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, 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 and Peter S. McPherson ()
Additional contact information
Emily Banks: McGill University
Vincent Francis: McGill University
Sheng-Jia Lin: Oklahoma Medical Research Foundation
Fares Kharfallah: McGill University
Vladimir Fonov: McGill University
Maxime Lévesque: McGill University
Chanshuai Han: McGill University
Gopinath Kulasekaran: McGill University
Marius Tuznik: McGill University
Armin Bayati: McGill University
Reem Al-Khater: Johns Hopkins Aramco Healthcare
Fowzan S. Alkuraya: King Faisal Specialist Hospital and Research Center
Loukas Argyriou: University Medical Center
Meisam Babaei: 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: Emory University
Lauren Bartik: School of Medicine
Mahmoud Bassiony: Alexandria University
Miriam Bertrand: University of Tübingen
Dominique Braun: University of Bern
Rebecca Buchert: University of Tübingen
Mauro Budetta: Cava de’ Tirreni AOU S. Giovanni di Dio e Ruggiero d’Aragona Hospital
Maxime Cadieux-Dion: Children’s Mercy Hospital
Daniel G. Calame: Baylor College of Medicine
Heidi Cope: Duke University Medical Center
Donna Cushing: Trillium Health Partners
Stephanie Efthymiou: University College London (UCL) Queen Square Institute of Neurology
Marwa Abd Elmaksoud: University of Alexandria
Huda G. El Said: University of Alexandria
Tawfiq Froukh: Philadelphia University
Harinder K. Gill: Provincial Medical Genetics Program at BC Women’s Health Centre
Joseph G. Gleeson: University of California San Diego
Laura Gogoll: University of Bern
Elaine S.-Y. Goh: Trillium Health Partners
Vykuntaraju K. Gowda: Indira Gandhi Institute of Child Health
Tobias B. Haack: University of Tübingen
Mais O. Hashem: King Faisal Specialist Hospital and Research Center
Stefan Hauser: German Center of Neurodegenerative Diseases (DZNE)
Trevor L. Hoffman: Southern California Kaiser Permanente Medical Group
Jacob S. Hogue: Madigan Army Medical Center
Akimoto Hosokawa: University of Otago
Henry Houlden: University College London (UCL) Queen Square Institute of Neurology
Kevin Huang: 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: University Medical Center
G. Christoph Korenke: Klinikum Oldenburg
Amy Kritzer: Boston Children’s Hospital
Hane Lee: 3billion Inc
James R. Lupski: Baylor College of Medicine
Elysa J. Marco: Cortica Healthcare
Kirsty McWalter: GeneDx
Arakel Minassian: Hospital for Sick Children
Berge A. Minassian: UT Southwestern Medical Center
David Murphy: University College London (UCL) Queen Square Institute of Neurology
Juanita Neira-Fresneda: Emory University
Hope Northrup: McGovern Medical School at the University of Texas Health Science Center at Houston (UTHealth) and Children’s Memorial Hermann Hospital
Denis M. Nyaga: University of Otago
Barbara Oehl-Jaschkowitz: BIOSCIENTIA-MVZ-Labor-Saar-Practice of Human Genetics
Matthew Osmond: University of Ottawa
Richard Person: GeneDx
Davut Pehlivan: Baylor College of Medicine
Cassidy Petree: Oklahoma Medical Research Foundation
Lynette G. Sadleir: University of Otago
Carol Saunders: School of Medicine
Ludger Schoels: German Center of Neurodegenerative Diseases (DZNE)
Vandana Shashi: Duke University Medical Center
Rebecca C. Spillmann: Duke University Medical Center
Varunvenkat M. Srinivasan: Indira Gandhi Institute of Child Health
Paria N. Torbati: Next Generation Genetic Polyclinic
Tulay Tos: University of Health Sciences, Zubeyde Hanim Research and Training Hospital of Women’s Health and Diseases
Maha S. Zaki: National Research Centre
Dihong Zhou: School of Medicine
Christiane Zweier: University of Bern
Jean-François Trempe: McGill University
Thomas M. Durcan: McGill University
Ziv Gan-Or: McGill University
Massimo Avoli: McGill University
Cesar Alves: Harvard Medical School
Gaurav K. Varshney: Oklahoma Medical Research Foundation
Reza Maroofian: University College London (UCL) Queen Square Institute of Neurology
David A. Rudko: McGill University
Peter S. McPherson: McGill University

Nature Communications, 2024, vol. 15, issue 1, 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.

Date: 2024
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DOI: 10.1038/s41467-024-51310-z

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