Nature Communications (Aug 2024)
Loss of symmetric cell division of apical neural progenitors drives DENND5A-related developmental and epileptic encephalopathy
- Emily Banks,
- Vincent Francis,
- Sheng-Jia Lin,
- Fares Kharfallah,
- Vladimir Fonov,
- Maxime Lévesque,
- Chanshuai Han,
- Gopinath Kulasekaran,
- Marius Tuznik,
- Armin Bayati,
- Reem Al-Khater,
- Fowzan S. Alkuraya,
- Loukas Argyriou,
- Meisam Babaei,
- Melanie Bahlo,
- Behnoosh Bakhshoodeh,
- Eileen Barr,
- Lauren Bartik,
- Mahmoud Bassiony,
- Miriam Bertrand,
- Dominique Braun,
- Rebecca Buchert,
- Mauro Budetta,
- Maxime Cadieux-Dion,
- Daniel G. Calame,
- Heidi Cope,
- Donna Cushing,
- Stephanie Efthymiou,
- Marwa Abd Elmaksoud,
- Huda G. El Said,
- Tawfiq Froukh,
- Harinder K. Gill,
- Joseph G. Gleeson,
- Laura Gogoll,
- Elaine S.-Y. Goh,
- Vykuntaraju K. Gowda,
- Tobias B. Haack,
- Mais O. Hashem,
- Stefan Hauser,
- Trevor L. Hoffman,
- Jacob S. Hogue,
- Akimoto Hosokawa,
- Henry Houlden,
- Kevin Huang,
- Stephanie Huynh,
- Ehsan G. Karimiani,
- Silke Kaulfuß,
- G. Christoph Korenke,
- Amy Kritzer,
- Hane Lee,
- James R. Lupski,
- Elysa J. Marco,
- Kirsty McWalter,
- Arakel Minassian,
- Berge A. Minassian,
- David Murphy,
- Juanita Neira-Fresneda,
- Hope Northrup,
- Denis M. Nyaga,
- Barbara Oehl-Jaschkowitz,
- Matthew Osmond,
- Richard Person,
- Davut Pehlivan,
- Cassidy Petree,
- Lynette G. Sadleir,
- Carol Saunders,
- Ludger Schoels,
- Vandana Shashi,
- Rebecca C. Spillmann,
- Varunvenkat M. Srinivasan,
- Paria N. Torbati,
- Tulay Tos,
- Undiagnosed Diseases Network,
- Maha S. Zaki,
- Dihong Zhou,
- Christiane Zweier,
- Jean-François Trempe,
- Thomas M. Durcan,
- Ziv Gan-Or,
- Massimo Avoli,
- Cesar Alves,
- Gaurav K. Varshney,
- Reza Maroofian,
- David A. Rudko,
- Peter S. McPherson
Affiliations
- Emily Banks
- Department of Neurology and Neurosurgery, the Neuro, McGill University
- Vincent Francis
- Department of Neurology and Neurosurgery, the Neuro, McGill University
- Sheng-Jia Lin
- Genes & Human Disease Research Program, Oklahoma Medical Research Foundation
- Fares Kharfallah
- Department of Neurology and Neurosurgery, the Neuro, McGill University
- Vladimir Fonov
- Department of Neurology and Neurosurgery, the Neuro, McGill University
- Maxime Lévesque
- Department of Neurology and Neurosurgery, the Neuro, McGill University
- Chanshuai Han
- Department of Neurology and Neurosurgery, the Neuro, McGill University
- Gopinath Kulasekaran
- Department of Neurology and Neurosurgery, the Neuro, McGill University
- Marius Tuznik
- Department of Neurology and Neurosurgery, the Neuro, McGill University
- Armin Bayati
- Department of Neurology and Neurosurgery, the Neuro, McGill University
- Reem Al-Khater
- Johns Hopkins Aramco Healthcare
- Fowzan S. Alkuraya
- Department of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
- Loukas Argyriou
- Institute of Human Genetics, University Medical Center
- Meisam Babaei
- Department of Pediatrics, North Khorasan University of Medical Sciences
- Melanie Bahlo
- Walter and Eliza Hall Institute for Medical Research
- Behnoosh Bakhshoodeh
- Mashhad University of Medical Sciences
- Eileen Barr
- Department of Human Genetics, Emory University
- Lauren Bartik
- University of Missouri-Kansas City, School of Medicine
- Mahmoud Bassiony
- Faculty of Medicine, Alexandria University
- Miriam Bertrand
- Institute of Medical Genetics and Applied Genomics, University of Tübingen
- Dominique Braun
- Department of Human Genetics, Inselspital, Bern University Hospital, University of Bern
