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1. Astroglial toxicity promotes synaptic degeneration in the thalamocortical circuit in frontotemporal dementia with GRN mutations

Author

Marsan, Elise, Velmeshev, Dmitry, Ramsey, Arren, Patel, Ravi K, Zhang, Jiasheng, Koontz, Mark, Andrews, Madeline G, de Majo, Martina, Mora, Cristina, Blumenfeld, Jessica, Li, Alissa N, Spina, Salvatore, Grinberg, Lea T, Seeley, William, Miller, Bruce L, Ullian, Erik M, Krummel, Matthew F, Kriegstein, Arnold, and Huang, Eric J

Subjects
Biochemistry and Cell Biology, Biomedical and Clinical Sciences, Biological Sciences, Frontotemporal Dementia (FTD), Neurodegenerative, Aging, Alzheimer's Disease Related Dementias (ADRD), Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Acquired Cognitive Impairment, Dementia, Alzheimer's Disease, Rare Diseases, Brain Disorders, Neurosciences, 2.1 Biological and endogenous factors, Aetiology, Neurological, Humans, Animals, Mice, Progranulins, Frontotemporal Dementia, Astrocytes, Intercellular Signaling Peptides and Proteins, Mutation, Frontotemporal Lobar Degeneration, Molecular pathology, Neurodegeneration, Neuroscience, Medical and Health Sciences, Immunology, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

Mutations in the human progranulin (GRN) gene are a leading cause of frontotemporal lobar degeneration (FTLD). While previous studies implicate aberrant microglial activation as a disease-driving factor in neurodegeneration in the thalamocortical circuit in Grn-/- mice, the exact mechanism for neurodegeneration in FTLD-GRN remains unclear. By performing comparative single-cell transcriptomics in the thalamus and frontal cortex of Grn-/- mice and patients with FTLD-GRN, we have uncovered a highly conserved astroglial pathology characterized by upregulation of gap junction protein GJA1, water channel AQP4, and lipid-binding protein APOE, and downregulation of glutamate transporter SLC1A2 that promoted profound synaptic degeneration across the two species. This astroglial toxicity could be recapitulated in mouse astrocyte-neuron cocultures and by transplanting induced pluripotent stem cell-derived astrocytes to cortical organoids, where progranulin-deficient astrocytes promoted synaptic degeneration, neuronal stress, and TDP-43 proteinopathy. Together, these results reveal a previously unappreciated astroglial pathology as a potential key mechanism in neurodegeneration in FTLD-GRN.

Published
2023

2. Granulin loss of function in human mature brain organoids implicates astrocytes in TDP-43 pathology

Author

de Majo, Martina, Koontz, Mark, Marsan, Elise, Salinas, Nir, Ramsey, Arren, Kuo, Yien-Ming, Seo, Kyounghee, Li, Huinan, Dräger, Nina, Leng, Kun, Gonzales, Santiago L, Kurnellas, Michael, Miyaoka, Yuichiro, Klim, Joseph R, Kampmann, Martin, Ward, Michael E, Huang, Eric J, and Ullian, Erik M

Subjects
Biochemistry and Cell Biology, Biological Sciences, Dementia, Brain Disorders, Neurosciences, ALS, Aging, Acquired Cognitive Impairment, Neurodegenerative, Alzheimer's Disease Related Dementias (ADRD), Stem Cell Research - Induced Pluripotent Stem Cell - Human, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Stem Cell Research - Induced Pluripotent Stem Cell, Frontotemporal Dementia (FTD), Stem Cell Research, Rare Diseases, 2.1 Biological and endogenous factors, Neurological, Good Health and Well Being, Humans, Amyotrophic Lateral Sclerosis, Frontotemporal Dementia, Granulins, Progranulins, Astrocytes, Mutation, DNA-Binding Proteins, Brain, FTD, astrocytes, iPSC, neurodegeneration, neurons, strocyte-neuronal signaling, Clinical Sciences, Biochemistry and cell biology
Abstract

