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J Clin Invest. 2018 Jun 1;128(6):2452-2458. doi: 10.1172/JCI99384. Epub 2018 Apr 30.

Second-hit mosaic mutation in mTORC1 repressor DEPDC5 causes focal cortical dysplasia-associated epilepsy.

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Institut du Cerveau et de la Moelle épinière (ICM), INSERM U 1127, CNRS UMR 7225, Sorbonne Université, Paris, France.
Department of Pediatric Neurosurgery, Fondation Rothschild, Paris, France.
Epileptology Unit, and.
Department of Genetics, Assistance Publique - Hôpitaux de Paris (AP-HP), Hôpital Pitié-Salpêtrière, Paris, France.


DEP domain-containing 5 protein (DEPDC5) is a repressor of the recently recognized amino acid-sensing branch of the mTORC1 pathway. So far, its function in the brain remains largely unknown. Germline loss-of-function mutations in DEPDC5 have emerged as a major cause of familial refractory focal epilepsies, with case reports of sudden unexpected death in epilepsy (SUDEP). Remarkably, a fraction of patients also develop focal cortical dysplasia (FCD), a neurodevelopmental cortical malformation. We therefore hypothesized that a somatic second-hit mutation arising during brain development may support the focal nature of the dysplasia. Here, using postoperative human tissue, we provide the proof of concept that a biallelic 2-hit - brain somatic and germline - mutational mechanism in DEPDC5 causes focal epilepsy with FCD. We discovered a mutation gradient with a higher rate of mosaicism in the seizure-onset zone than in the surrounding epileptogenic zone. Furthermore, we demonstrate the causality of a Depdc5 brain mosaic inactivation using CRISPR-Cas9 editing and in utero electroporation in a mouse model recapitulating focal epilepsy with FCD and SUDEP-like events. We further unveil a key role of Depdc5 in shaping dendrite and spine morphology of excitatory neurons. This study reveals promising therapeutic avenues for treating drug-resistant focal epilepsies with mTORC1-targeting molecules.


Epilepsy; Genetics; Molecular genetics; Neurodevelopment; Neuroscience

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