The DOI matches its Crossref record; 28 of the 28 references it cites were found in a registry or an index.
Second-hit mosaic mutation in mTORC1 repressor DEPDC5 causes focal cortical dysplasia–associated epilepsy
Open accessAbstract
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.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“In some individuals, a second genetic hit with a combination of both somatic and germline mutations in the same gene or genes in related pathways (eg.mTOR pathway) is identified 124 .”
From Developmental and epileptic encephalopathies (2024) · cites this paper as [124]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“MCD, including FCD, may be associated with a pathogenic germline or somatic variant, which may show a mutation gradient in resected brain tissue.”
From Developmental and epileptic encephalopathies (2024) · cites this paper as [124]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
CRISPR-Cas9 Knockin Mice for Genome Editing and Cancer Modeling
Platt, R. J., Chen, S., Zhou, Y., Yim, M. J., Swiech, L., Kempton, H. R., Dahlman, J. E., Parnas, O., Eisenhaure, T. M., Jovanovic, M., et al. (2014) · Cell · doi:10.1016/j.cell.2014.09.014 · Cited by 2,001
Blümcke, I., Thom, M., Aronica, E., Armstrong, D. D., Vinters, H. V., Palmini, A., Jacques, T. S., AVANZINI, G., Barkovich, A. J., Battaglia, G. S., et al. (2010) · Epilepsia · doi:10.1111/j.1528-1167.2010.02777.x · Cited by 1,746
Dendritic spine pathology in neuropsychiatric disorders
Penzes, P., Cahill, M. E., Jones, K. A., VanLeeuwen, J.-E., & Woolfrey, K. M. (2011) · Nature Neuroscience · doi:10.1038/nn.2741 · Cited by 1,523
Bar-Peled, L., Chantranupong, L., Cherniack, A. D., Chen, W. W., Ottina, K. A., Grabiner, B. C., Spear, E. D., Carter, S. L., Meyerson, M., & Sabatini, D. M. (2013) · Science · doi:10.1126/science.1232044 · Cited by 1,080
Histopathological Findings in Brain Tissue Obtained during Epilepsy Surgery
Blümcke, I., Spreafico, R., Haaker, G., Coras, R., Kobow, K., Bien, C. G., Pfäfflin, M., Elger, C. E., Widman, G., Schramm, J., et al. (2017) · New England Journal of Medicine · doi:10.1056/nejmoa1703784 · Cited by 935
French, J. A., Lawson, J. A., Yapici, Z., Ikeda, H., Polster, T., Nabbout, R., Curatolo, P., de Vries, P. J., Dlugos, D. J., Berkowitz, N., et al. (2016) · The Lancet · doi:10.1016/s0140-6736(16)31419-2 · Cited by 764
Somatic mutation, genomic variation, and neurological disease
Poduri, A., Evrony, G. D., Cai, X., & Walsh, C. A. (2013) · Science · doi:10.1126/science.1237758 · Cited by 584
Lim, J. S., Kim, W.-I., Kang, H., Kim, S. H., Park, A. H., Park, E. K., Cho, Y., Kim, H. M., Kim, J. A., Kim, J. A., et al. (2015) · Nature Medicine · doi:10.1038/nm.3824 · Cited by 518
Aiba, I., & Noebels, J. L. (2015) · Science Translational Medicine · doi:10.1126/scitranslmed.aaa4050 · Cited by 333
Bagnall, R. D., Crompton, D. E., Petrovski, S., Lam, L., Cutmore, C., Garry, S. I., Sadleir, L. G., Dibbens, L. M., Cairns, A. G., Kivity, S., et al. (2015) · Annals of Neurology · doi:10.1002/ana.24596 · Cited by 289
Flagged first, then by citations
Cited by
Sorted by citations
Items 201–241 of 241
2016 in Review and Message from the Editors to our Reviewers
Pulst, S. M., Johnson, N. E., Dürr, A., Pandolfo, M., Roos, R. P., & Vance, J. M. (2017) · Neurology Genetics · doi:10.1212/nxg.0000000000000132
The Spectrum of DEPDC5 -Related Epilepsy
Salomone, G., Comella, M., Portale, A., Pecora, G., Costanza, G., Bianco, M. L., Sciuto, S., Praticò, E., & Falsaperla, R. (2020) · Journal of Pediatric Neurology online · doi:10.1055/s-0041-1727139
Lightning progress in child neurology in the past 20 years
Scheffer, I. E. (2022) · The Lancet Neurology · doi:10.1016/s1474-4422(22)00002-3