Loss of function (LoF) of TAR-DNA binding protein 43 (TDP-43) and mis-localization, together with TDP-43-positive and hyperphosphorylated inclusions, are found in post-mortem tissue of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) patients, including those carrying LoF variants in the progranulin gene (GRN). Modeling TDP-43 pathology has been challenging in vivo and in vitro. We present a three-dimensional induced pluripotent stem cell (iPSC)-derived paradigm-mature brain organoids (mbOrg)-composed of cortical-like-astrocytes (iA) and neurons. When devoid of GRN, mbOrgs spontaneously recapitulate TDP-43 mis-localization, hyperphosphorylation, and LoF phenotypes. Mixing and matching genotypes in mbOrgs showed that GRN-/- iA are drivers for TDP-43 pathology. Finally, we rescued TDP-43 LoF by adding exogenous progranulin, demonstrating a link between TDP-43 LoF and progranulin expression. In conclusion, we present an iPSC-derived platform that shows striking features of human TDP-43 proteinopathy and provides a tool for the mechanistic modeling of TDP-43 pathology and patient-tailored therapeutic screening for FTD and ALS.

Published
2023

3. Endosomal recycling defects link Huntington’s disease with McLeod syndrome

Author

Marsan, Elise and Huang, Eric J

Subjects
Biochemistry and Cell Biology, Biological Sciences, Rare Diseases, Neurodegenerative, Brain Disorders, Neurosciences, Huntington's Disease, Amino Acid Transport Systems, Neutral, Cell Membrane, Endosomes, Humans, Huntington Disease, Manganese, Neuroacanthocytosis, rab GTP-Binding Proteins, Medical and Health Sciences, Developmental Biology, Biological sciences, Biomedical and clinical sciences
Abstract

Chhetri and colleagues (2022. J. Cell Biol.https://doi.org/10.1083/jcb.202112073) show that Rab11-mediated endosomal recycling regulates cell surface expression of McLeod syndrome protein XK. Mutant huntingtin interferes with the recycling of XK to the cell surface and significantly reduces manganese transport across cell membrane.

Published
2022

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

Author

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

Subjects
Epilepsy -- Genetic aspects -- Risk factors -- Care and treatment -- Research, Gene mutation -- Research, Drug resistance -- Research, Focal dermal hypoplasia -- Genetic aspects -- Complications and side effects -- Research, Health care industry
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., Introduction The human brain is genetically mosaic. Accumulation of somatic variants in postmitotic cells from healthy human cerebral tissues has recently been described, emphasizing that somatic mutational events are frequent [...]

Published
2018
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7. Granulin Loss of Function in Human Mature Brain Organoids Implicates Astrocytes in TDP-43 Pathology

Author

de Majo, Martina, primary, Koontz, Mark, additional, Marsan, Elise, additional, Salinas, Nir, additional, Ramsey, Arren, additional, Kuo, Yien-Ming, additional, Seo, Kyounghee, additional, Li, Huinan, additional, Dräger, Nina M, additional, Leng, Kun, additional, Gonzales, Santiago L, additional, Kurnellas, Michael, additional, Miyaoka, Yuichiro, additional, Klim, Joseph R, additional, Kampmann, Martin, additional, Ward, Michael E, additional, Huang, Eric J, additional, and Ullian, Erik M, additional

Published
2022
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11. Depdc5 knockdown causes mTOR‐dependent motor hyperactivity in zebrafish

Author

de Calbiac, Hortense, Dabacan, Adriana, Marsan, Elise, Tostivint, Hervé, Devienne, Gabrielle, Ishida, Saeko, Leguern, Eric, Baulac, Stéphanie, Muresan, Raul C., Kabashi, Edor, and Ciura, Sorana

