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

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

  • Nat Genet. 2016 Nov;48(11):1349-1358. doi: 10.1038/ng.3676.
Loïc Broix # 1 2 3 4 5,  Hélène Jagline # 1 2 3 4,  Ekaterina Ivanova 1 2 3 4,  Stéphane Schmucker 1 2 3 4,  Nathalie Drouot 1 2 3 4,  Jill Clayton-Smith 6,  Alistair T Pagnamenta 7,  Kay A Metcalfe 6,  Bertrand Isidor 8,  Ulrike Walther Louvier 9,  Annapurna Poduri 10,  Jenny C Taylor 7,  Peggy Tilly 1 2 3 4,  Karine Poirier 5,  Yoann Saillour 5,  Nicolas Lebrun 5,  Tristan Stemmelen 1 2 3 4,  Gabrielle Rudolf 2 3 4,  Giuseppe Muraca 5,  Benjamin Saintpierre 5,  Adrienne Elmorjani 5,  Deciphering Developmental Disorders study,  Martin Moïse 11,  Nathalie Bednarek Weirauch 12,  Renzo Guerrini 13,  Anne Boland 14,  Robert Olaso 14,  Cecile Masson 15,  Ratna Tripathy 16,  David Keays 16,  Cherif Beldjord 17,  Laurent Nguyen 11,  Juliette Godin 1 2 3 4,  Usha Kini 18,  Patrick Nischké 15,  Jean-François Deleuze 14,  Nadia Bahi-Buisson 19,  Izabela Sumara 1 2 3 4,  Maria-Victoria Hinckelmann 1 2 3 4,  Jamel Chelly 1 2 3 4 20
Affiliations

Affiliations

  • 1 Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France.
  • 2 Centre National de la Recherche Scientifique, U7104, Illkirch, France.
  • 3 Institut National de la Santé et de la Recherche Médicale, U964, Illkirch, France.
  • 4 Université de Strasbourg, Illkirch, France.
  • 5 Institut Cochin, Institut National de la Santé et de la Recherche Médicale U1016, Centre National de la Recherche Scientifique U 8104, Paris Descartes University, Paris, France.
  • 6 Manchester Centre For Genomic medicine, Central Manchester University Hospitals National Health Service Trust, Manchester Academic Health Science Centre, Manchester, UK.
  • 7 National Institute for Health Research Biomedical Research Centre, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
  • 8 Service de Génétique Médicale, University Hospital of Nantes, Nantes, France.
  • 9 Unité de Neuropédiatrie et d'épileptologie infantile, University Hospital of Montpellier, Montpellier, France.
  • 10 Epilepsy Genetics Program, Division of Epilepsy and Clinical Neurophysiology Department of Neurology, Boston Children's Hospital, Boston, MA, USA.
  • 11 Grappe Interdisciplinaire de Génoprotéomique Appliquée- Neurosciences, University of Liège,, Liège, Belgium.
  • 12 Hôpital Maison Blanche, University Hospital of de Reims, France.
  • 13 Paediatric Neurology Unit, A. Meyer Children's Hospital-University of Florence, Florence, Italy.
  • 14 Centre National de Génotypage , Evry, France.
  • 15 Institut Imagine, Bioinformatics Platform, Paris Descartes University, Paris, France.
  • 16 Institute of Molecular Pathology, Vienna, Austria.
  • 17 Laboratoire de biochimie et génétique moléculaire, Hôpital Cochin, Paris, France.
  • 18 Department of Clinical Genetics, Oxford University Hospitals National Health Service Trust, UK.
  • 19 Institut Imagine, Institut National de la Santé et de la Recherche Médicale U1163- Paris Descartes University, Hôpital Necker-Enfants Malades, Paris, France.
  • 20 Service de Diagnostic Génétique, Hôpital Civil de Strasbourg, Hôpitaux Universitaires de Strasbourg, France.
  • # Contributed equally.
PMID: 27694961 DOI: 10.1038/ng.3676
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.

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