencephalic Progenitors Cause a Continuum of Cortical Dysplasias

“…Several new genes have also been described that act analogously to TSC1 and TSC2 as negative regulators of MTOR , causing FCD and HME via germline loss-of-function mutation coupled to demonstrated or inferred somatic loss of the second allele (Baulac et al, 2015; D’Gama et al, 2015; Lim et al, 2017; Scheffer et al, 2014; Sim et al, 2016; Weckhuysen et al, 2016). Surprisingly, TSC mutations can cause isolated FCD or HME in the absence of widespread hamartomas (D’Gama et al, 2015; Hoelz et al, 2017; Lim et al, 2017).…”

Cerebral palsy and seizures in a child with tubulinopathy pattern dysgenesis and focal cortical dysplasia

“…Though the MR appearance in the current case is characteristic of a tubulin defect, the underlying defect in this case is not defined and may represent a unique defect resulting in deformities typical of tubulin dysfunction and well as producing FCD. A number of genetic defects associated with FCD have been identified [17], [18], [19], [20], [21], [22], [23]. These include both germline mutations (Dishevelled Egl-10 and Pleckstrin domain-containing protein 5, DEPDC5; nitrogen permease regulator-like proteins, NPRL2 and NPRL3; GTPase-activating protein activity toward Rags complex 1, GATOR1) and spontaneous mutations (rapamycin/mTOR signal transduction pathway; phosphatidylinositol 3-kinase PIK3).…”