Subjects
Research Articles, Research Article
Abstract

Objective DEPDC5 was identified as a major genetic cause of focal epilepsy with deleterious mutations found in a wide range of inherited forms of focal epilepsy, associated with malformation of cortical development in certain cases. Identification of frameshift, truncation, and deletion mutations implicates haploinsufficiency of DEPDC5 in the etiology of focal epilepsy. DEPDC5 is a component of the GATOR1 complex, acting as a negative regulator of mTOR signaling. Methods Zebrafish represents a vertebrate model suitable for genetic analysis and drug screening in epilepsy‐related disorders. In this study, we defined the expression of depdc5 during development and established an epilepsy model with reduced Depdc5 expression. Results Here we report a zebrafish model of Depdc5 loss‐of‐function that displays a measurable behavioral phenotype, including hyperkinesia, circular swimming, and increased neuronal activity. These phenotypic features persisted throughout embryonic development and were significantly reduced upon treatment with the mTORC1 inhibitor, rapamycin, as well as overexpression of human WT DEPDC5 transcript. No phenotypic rescue was obtained upon expression of epilepsy‐associated DEPDC5 mutations (p.Arg487* and p.Arg485Gln), indicating that these mutations cause a loss of function of the protein. Interpretation This study demonstrates that Depdc5 knockdown leads to early‐onset phenotypic features related to motor and neuronal hyperactivity. Restoration of phenotypic features by WT but not epilepsy‐associated Depdc5 mutants, as well as by mTORC1 inhibition confirm the role of Depdc5 in the mTORC1‐dependent molecular cascades, defining this pathway as a potential therapeutic target for DEPDC5‐inherited forms of focal epilepsy.

Published
2018

12. Familial focal epilepsy with focal cortical dysplasia due to DEPDC5 mutations

Author

Baulac, Stéphanie, Ishida, Saeko, Marsan, Elise, Miquel, Catherine, Biraben, Arnaud, Nguyen, Dang Khoa, Nordli, Doug, Cossette, Patrick, Nguyen The Tich, Sylvie, Lambrecq, Virginie, Vlaicu, Mihaela, Daniau, Maïlys, Bielle, Franck, Andermann, Eva, Andermann, Frederick, Leguern, Eric, Chassoux, Francine, Picard, Fabienne, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Service de Neuropathologie [Sainte-Anne], Hôpital Sainte-Anne, Laboratoire Traitement du Signal et de l'Image (LTSI), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Neurologie [Rennes], Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Centre hospitalier universtaire de Montréal, Epilepsy Division, Ann & Robert H. Lurie Children's Hospital of Chicago, Centre of Excellence in Neuromics Montréal, Laboratoire Angevin de Recherche en Ingénierie des Systèmes (LARIS), Université d'Angers (UA), Service de neurologie 1 [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], CHU Pitié-Salpêtrière [APHP], Neurogenetics unit and Epilepsy Research group, Montreal Neurological Institute and Hospital, McGill University-McGill University, McGill University, Seizure clinic and epilepsy research group, Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Epilepsies de l'Enfant et Plasticité Cérébrale (U1129), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Patrimoines et Langages Musicaux (UP4 PLM), Université Paris-Sorbonne (UP4), Department of neurology, Hôpitaux Universitaires de Genève (HUG), Japan Society for the Promotion of Science, 320030-127608, Swiss National Foundation, Fondation pour la recherche sur le cerveau, Fondation Française pour la recherche sur les épilepsies, Carnot Institute, ANR-10-IAIHU-06, program 'Investissements d'avenir', Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière ( CRICM ), Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ), Laboratoire Traitement du Signal et de l'Image ( LTSI ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Université de Montréal, Laboratoire angevins de recherche en ingénierie des systèmes (EA 7315) ( LARIS ), Université d'Angers ( UA ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP], Département de neurochirurgie, Département de neuropathologie, Montreal Neurological Institute, Departments of neurology & neurosurgery and pediatrics, UQAM-McGill, Epilepsies de l'Enfant et Plasticité Cérébrale ( U1129 ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Patrimoines et Langages Musicaux ( UP4 PLM ), Université Paris-Sorbonne ( UP4 ), Hôpitaux Universitaires de Genève ( HUG ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Service de Neurologie [Rennes] = Neurology [Rennes], CHU Pontchaillou [Rennes], Service de Neurologie [CHU Pitié-Salpêtrière], IFR70-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), McGill University = Université McGill [Montréal, Canada]-McGill University = Université McGill [Montréal, Canada], McGill University = Université McGill [Montréal, Canada], ANR-10-IAHU-0006,IHU-A-ICM,Institut de Neurosciences Translationnelles de Paris(2010), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Administateur, HAL Sorbonne Université, and Institut de Neurosciences Translationnelles de Paris - - IHU-A-ICM2010 - ANR-10-IAHU-0006 - IAHU - VALID