2018: Year in Review and Message from the Editors to Our Reviewers
Pulst, S. M., Roos, R. P., Dürr, A., Vance, J. M., Milone, M., & Pandolfo, M. (2019) · Neurology Genetics · doi:10.1212/nxg.0000000000000309
Yang, X., Zhang, X., Wang, Z., Liu, G., Shen, K., Zhu, G., Wang, T., Lv, S., Zhang, C., Yang, H., et al. (2020) · Research Square · doi:10.21203/rs.3.rs-115999/v1
The road towards precision therapy for genetic epilepsies
Stevelink, R. (2022) · Utrecht University Repository (Utrecht University) · doi:10.33540/1102
Nguyen, L. H., Xu, Y., Nair, M., & Bordey, A. (2024) · eLife · doi:10.7554/elife.91010.2
Familial occurrence of seizure disorders across MRI defined structural focal epilepsy etiology
Kovačević, M., Sokić, D. V., Ristić, A. J., Berisavac, I., Ercegovac, M., Milicevic, O. S., & Vojvodić, N. M. (2024) · Journal of Clinical Neuroscience · doi:10.1016/j.jocn.2024.03.010
Brain Mosaicism in Epileptogenic Cortical Malformations
Ribierre, T., & Baulac, S. (2024) · Oxford University Press eBooks · doi:10.1093/med/9780197549469.003.0043
Self-citationKobow, K., & Mahoney, J. M. (2024) · Oxford University Press eBooks · doi:10.1093/med/9780197549469.003.0049
Epilepsy genetics in clinical practice today and for the future
Goldman, A. M., & Noebels, J. L. (2024) · Elsevier eBooks · doi:10.1016/b978-0-443-19176-3.00033-9 · Cited by 1
Guerrini, R., & Parrini, E. (2024) · Elsevier eBooks · doi:10.1016/b978-0-443-19041-4.00062-5
Neuronal cell type specific roles for Nprl2 in neurodevelopmental disorder-relevant behaviors
Dentel, B., Angeles-Perez, L., Flores, A. Y., Lei, K., Ren, C., Sanchez, A. P., & Tsai, P. T. (2025) · Neurobiology of Disease · doi:10.1016/j.nbd.2025.106790
Microcephaly and Megalencephaly: Disorders of Brain Size
Dobyns, W. B. (2025) · Elsevier eBooks · doi:10.1016/b978-0-443-10944-7.00043-3
Emerging Gene-Based Pathways: mTORopathies
Ziobro, J. M., & Dang, L. T. (2025) · Elsevier eBooks · doi:10.1016/b978-0-443-10944-7.00054-8
Splicing variants in DEPDC5 ‐related epilepsies: From functional characterization to correction
Osipova, E., Bychkov, I. O., Filatova, A. Y., Borovikov, A. O., Sharkov, A. A., Sharkova, S. M., Saushev, D., Lozier, E., Tabakov, V. Y., & Skoblov, M. Y. (2025) · Epilepsia · doi:10.1111/epi.18506
Deep tissue sequencing improves genetic diagnostic yield in focal cortical dysplasia
Galea, B., Reid, J., Gooley, S., Witkowski, T., Lane, T., Macdonald, S., Green, T. E., Ye, Z., Adikari, T. N., Bulluss, K. J., et al. (2026) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2026.111920
Early death and neuronal abnormalities in depdc5 loss-of-function mosaic zebrafish modelsPreprint
Tiwari, S., LaCoursiere, C. M., Koh, H. Y., Pascucci, J., Chaudhary, P., Goldstein, R. D., & Poduri, A. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2025.12.04.692362 · Cited by 1
Honke, J., Hoffmann, L., Coras, R., Kobow, K., Leu, C., Pieper, T., Hartlieb, T., Bien, C. G., Woermann, F. G., Cloppenborg, T., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26637885
Self-citationMabika, M., Agbogba, K., Cote, S. R., Lippé, S., Riou, É., Cieuta‐Walti, C., & Lepage, J. (2024) · Figshare · doi:10.6084/m9.figshare.26561368
Moreau, L., & Bernard, C. D. (2021) · Annals of Pharmacy Practice and Pharmacotherapy · doi:10.51847/r4zodtw5ue
Ruan, Y., Chen, L., Xia, S., Lu, Q., Wang, J., Zhu, F., Li, N., Du, H., & Sun, D. (2026) · Frontiers in Pediatrics · doi:10.3389/fped.2026.1751113
Zhou, C., Wei, X., Xiang, Q., Mai, J., & Wang, J. (2026) · Neurogenetics · doi:10.1007/s10048-026-00890-7
Cortical organoid model of DEPDC5-related focal cortical dysplasia and epilepsy
Maletić, M. (2022) · theses.fr (ABES) · doi:10.70675/ce51a4c6zec09z49b3z8571zd518d7fa745c
Investigations génétiques et physiopathologiques des dysplasies corticales focales de type 2
