Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Alerts
  • Advertising
  • Job board
  • Subscribe
  • Contact
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Author's Takes
  • Reviews
    • View all reviews ...
    • Next-Generation Sequencing in Medicine (Upcoming)
    • New Therapeutic Targets in Cardiovascular Diseases (Mar 2022)
    • Immunometabolism (Jan 2022)
    • Circadian Rhythm (Oct 2021)
    • Gut-Brain Axis (Jul 2021)
    • Tumor Microenvironment (Mar 2021)
    • 100th Anniversary of Insulin's Discovery (Jan 2021)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Commentaries
    • Concise Communication
    • Editorials
    • Viewpoint
    • Top read articles
  • Clinical Medicine
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Author's Takes
  • In-Press Preview
  • Commentaries
  • Concise Communication
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Alerts
  • Advertising
  • Job board
  • Subscribe
  • Contact
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.
View: Text | PDF
Concise Communication Genetics Neuroscience

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

  • Text
  • PDF
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

×

Figure 2

Delayed migration and increased mTORC1 activity in brain cortex of Depdc5fKO mice.

Options: View larger image (or click on image) Download as PowerPoint
Delayed migration and increased mTORC1 activity in brain cortex of Depdc...
(A) Schema of IUE (in utero electroporation) procedure. (B) Representative coronal sections of control (n = 5), Depdc5fKO-gRNA1 (n = 6), and Depdc5fKO-gRNA1 plus rapamycin (n = 6) E18.5 embryo neocortices. DAPI, blue; GFP, green. Bottom: Histogram shows the distribution of electroporated GFP+ cells in neocortex. VZ, ventricular zone; SVZ, subventricular zone; IZ, intermediate zone; CP, cortical plate. ***P < 0.0001, by 2-way ANOVA. Scale bars: 100 μm. (C) Representative coronal sections of control (n = 5), Depdc5fKO-gRNA1 (n = 5), and Depdc5fKO-gRNA2 (n = 4) adult brain cortices. DAPI, blue; GFP, green. White arrowheads indicate ectopic neurons in the deeper cortical layers. CC, corpus callosum. Histogram shows the percentage of GFP+ cells in cortical layers II/III and IV. ***P = 0.0001, by 2-way-ANOVA. Scale bars: 100 μm. (D) Representative coronal sections of control (n = 5), Depdc5fKO-gRNA1 (n = 5), and Depdc5fKO-gRNA2 (n = 4) adult brain over the cortical layer III/IV boundary. GFP, green; pS6, red. Box and whisker plot shows fold changes in pS6 levels and soma size between ipsilateral GFP+ cells and contralateral GFP– cells in control, Depdc5fKO-gRNA1, and Depdc5fKO-gRNA2 adult brain cortices. ***P < 0.0001, by 1-way ANOVA (mean fold change in pS6: control = 1.05, Depdc5fKO-gRNA1 = 2.69, Depdc5fKO-gRNA2 = 3.82; mean fold change in soma size: control = 1.05, Depdc5fKO-gRNA1 = 1.8, Depdc5fKO-gRNA2 = 2.13; n = 30–70 cells per slice). Scale bars: 70 μm. (E) H&E staining of coronal brain sections from control (n = 3), Depdc5fKO-gRNA1 (n = 5), and Depdc5fKO-gRNA2 (n = 4) adult mice over cortical layers III/IV. Red arrowheads indicate balloon-like cells. Scale bars: 20 μm.

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

Sign up for email alerts