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Second-hit mosaic mutation in mTORC1 repressor DEPDC5 causes focal cortical dysplasia–associated epilepsy
Théo Ribierre, … , Richard Miles, Stéphanie Baulac
Théo Ribierre, … , Richard Miles, Stéphanie Baulac
Published April 30, 2018
Citation Information: J Clin Invest. 2018;128(6):2452-2458. https://doi.org/10.1172/JCI99384.
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Concise Communication Genetics Neuroscience

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

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Abstract

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.

Authors

Théo Ribierre, Charlotte Deleuze, Alexandre Bacq, Sara Baldassari, Elise Marsan, Mathilde Chipaux, Giuseppe Muraca, Delphine Roussel, Vincent Navarro, Eric Leguern, Richard Miles, Stéphanie Baulac

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Figure 3

Epileptic activity of adult Depdc5fKO mice.

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Epileptic activity of adult Depdc5fKO mice.
(A) Schematic representation...
(A) Schematic representation of implanted electrode locations. (B) EEG recordings of a cluster of seizures in a mouse aged P54. Hp, hippocampal; M1, primary motor cortex (R, right; L, left); LPtA, lateral parietal-temporal–associated cortex. Boxes below show different phases of EEG activity or suppression. A flat EEG after the last seizure was associated with the death of the animal.

Copyright © 2022 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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