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.
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“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]
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“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]
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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
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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
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Neurodevelopmental Disorders: From Genetics to Functional Pathways
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Najm, I., Lal, D., Alonso‐Vanegas, M., Cendes, F., Lopes‐Cendes, Í., Palmini, A., Paglioli, E., Sarnat, H. B., Walsh, C. A., Wiebe, S., et al. (2022) · Epilepsia · doi:10.1111/epi.17301 · Cited by 368
Self-citationDissecting the genetic basis of focal cortical dysplasia: a large cohort study
Baldassari, S., Ribierre, T., Marsan, E., Adle-Biassette, H., Ferrand-Sorbets, S., Bulteau, C., Dorison, N., Fohlen, M., Polivka, M., Weckhuysen, S., et al. (2019) · Acta Neuropathologica · doi:10.1007/s00401-019-02061-5 · Cited by 356
Self-citationDefinitions and classification of malformations of cortical development: practical guidelines
Severino, M., Geraldo, A. F., Utz, N., Tortora, D., Pogledić, I., Klonowski, W., Triulzi, F. M., Arrigoni, F., Mankad, K., Leventer, R. J., et al. (2020) · Brain · doi:10.1093/brain/awaa174 · Cited by 312
The landscape of epilepsy-related GATOR1 variants
Baldassari, S., Picard, F., Verbeek, N. E., van Kempen, M. J. A., Brilstra, E. H., Lesca, G., Conti, V., Guerrini, R., Bisulli, F., Licchetta, L., et al. (2018) · Genetics in Medicine · doi:10.1038/s41436-018-0060-2 · Cited by 251
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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
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