Subjects
Adult, Male, Adolescent, [SCCO.NEUR]Cognitive science/Neuroscience, [SCCO.NEUR] Cognitive science/Neuroscience, GTPase-Activating Proteins, Middle Aged, ddc:616.8, Pedigree, Malformations of Cortical Development, Repressor Proteins, Young Adult, [ SCCO.NEUR ] Cognitive science/Neuroscience, Mutation, Humans, Female, Epilepsies, Partial, Child
Abstract

Objective: The DEPDC5 (DEP domain-containing protein 5) gene, encoding a repressor of the mTORC1 signaling pathway, has recently emerged as a major gene mutated in familial focal epilepsies. We aimed to further extend the role of DEPDC5 to focal cortical dysplasias (FCDs). Methods: Seven patients from four families with DEPDC5 mutations, and focal epilepsy associated with FCD were recruited and investigated at the clinical, neuroimaging and histopathological levels. The DEPDC5 gene was sequenced from genomic blood and brain DNA. Results: All patients had drug-resistant focal epilepsy, five of them underwent surgery, and one a brain biopsy. Electroclinical phenotypes were compatible with FCD II, although MRI was typical in only four cases. Histopathology confirmed FCD IIa in two patients (including one MRI-negative case) and showed FCD I in two other patients, and remained inconclusive in the last two. Three patients were seizure-free post-surgically and one had a worthwhile improvement. Sequencing of blood DNA revealed truncating DEPDC5 mutations in all four families; one mutation was found to be mosaic in an asymptomatic father. A brain somatic DEPDC5 mutation was identified in one patient in addition to the germline mutation. Interpretation: Germline, germline mosaic and brain somatic DEPDC5 mutations may cause epilepsy associated with FCD, reinforcing the link between mTORC1 pathway and FCDs. Similarly to other mTORopathies, a "two-hit" mutational model could be responsible for cortical lesions. Our study also indicates that epilepsy surgery is a valuable alternative in the treatment of drug-resistant DEPDC5-positive focal epilepsies, even if the MRI is unremarkable. This article is protected by copyright. All rights reserved.

Published
2014

13. Germline and somatic mutations in theMTORgene in focal cortical dysplasia and epilepsy

Author

Møller, Rikke S., primary, Weckhuysen, Sarah, additional, Chipaux, Mathilde, additional, Marsan, Elise, additional, Taly, Valerie, additional, Bebin, E. Martina, additional, Hiatt, Susan M., additional, Prokop, Jeremy W., additional, Bowling, Kevin M., additional, Mei, Davide, additional, Conti, Valerio, additional, de la Grange, Pierre, additional, Ferrand-Sorbets, Sarah, additional, Dorfmüller, Georg, additional, Lambrecq, Virginie, additional, Larsen, Line H.G., additional, Leguern, Eric, additional, Guerrini, Renzo, additional, Rubboli, Guido, additional, Cooper, Gregory M., additional, and Baulac, Stéphanie, additional

Published
2016
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14. Involvement of GATOR complex genes in familial focal epilepsies and focal cortical dysplasia

Author

Weckhuysen, Sarah, primary, Marsan, Elise, additional, Lambrecq, Virginie, additional, Marchal, Cécile, additional, Morin‐Brureau, Mélanie, additional, An‐Gourfinkel, Isabelle, additional, Baulac, Michel, additional, Fohlen, Martine, additional, Kallay Zetchi, Christine, additional, Seeck, Margitta, additional, de la Grange, Pierre, additional, Dermaut, Bart, additional, Meurs, Alfred, additional, Thomas, Pierre, additional, Chassoux, Francine, additional, Leguern, Eric, additional, Picard, Fabienne, additional, and Baulac, Stéphanie, additional

Published
2016
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15. Depdc5 knockout rat: A novel model of mTORopathy

Author

Marsan, Elise, primary, Ishida, Saeko, additional, Schramm, Adrien, additional, Weckhuysen, Sarah, additional, Muraca, Giuseppe, additional, Lecas, Sarah, additional, Liang, Ning, additional, Treins, Caroline, additional, Pende, Mario, additional, Roussel, Delphine, additional, Le Van Quyen, Michel, additional, Mashimo, Tomoji, additional, Kaneko, Takehito, additional, Yamamoto, Takashi, additional, Sakuma, Tetsushi, additional, Mahon, Séverine, additional, Miles, Richard, additional, Leguern, Eric, additional, Charpier, Stéphane, additional, and Baulac, Stéphanie, additional

Published
2016
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16. Familial focal epilepsy with focal cortical dysplasia due to DEPDC 5 mutations.