Ribierre, T. (2020) · theses.fr (ABES) · doi:10.70675/7ac267e2z8712z4e0fza9a1z424bc9445787
Self-citationThe role of GATOR1 complex, upstream regulator of mTORC1 pathway, in mitochondrial function
Loissell-Baltazar, Y. A. (2022) · theses.fr (ABES) · doi:10.70675/1f481059zb480z4ff6zb971z48706d3ff583
Role of brain somatic mutations in epileptogenic malformations
Sami, L. (2024) · theses.fr (ABES) · doi:10.70675/a5203ae5zaabez4145zb59fzd7cf74e18443
Pineau, L. (2023) · theses.fr (ABES) · doi:10.70675/39c790cfzdf57z416bzb9cez06eca43d9cda
Introduction to Neurogenetic Disability
Malviya, R., & Rajput, S. (2026) · SpringerBriefs in modern perspectives on disability research. · doi:10.1007/978-981-95-9223-4_1
Neuroimaging spectrum of GATOR1-related epilepsy (GATORopathies)
Revanth, R., Ajith, A., Nayak, A., Radhakrishnan, A., Thomas, B., & Kesavadas, C. (2026) · Neuroradiology · doi:10.1007/s00234-026-04036-2
DEPDC5: Modeling of the Two-Hit Wonder in Cortical Organoids
Heinzen, E. L. (2026) · Epiliepsy currents/Epilepsy currents · doi:10.1177/15357597261464330
Cai, M.-S., Li, H.-R., Liao, P., Hu, Z., & Chen, Y.-J. (2026) · Frontiers in Genetics · doi:10.3389/fgene.2026.1902275
Yetkin, O., Baykan, B. B., & Żarowski, M. (2026) · Current Issues in Molecular Biology · doi:10.3390/cimb48090931
Li, Z., Wang, Y.-Z., Shi, J., Luo, Y., Shan, Y., & Zhao, G. (2026) · CNS Neuroscience & Therapeutics · doi:10.1002/cns.71170
Synergistic role of TFEB/TFE3 and mTORC1 in kidney cystogenesis and tumorigenesis
Ferniani, M., Sambri, I., Huynh, T., Pennella, R., Tufano, G., Herz, N. J., Rossi, B., Iannaccone, A., Trepiccione, F., Calcagnì, A., et al. (2026) · Cell Death and Differentiation · doi:10.1038/s41418-026-01881-9
Gao, Y., Ji, X., Feng, S., Gao, Y., Li, L., Wang, B., Zhang, X., & Chen, Q. (2026) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2026.1963535
Somatic variants in focal cortical malformations
Czajewski, I., Baulac, S., & Baldassari, S. (2026) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2026.102550
Self-citationLi, T. L., & Bateup, H. S. (2026) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2026.102552
Metadata
- Authors
- Ribierre, T., Deleuze, C., Bacq, A., Baldassari, S., Marsan, E., Chipaux, M., Muraca, G., Roussel, D., Navarro, V., Leguern, E., Miles, R., & Baulac, S.
- Affiliations
- Centre National de la Recherche Scientifique (FR)
- Fondation de Rothschild (FR)
- Corresponding author
- Baulac, Stéphanie
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2018-04-30
- Volume
- 128
- Issue
- 6
- Pages
- 2452-2458
- ISSN
- 0021-9738 (ISSN-L)
- 1558-8238
- PMC
- PMC5983335
- OpenAlex
- W2802211669
- Cited by
- 241
- References
- 28
- Citations by year
- 2026: 17 · 2025: 28 · 2024: 30 · 2023: 37 · 2022: 27 · 2021: 38 · 2020: 27 · 2019: 26 · 2018: 10
- FWCI
- 19.73
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Funders
- European Research Council (No 322721, No 682345)
- Topics
- Health Sciences › Medicine › Clinical Neurology › Epilepsy research and treatment
- Health Sciences › Medicine › Genetics (clinical) › Tuberous Sclerosis Complex Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- DEPDC5, mTORC1, focal cortical dysplasia, focal epilepsy, second-hit mutations, somatic mosaicism, sudden unexpected death in epilepsy, amino acid sensing, seizure onset zone, excitatory neurons, drug-resistant epilepsy
- MeSH terms
- Mechanistic Target of Rapamycin Complex 1, Animals, Dendrites, Epilepsies, Partial, Female, Humans, Male, Mice, Mutant Strains, Neurons, Repressor Proteins, Spine, Germ-Line Mutation, GTPase-Activating Proteins, Mice, Malformations of Cortical Development, CRISPR-Cas Systems
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
