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1. Mutations in the HECT domain of NEDD4L lead to AKT-mTOR pathway deregulation and cause periventricular nodular heterotopia.

Author

Broix L, Jagline H, Ivanova E, Schmucker S, Drouot N, Clayton-Smith J, Pagnamenta AT, Metcalfe KA, Isidor B, Louvier UW, Poduri A, Taylor JC, Tilly P, Poirier K, Saillour Y, Lebrun N, Stemmelen T, Rudolf G, Muraca G, Saintpierre B, Elmorjani A, Moïse M, Weirauch NB, Guerrini R, Boland A, Olaso R, Masson C, Tripathy R, Keays D, Beldjord C, Nguyen L, Godin J, Kini U, Nischké P, Deleuze JF, Bahi-Buisson N, Sumara I, Hinckelmann MV, and Chelly J

Subjects
Animals, Cells, Cultured, Female, Humans, Male, Mice, Nedd4 Ubiquitin Protein Ligases, Protein Domains genetics, Proto-Oncogene Proteins c-akt metabolism, Signal Transduction, TOR Serine-Threonine Kinases metabolism, Ubiquitin metabolism, Endosomal Sorting Complexes Required for Transport genetics, Mutation, Missense, Periventricular Nodular Heterotopia genetics, Ubiquitin-Protein Ligases genetics
Abstract

Neurodevelopmental disorders with periventricular nodular heterotopia (PNH) are etiologically heterogeneous, and their genetic causes remain in many cases unknown. Here we show that missense mutations in NEDD4L mapping to the HECT domain of the encoded E3 ubiquitin ligase lead to PNH associated with toe syndactyly, cleft palate and neurodevelopmental delay. Cellular and expression data showed sensitivity of PNH-associated mutants to proteasome degradation. Moreover, an in utero electroporation approach showed that PNH-related mutants and excess wild-type NEDD4L affect neurogenesis, neuronal positioning and terminal translocation. Further investigations, including rapamycin-based experiments, found differential deregulation of pathways involved. Excess wild-type NEDD4L leads to disruption of Dab1 and mTORC1 pathways, while PNH-related mutations are associated with deregulation of mTORC1 and AKT activities. Altogether, these data provide insights into the critical role of NEDD4L in the regulation of mTOR pathways and their contributions in cortical development., Competing Interests: The authors declare no competing financial interests.

Published
2016
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2. Mutations in the HECT domain of NEDD4L lead to AKT-mTOR pathway deregulation and cause periventricular nodular heterotopia

Author

Broix, L, Jagline, H, L Ivanova, E, Schmucker, S, Drouot, N, Clayton-Smith, J, Pagnamenta, A, Metcalfe, K, Isidor, B, Louvier, U, Poduri, A, Taylor, J, Tilly, P, Poirier, K, Saillour, Y, Lebrun, N, Stemmelen, T, Rudolf, G, Muraca, G, Saintpierre, B, Elmorjani, A, study, Deciphering Developmental Disorders, Moïse, M, Weirauch, N, Guerrini, R, Boland, A, Olaso, R, Masson, C, Tripathy, R, Keays, D, Beldjord, C, Nguyen, L, Godin, J, Kini, U, Nischké, P, Deleuze, J, Bahi-Buisson, N, Sumara, I, Hinckelmann, M, Chelly, J, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Regional Genetic Service, St Mary's Hospital, Manchester, The Wellcome Trust Centre for Human Genetics [Oxford], University of Oxford [Oxford], Central Manchester University Hospitals NHS Foundation Trust, Service de génétique médicale - Unité de génétique clinique [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), 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)-CHU Pitié-Salpêtrière [APHP], Pediatric Neurology & Neurogenetics Unit and Laboratories, Children's Hospital A. Meyer-University of Florence (UNIFI), Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Plate Forme Paris Descartes de Bioinformatique (BIP-D), Université Paris Descartes - Paris 5 (UPD5), Institut Cochin (UMR_S567 / UMR 8104), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5), Department of Clinical Genetics [Churchill Hospital], Churchill Hospital Oxford Centre for Haematology, Service de neurologie pédiatrique [CHU Necker], CHU Necker - Enfants Malades [AP-HP]-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Institute of Biochemistry (IBC), Eidgenössische Technische Hochschule - Swiss Federal Institute of Technology in Zürich [Zürich] (ETH Zürich), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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)-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), Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI)-Children's Hospital A. Meyer, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Eidgenössische Technische Hochschule - Swiss Federal Institute of Technology [Zürich] (ETH Zürich), University of Oxford, Université Pierre et Marie Curie - Paris 6 (UPMC)-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)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), and Università degli Studi di Firenze = University of Florence (UniFI)-Children's Hospital A. Meyer

Subjects
0301 basic medicine, HECT domain, Male, Nedd4 Ubiquitin Protein Ligases, Ubiquitin-Protein Ligases, [SDV]Life Sciences [q-bio], Mutation, Missense, mTORC1, Bioinformatics, medicine.disease_cause, Article, 03 medical and health sciences, Mice, 0302 clinical medicine, Ubiquitin, Periventricular Nodular Heterotopia, Protein Domains, hemic and lymphatic diseases, Genetics, medicine, Animals, Humans, Protein kinase B, PI3K/AKT/mTOR pathway, Cells, Cultured, ComputingMilieux_MISCELLANEOUS, Mutation, biology, Endosomal Sorting Complexes Required for Transport, TOR Serine-Threonine Kinases, DAB1, Cell biology, Ubiquitin ligase, 030104 developmental biology, biology.protein, Female, Proto-Oncogene Proteins c-akt, 030217 neurology & neurosurgery, Signal Transduction
Abstract

Neurodevelopmental disorders with periventricular nodular heterotopia (PNH) are etiologically heterogeneous, and their genetic causes remain in many cases unknown. Here we show that missense mutations in the HECT domain of the E3 ubiquitin ligase NEDD4L lead to PNH associated with toes syndactyly, cleft palate and neurodevelopmental delay. Cellular and expression data showed a sensitivity of PNH-associated mutants to proteasome degradation. Moreover, in utero electroporation approach showed that PNH-related mutants and excess of wild type (WT) NEDD4L affect neurogenesis, neuronal positioning and terminal translocation. Further investigations, including rapamycin based experiments, revealed differential deregulation of pathways involved. Excess of WT NEDD4L leads to a disruption of Dab1 and mTORC1 pathways, while PNH-related mutations are associated with a deregulation of mTORC1 and AKT activities. Altogether, these data provide insights to better understand the critical role of NEDD4L in the regulation of mTOR pathways and their contributions in cortical development.

Published
2017
Full Text
View/download PDF

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