ArticleNature communications2024
Loss of symmetric cell division of apical neural progenitors drives DENND5A-related developmental and epileptic encephalopathy.
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Article in Nature communications, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.
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3citing papers in PubMed
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3 citing papers in PubMed.
- SAPCD2 phosphorylation modulates astral microtubule stability to control spindle orientation.Communications biology · 2026Article
- Shared Disease Mechanisms in Neurodevelopmental Disorders: A Cellular and Molecular Biology Perspective.Brain sciences · 2025Review
- GREGoR: Accelerating Genomics for Rare Diseases.ArXiv · 2024Article
Corrections and comments
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Authors and funding
85 authors.
Emily BanksDepartment of Neurology and Neurosurgery, the Neuro, McGill University, Montréal, QC, Canada.ORCID 0000-0001-9908-1151
Vincent FrancisDepartment of Neurology and Neurosurgery, the Neuro, McGill University, Montréal, QC, Canada.
Sheng-Jia LinGenes & Human Disease Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA.ORCID 0000-0002-7559-6529
Fares KharfallahDepartment of Neurology and Neurosurgery, the Neuro, McGill University, Montréal, QC, Canada.
Vladimir FonovDepartment of Neurology and Neurosurgery, the Neuro, McGill University, Montréal, QC, Canada.ORCID 0000-0003-3402-7749
Maxime LévesqueDepartment of Neurology and Neurosurgery, the Neuro, McGill University, Montréal, QC, Canada.ORCID 0000-0002-1593-7037
Chanshuai HanDepartment of Neurology and Neurosurgery, the Neuro, McGill University, Montréal, QC, Canada.
Gopinath KulasekaranDepartment of Neurology and Neurosurgery, the Neuro, McGill University, Montréal, QC, Canada.
Marius TuznikDepartment of Neurology and Neurosurgery, the Neuro, McGill University, Montréal, QC, Canada.
Armin BayatiDepartment of Neurology and Neurosurgery, the Neuro, McGill University, Montréal, QC, Canada.ORCID 0000-0002-5960-0479
Reem Al-KhaterJohns Hopkins Aramco Healthcare, Dhahran, Saudi Arabia.ORCID 0000-0002-7965-2532
Fowzan S AlkurayaDepartment of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.ORCID 0000-0003-4158-341X
Loukas ArgyriouInstitute of Human Genetics, University Medical Center, Göttingen, Germany.
Meisam BabaeiDepartment of Pediatrics, North Khorasan University of Medical Sciences, Bojnurd, Iran.
Melanie BahloWalter and Eliza Hall Institute for Medical Research, Parkville, VIC, Australia.ORCID 0000-0001-5132-0774
Behnoosh BakhshoodehMashhad University of Medical Sciences, Mashhad, Iran.
Eileen BarrDepartment of Human Genetics, Emory University, Atlanta, GA, USA.ORCID 0000-0002-6330-4680
Lauren BartikUniversity of Missouri-Kansas City, School of Medicine, Kansas City, MO, USA.
Mahmoud BassionyFaculty of Medicine, Alexandria University, Alexandria, Egypt.ORCID 0000-0002-7690-8029
Miriam BertrandInstitute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.
Dominique BraunDepartment of Human Genetics, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.ORCID 0000-0002-4340-4334
Rebecca BuchertInstitute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.ORCID 0000-0001-7576-3326
Mauro BudettaPaediatric and Child Neurology Unit, Cava de' Tirreni AOU S. Giovanni di Dio e Ruggiero d'Aragona Hospital, Salerno, Italy.
Maxime Cadieux-DionDepartment of Pathology and Laboratory Medicine, Children's Mercy Hospital, Kansas City, MO, USA.
Daniel G CalameDepartment of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
Heidi CopeDivision of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, NC, USA.
Donna CushingLaboratory Medicine and Genetics, Trillium Health Partners, Mississauga, ON, Canada.