Author

Baulac, Stéphanie, Ishida, Saeko, Marsan, Elise, Miquel, Catherine, Biraben, Arnaud, Nguyen, Dang Khoa, Nordli, Doug, Cossette, Patrick, Nguyen, Sylvie, Lambrecq, Virginie, Vlaicu, Mihaela, Daniau, Maïlys, Bielle, Franck, Andermann, Eva, Andermann, Frederick, Leguern, Eric, Chassoux, Francine, and Picard, Fabienne

Abstract

Objective The DEPDC5 (DEP domain-containing protein 5) gene, encoding a repressor of the mTORC1 signaling pathway, has recently emerged as a major gene mutated in familial focal epilepsies. We aimed to further extend the role of DEPDC5 to focal cortical dysplasias (FCDs). Methods Seven patients from 4 families with DEPDC5 mutations and focal epilepsy associated with FCD were recruited and investigated at the clinical, neuroimaging, and histopathological levels. The DEPDC5 gene was sequenced from genomic blood and brain DNA. Results All patients had drug-resistant focal epilepsy, 5 of them underwent surgery, and 1 had a brain biopsy. Electroclinical phenotypes were compatible with FCD II, although magnetic resonance imaging (MRI) was typical in only 4 cases. Histopathology confirmed FCD IIa in 2 patients (including 1 MRI-negative case) and showed FCD I in 2 other patients, and remained inconclusive in the last 2 patients. Three patients were seizure-free postsurgically, and 1 had a worthwhile improvement. Sequencing of blood DNA revealed truncating DEPDC5 mutations in all 4 families; 1 mutation was found to be mosaic in an asymptomatic father. A brain somatic DEPDC5 mutation was identified in 1 patient in addition to the germline mutation. Interpretation Germline, germline mosaic, and brain somatic DEPDC5 mutations may cause epilepsy associated with FCD, reinforcing the link between mTORC1 pathway and FCDs. Similarly to other mTORopathies, a '2-hit' mutational model could be responsible for cortical lesions. Our study also indicates that epilepsy surgery is a valuable alternative in the treatment of drug-resistant DEPDC5-positive focal epilepsies, even if the MRI is unremarkable. Ann Neurol 2015;77:675-683 [ABSTRACT FROM AUTHOR]

Published
2015
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17. Dissecting the genetic basis of focal cortical dysplasia: a large cohort study

Author

Baldassari, Sara, Ribierre, Théo, Marsan, Elise, Adle-Biassette, Homa, Ferrand-Sorbets, Sarah, Bulteau, Christine, Dorison, Nathalie, Fohlen, Martine, Polivka, Marc, Weckhuysen, Sarah, Dorfmüller, Georg, Chipaux, Mathilde, Baulac, Stéphanie, Gestionnaire, Hal Sorbonne Université, Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Sorbonne Université (SU), Service d'anatomie et cytologie pathologiques, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Neuroprotection du Cerveau en Développement / Promoting Research Oriented Towards Early Cns Therapies (PROTECT), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Robert Debré Paris, Hôpital Robert Debré, Université Paris Diderot - Paris 7 (UPD7), Hôpital Lariboisière, Fondation Ophtalmologique Adolphe de Rothschild [Paris], Antwerp University Hospital [Edegem] (UZA), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Male, Neurons, Original Paper, Epilepsy, Adolescent, [SDV]Life Sciences [q-bio], Epilepsy-associated focal cortical dysplasia, Brain, Infant, Somatic variant, Hemimegalencephaly, Brain mosaicism, Cohort Studies, Malformations of Cortical Development, [SDV] Life Sciences [q-bio], mTOR pathway, Child, Preschool, Mutation, Humans, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Human medicine, Child, Neurogenetics
Abstract

