Your browser doesn't support javascript.
loading
Loss of symmetric cell division of apical neural progenitors drives DENND5A-related developmental and epileptic encephalopathy.
Banks, Emily; Francis, Vincent; Lin, Sheng-Jia; Kharfallah, Fares; Fonov, Vladimir; Levesque, Maxime; Han, Chanshuai; Kulasekaran, Gopinath; Tuznik, Marius; Bayati, Armin; Al-Khater, Reem; Alkuraya, Fowzan S; Argyriou, Loukas; Babaei, Meisam; Bahlo, Melanie; Bakhshoodeh, Behnoosh; Barr, Eileen; Bartik, Lauren; Bassiony, Mahmoud; Bertrand, Miriam; Braun, Dominique; Buchert, Rebecca; Budetta, Mauro; Cadieux-Dion, Maxime; Calame, Daniel; Cope, Heidi; Cushing, Donna; Efthymiou, Stephanie; Elmaksoud, Marwa A; El Said, Huda G; Froukh, Tawfiq; Gill, Harinder K; Gleeson, Joseph G; Gogoll, Laura; Goh, Elaine S-Y; Gowda, Vykuntaraju K; Haack, Tobias B; Hashem, Mais O; Hauser, Stefan; Hoffman, Trevor L; Hogue, Jacob S; Hosokawa, Akimoto; Houlden, Henry; Huang, Kevin; Huynh, Stephanie; Karimiani, Ehsan G; Kaulfuß, Silke; Korenke, G Christoph; Kritzer, Amy; Lee, Hane.
Afiliação
  • Banks E; Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montréal, QC H3A 2B4, Canada.
  • Francis V; Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montréal, QC H3A 2B4, Canada.
  • Lin SJ; Genes & Human Disease Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, 73104, USA.
  • Kharfallah F; Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montréal, QC H3A 2B4, Canada.
  • Fonov V; Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montréal, QC H3A 2B4, Canada.
  • Levesque M; Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montréal, QC H3A 2B4, Canada.
  • Han C; Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montréal, QC H3A 2B4, Canada.
  • Kulasekaran G; Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montréal, QC H3A 2B4, Canada.
  • Tuznik M; Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montréal, QC H3A 2B4, Canada.
  • Bayati A; Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montréal, QC H3A 2B4, Canada.
  • Al-Khater R; Johns Hopkins Aramco Healthcare, Dhahran 34465, Saudi Arabia.
  • Alkuraya FS; Department of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia.
  • Argyriou L; Institute of Human Genetics, University Medical Center, Göttingen 37073, Germany.
  • Babaei M; Department of Pediatrics, North Khorasan University of Medical Sciences, Bojnurd, Iran.
  • Bahlo M; Walter and Eliza Hall Institute for Medical Research, Parkville Victoria 3052, Australia.
  • Bakhshoodeh B; Mashhad University of Medical Sciences, Mashhad, Iran.
  • Barr E; Emory University, Department of Human Genetics, Atlanta, GA 30322, USA.
  • Bartik L; University of Missouri-Kansas City, School of Medicine, Kansas City, MO 64108, USA.
  • Bassiony M; Department of Pediatrics, Division of Clinical Genetics, Children's Mercy Hospital, Kansas City, MO 64108, USA.
  • Bertrand M; Faculty of Medicine, Alexandria University, Alexandria, Egypt.
  • Braun D; Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen 72076, Germany.
  • Buchert R; Department of Human Genetics, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
  • Budetta M; Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen 72076, Germany.
  • Cadieux-Dion M; Paediatric and Child Neurology Unit, Cava de' Tirreni AOU S. Giovanni di Dio e Ruggiero d'Aragona Hospital, Salerno, Italy.
  • Calame D; Department of Pathology and Laboratory Medicine, Children's Mercy Hospital, Kansas City, MO 64108, USA.
  • Cope H; Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
  • Cushing D; Texas Children's Hospital, Houston, TX, USA.
  • Efthymiou S; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
  • Elmaksoud MA; Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, NC 27710, USA.
