Involvement of GATOR complex genes in familial focal epilepsies and focal cortical dysplasiaReportar como inadecuado

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* Corresponding author 1 ICM - Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute 2 Centre de référence des épilepsies rares CHU Pitié-Salpêtrière 3 Service d-épileptologie CHU de Bordeaux 4 Service de Neurochirurgie Pediatrique 5 Department of Neurology Genève 6 University of Geneva Medical School 7 Center for Medical Genetics 8 Institut Pasteur de Lille 9 Dpt of Neurology Gent 10 Service de Neurologie CHU Nice 11 Centre Hospitalier Sainte Anne 12 Service de Génétique et Cytogénétique CHU Pitié-Salpêtrière

Abstract : ObjectiveThe 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.MethodsWe 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.ResultsWe 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.SignificanceGATOR1 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 : SUDEP 22 text pages 3249 words including summary NPRL2 NPRL3 DEPDC5 mTOR pathway genetics 5 figures 1 table 35 references

Autor: Sarah Weckhuysen - Elise Marsan - Virginie Lambrecq - Cécile Marchal - Mélanie Morin-Brureau - Isabelle An-Gourfinkel - Michel



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