- Rebecca Buchert
- Institute of Medical Genetics and Applied Genomics, University of Tübingen
- Mauro Budetta
- Paediatric and Child Neurology Unit, Cava de’ Tirreni AOU S. Giovanni di Dio e Ruggiero d’Aragona Hospital
- Maxime Cadieux-Dion
- Department of Pathology and Laboratory Medicine, Children’s Mercy Hospital
- Daniel G. Calame
- Department of Pediatrics, Baylor College of Medicine
- Heidi Cope
- Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center
- Donna Cushing
- Laboratory Medicine and Genetics, Trillium Health Partners
- Stephanie Efthymiou
- Department of Neuromuscular Diseases, University College London (UCL) Queen Square Institute of Neurology
- Marwa Abd Elmaksoud
- Neurology Unit, Department of Pediatrics, Faculty of Medicine, University of Alexandria
- Huda G. El Said
- Neurology Unit, Department of Pediatrics, Faculty of Medicine, University of Alexandria
- Tawfiq Froukh
- Department of Biotechnology and Genetic Engineering, Philadelphia University
- Harinder K. Gill
- Provincial Medical Genetics Program at BC Women’s Health Centre
- Joseph G. Gleeson
- Department of Neurosciences, University of California San Diego
- Laura Gogoll
- Department of Human Genetics, Inselspital, Bern University Hospital, University of Bern
- Elaine S.-Y. Goh
- Laboratory Medicine and Genetics, Trillium Health Partners
- Vykuntaraju K. Gowda
- Department of Pediatric Neurology, Indira Gandhi Institute of Child Health
- Tobias B. Haack
- Institute of Medical Genetics and Applied Genomics, University of Tübingen
- Mais O. Hashem
- Department of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
- Stefan Hauser
- German Center of Neurodegenerative Diseases (DZNE)
- Trevor L. Hoffman
- Department of Regional Genetics, Southern California Kaiser Permanente Medical Group
- Jacob S. Hogue
- Madigan Army Medical Center
- Akimoto Hosokawa
- Department of Paediatrics and Child Health, University of Otago
- Henry Houlden
- Department of Neuromuscular Diseases, University College London (UCL) Queen Square Institute of Neurology
- Kevin Huang
- Genes & Human Disease Research Program, Oklahoma Medical Research Foundation
- Stephanie Huynh
- Provincial Medical Genetics Program at BC Women’s Health Centre
- Ehsan G. Karimiani
- Molecular and Clinical Sciences Institute, St. George’s, University of London, Cranmer Terrace
- Silke Kaulfuß
- Institute of Human Genetics, University Medical Center
- G. Christoph Korenke
- Department of Neuropediatrics, University Children’s Hospital, Klinikum Oldenburg
- Amy Kritzer
- Division of Genetics and Genomics, Boston Children’s Hospital
- Hane Lee
- 3billion Inc
- James R. Lupski
- Department of Pediatrics, Baylor College of Medicine
- Elysa J. Marco
- Cortica Healthcare
- Kirsty McWalter
- GeneDx
- Arakel Minassian
- Centre for Applied Genomics, Genetics, and Genome Biology, Hospital for Sick Children
- Berge A. Minassian
- Department of Pediatrics and Neurology, UT Southwestern Medical Center
- David Murphy
- Department of Clinical and Movement Neurosciences, University College London (UCL) Queen Square Institute of Neurology
- Juanita Neira-Fresneda
- Department of Human Genetics, Emory University
- Hope Northrup
- Department of Pediatrics, McGovern Medical School at the University of Texas Health Science Center at Houston (UTHealth) and Children’s Memorial Hermann Hospital
- Denis M. Nyaga
- Department of Paediatrics and Child Health, University of Otago
- Barbara Oehl-Jaschkowitz
- BIOSCIENTIA-MVZ-Labor-Saar-Practice of Human Genetics