Genetic malformations of cortical development (MCDs), such as mild MCDs (mMCD), focal cortical dysplasia (FCD), and hemimegalencephaly (HME), are major causes of severe pediatric refractory epilepsies subjected to neurosurgery. FCD2 are characterized by neuropathological hallmarks that include enlarged dysmorphic neurons (DNs) and balloon cells (BCs). Here, we provide a comprehensive assessment of the contribution of germline and somatic variants in a large cohort of surgical MCD cases. We enrolled in a monocentric study 80 children with drug-resistant epilepsy and a postsurgical neuropathological diagnosis of mMCD, FCD1, FCD2, or HME. We performed targeted gene sequencing ( ≥ 2000X read depth) on matched blood–brain samples to search for low-allele frequency variants in mTOR pathway and FCD genes. We were able to elucidate 29% of mMCD/FCD1 patients and 63% of FCD2/HME patients. Somatic loss-of-function variants in the N-glycosylation pathway-associated SLC35A2 gene were found in mMCD/FCD1 cases. Somatic gain-of-function variants in MTOR and its activators (AKT3, PIK3CA, RHEB), as well as germline, somatic and two-hit loss-of-function variants in its repressors (DEPDC5, TSC1, TSC2) were found exclusively in FCD2/HME cases. We show that panel-negative FCD2 cases display strong pS6-immunostaining, stressing that all FCD2 are mTORopathies. Analysis of microdissected cells demonstrated that DNs and BCs carry the pathogenic variants. We further observed a correlation between the density of pathological cells and the variant-detection likelihood. Single-cell microdissection followed by sequencing of enriched pools of DNs unveiled a somatic second-hit loss-of-heterozygosity in a DEPDC5 germline case. In conclusion, this study indicates that mMCD/FCD1 and FCD2/HME are two distinct genetic entities: while all FCD2/HME are mosaic mTORopathies, mMCD/FCD1 are not caused by mTOR-pathway-hyperactivating variants, and ~ 30% of the cases are related to glycosylation defects. We provide a framework for efficient genetic testing in FCD/HME, linking neuropathology to genetic findings and emphasizing the usefulness of molecular evaluation in the pediatric epileptic neurosurgical population. Electronic supplementary material The online version of this article (10.1007/s00401-019-02061-5) contains supplementary material, which is available to authorized users.

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18. Germline and somatic mutations in the MTOR gene in focal cortical dysplasia and epilepsy.

Author

Møller RS, Weckhuysen S, Chipaux M, Marsan E, Taly V, Bebin EM, Hiatt SM, Prokop JW, Bowling KM, Mei D, Conti V, de la Grange P, Ferrand-Sorbets S, Dorfmüller G, Lambrecq V, Larsen LH, Leguern E, Guerrini R, Rubboli G, Cooper GM, and Baulac S

Abstract

Objective: To assess the prevalence of somatic MTOR mutations in focal cortical dysplasia (FCD) and of germline MTOR mutations in a broad range of epilepsies., Methods: We collected 20 blood-brain paired samples from patients with FCD and searched for somatic variants using deep-targeted gene panel sequencing. Germline mutations in MTOR were assessed in a French research cohort of 93 probands with focal epilepsies and in a diagnostic Danish cohort of 245 patients with a broad range of epilepsies. Data sharing among collaborators allowed us to ascertain additional germline variants in MTOR ., Results: We detected recurrent somatic variants (p.Ser2215Phe, p.Ser2215Tyr, and p.Leu1460Pro) in the MTOR gene in 37% of participants with FCD II and showed histologic evidence for activation of the mTORC1 signaling cascade in brain tissue. We further identified 5 novel de novo germline missense MTOR variants in 6 individuals with a variable phenotype from focal, and less frequently generalized, epilepsies without brain malformations, to macrocephaly, with or without moderate intellectual disability. In addition, an inherited variant was found in a mother-daughter pair with nonlesional autosomal dominant nocturnal frontal lobe epilepsy., Conclusions: Our data illustrate the increasingly important role of somatic mutations of the MTOR gene in FCD and germline mutations in the pathogenesis of focal epilepsy syndromes with and without brain malformation or macrocephaly.

Published
2016
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