  • El Said HG; Laboratory Medicine and Genetics, Trillium Health Partners, Mississauga, ON L5B 1B8, Canada.
  • Froukh T; Department of Neuromuscular Diseases, University College London (UCL) Institute of Neurology, Queen Square, London, WC1N 3BG, UK.
  • Gill HK; Neurology Unit, Department of Pediatrics, Faculty of Medicine, University of Alexandria, Alexandria, Egypt.
  • Gleeson JG; Department of Family Health, High Institute of Public Health, Faculty of Medicine, University of Alexandria, Alexandria, Egypt.
  • Gogoll L; Department of Biotechnology and Genetic Engineering, Philadelphia University, Amman 19392, Jordan.
  • Goh ES; Provincial Medical Genetics Program at BC Women's Health Centre, Vancouver, BC V6H 3N1, Canada.
  • Gowda VK; Department of Neurosciences, University of California San Diego, La Jolla, CA, USA.
  • Haack TB; Rady Children's Institute for Genomic Medicine, San Diego, CA, USA.
  • Hashem MO; Department of Human Genetics, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
  • Hauser S; Laboratory Medicine and Genetics, Trillium Health Partners, Mississauga, ON L5B 1B8, Canada.
  • Hoffman TL; Department of Pediatric Neurology, Indira Gandhi Institute of Child Health, Bangalore, India.
  • Hogue JS; Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen 72076, Germany.
  • Hosokawa A; Department of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia.
  • Houlden H; Center for Neurology and Hertie Institute for Clinical Brain Research, University Tübingen, Tübingen 72076, Germany.
  • Huang K; German Center of Neurodegenerative Diseases (DZNE), Tübingen 72076, Germany.
  • Huynh S; Southern California Kaiser Permanente Medical Group, Department of Regional Genetics, Anaheim, CA 92806, USA.
  • Karimiani EG; Madigan Army Medical Center, Tacoma, WA 98431, USA.
  • Kaulfuß S; Department of Paediatrics and Child Health, University of Otago, Wellington, 6242, New Zealand.
  • Korenke GC; Department of Neuromuscular Diseases, University College London (UCL) Institute of Neurology, Queen Square, London, WC1N 3BG, UK.
  • Kritzer A; Genes & Human Disease Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, 73104, USA.
  • Lee H; Provincial Medical Genetics Program at BC Women's Health Centre, Vancouver, BC V6H 3N1, Canada.
medRxiv ; 2024 Jan 31.
Article em En | MEDLINE | ID: mdl-38352438
ABSTRACT
Developmental and epileptic encephalopathies (DEEs) are a heterogenous group of epilepsies in which altered brain development leads to developmental delay and seizures, with the epileptic activity further negatively impacting neurodevelopment. Identifying the underlying cause of DEEs is essential for progress toward precision therapies. Here we describe a group of individuals with biallelic variants in DENND5A and determine that variant type is correlated with disease severity. We demonstrate that DENND5A interacts with MUPP1 and PALS1, components of the Crumbs apical polarity complex, which is required for both neural progenitor cell identity and the ability of these stem cells to divide symmetrically. Induced pluripotent stem cells lacking DENND5A fail to undergo symmetric cell division during neural induction and have an inherent propensity to differentiate into neurons, and transgenic DENND5A mice, with phenotypes like the human syndrome, have an increased number of neurons in the adult subventricular zone. Disruption of symmetric cell division following loss of DENND5A results from misalignment of the mitotic spindle in apical neural progenitors. A subset of DENND5A is localized to centrosomes, which define the spindle poles during mitosis. Cells lacking DENND5A orient away from the proliferative apical domain surrounding the ventricles, biasing daughter cells towards a more fate-committed state and ultimately shortening the period of neurogenesis. This study provides a mechanism behind DENND5A-related DEE that may be generalizable to other developmental conditions and provides variant-specific clinical information for physicians and families.

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Idioma: En Revista: MedRxiv Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Canadá

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Idioma: En Revista: MedRxiv Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Canadá