- Matthew Osmond
- Children’s Hospital of Eastern Ontario Research Institute, University of Ottawa
- Richard Person
- GeneDx
- Davut Pehlivan
- Department of Pediatrics, Baylor College of Medicine
- Cassidy Petree
- Genes & Human Disease Research Program, Oklahoma Medical Research Foundation
- Lynette G. Sadleir
- Department of Paediatrics and Child Health, University of Otago
- Carol Saunders
- University of Missouri-Kansas City, School of Medicine
- Ludger Schoels
- German Center of Neurodegenerative Diseases (DZNE)
- Vandana Shashi
- Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center
- Rebecca C. Spillmann
- Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center
- Varunvenkat M. Srinivasan
- Department of Pediatric Neurology, Indira Gandhi Institute of Child Health
- Paria N. Torbati
- Department of Medical Genetics, Next Generation Genetic Polyclinic
- Tulay Tos
- Department of Medical Genetics, University of Health Sciences, Zubeyde Hanim Research and Training Hospital of Women’s Health and Diseases
- Undiagnosed Diseases Network
- Maha S. Zaki
- Human Genetics and Genome Research Institute, Clinical Genetics Department, National Research Centre
- Dihong Zhou
- University of Missouri-Kansas City, School of Medicine
- Christiane Zweier
- Department of Human Genetics, Inselspital, Bern University Hospital, University of Bern
- Jean-François Trempe
- Department of Pharmacology & Therapeutics and Centre de Recherche en Biologie Structurale, McGill University
- Thomas M. Durcan
- Department of Neurology and Neurosurgery, the Neuro, McGill University
- Ziv Gan-Or
- Department of Neurology and Neurosurgery, the Neuro, McGill University
- Massimo Avoli
- Department of Neurology and Neurosurgery, the Neuro, McGill University
- Cesar Alves
- Division of Neuroradiology, Boston Children’s Hospital, Harvard Medical School
- Gaurav K. Varshney
- Genes & Human Disease Research Program, Oklahoma Medical Research Foundation
- Reza Maroofian
- Department of Neuromuscular Diseases, University College London (UCL) Queen Square Institute of Neurology
- David A. Rudko
- Department of Neurology and Neurosurgery, the Neuro, McGill University
- Peter S. McPherson
- Department of Neurology and Neurosurgery, the Neuro, McGill University
- DOI
- https://doi.org/10.1038/s41467-024-51310-z
- Journal volume & issue
-
Vol. 15,
no. 1
pp. 1 – 22
Abstract
Abstract Developmental and epileptic encephalopathies (DEEs) feature altered brain development, developmental delay and seizures, with seizures exacerbating developmental delay. Here we identify a cohort with biallelic variants in DENND5A, encoding a membrane trafficking protein, and develop animal models with phenotypes like the human syndrome. We demonstrate that DENND5A interacts with Pals1/MUPP1, components of the Crumbs apical polarity complex required for symmetrical division of neural progenitor cells. Human induced pluripotent stem cells lacking DENND5A fail to undergo symmetric cell division with an inherent propensity to differentiate into neurons. These phenotypes result from misalignment of the mitotic spindle in apical neural progenitors. Cells lacking DENND5A orient away from the proliferative apical domain surrounding the ventricles, biasing daughter cells towards a more fate-committed state, ultimately shortening the period of neurogenesis. This study provides a mechanism for DENND5A-related DEE that may be generalizable to other developmental conditions and provides variant-specific clinical information for physicians and families.