Stephanie EfthymiouDepartment of Neuromuscular Diseases, University College London (UCL) Queen Square Institute of Neurology, London, UK.ORCID 0000-0003-4900-9877
Marwa Abd ElmaksoudNeurology Unit, Department of Pediatrics, Faculty of Medicine, University of Alexandria, Alexandria, Egypt.ORCID 0000-0001-5827-4459
Huda G El SaidNeurology Unit, Department of Pediatrics, Faculty of Medicine, University of Alexandria, Alexandria, Egypt.
Tawfiq FroukhDepartment of Biotechnology and Genetic Engineering, Philadelphia University, Amman, Jordan.ORCID 0000-0002-2862-0733
Harinder K GillProvincial Medical Genetics Program at BC Women's Health Centre, Vancouver, BC, Canada.
Joseph G GleesonDepartment of Neurosciences, University of California San Diego, La Jolla, CA, USA.ORCID 0000-0002-0889-9220
Laura GogollDepartment of Human Genetics, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
Elaine S-Y GohLaboratory Medicine and Genetics, Trillium Health Partners, Mississauga, ON, Canada.ORCID 0000-0002-2477-1665
Vykuntaraju K GowdaDepartment of Pediatric Neurology, Indira Gandhi Institute of Child Health, Bangalore, India.ORCID 0000-0001-7244-0492
Tobias B HaackInstitute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.ORCID 0000-0001-6033-4836
Mais O HashemDepartment of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
Stefan HauserGerman Center of Neurodegenerative Diseases (DZNE), Tübingen, Germany.ORCID 0000-0002-1022-7482
Trevor L HoffmanDepartment of Regional Genetics, Southern California Kaiser Permanente Medical Group, Anaheim, CA, USA.
Jacob S HogueMadigan Army Medical Center, Tacoma, WA, USA.
Akimoto HosokawaDepartment of Paediatrics and Child Health, University of Otago, Wellington, New Zealand.
Henry HouldenDepartment of Neuromuscular Diseases, University College London (UCL) Queen Square Institute of Neurology, London, UK.ORCID 0000-0002-2866-7777
Kevin HuangGenes & Human Disease Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA.ORCID 0000-0002-2512-7812
Stephanie HuynhProvincial Medical Genetics Program at BC Women's Health Centre, Vancouver, BC, Canada.
Ehsan G KarimianiMolecular and Clinical Sciences Institute, St. George's, University of London, Cranmer Terrace, London, UK.
Silke KaulfußInstitute of Human Genetics, University Medical Center, Göttingen, Germany.
G Christoph KorenkeDepartment of Neuropediatrics, University Children's Hospital, Klinikum Oldenburg, Oldenburg, Germany.
Amy KritzerDivision of Genetics and Genomics, Boston Children's Hospital, Boston, MA, USA.
Hane Lee3billion Inc, Seoul, South Korea.ORCID 0000-0002-4736-0412
James R LupskiDepartment of Pediatrics, Baylor College of Medicine, Houston, TX, USA.ORCID 0000-0001-9907-9246
Elysa J MarcoCortica Healthcare, San Rafael, CA, USA.
Kirsty McWalterGeneDx, Gaithersburg, MD, USA.ORCID 0000-0002-1654-9036
Arakel MinassianCentre for Applied Genomics, Genetics, and Genome Biology, Hospital for Sick Children, Toronto, ON, Canada.
Berge A MinassianDepartment of Pediatrics and Neurology, UT Southwestern Medical Center, Dallas, TX, USA.
David MurphyDepartment of Clinical and Movement Neurosciences, University College London (UCL) Queen Square Institute of Neurology, London, UK.
Juanita Neira-FresnedaDepartment of Human Genetics, Emory University, Atlanta, GA, USA.
Hope NorthrupDepartment of Pediatrics, McGovern Medical School at the University of Texas Health Science Center at Houston (UTHealth) and Children's Memorial Hermann Hospital, Houston, TX, USA.ORCID 0000-0002-2892-0840
Denis M NyagaDepartment of Paediatrics and Child Health, University of Otago, Wellington, New Zealand.ORCID 0000-0001-6240-4017
Barbara Oehl-JaschkowitzBIOSCIENTIA-MVZ-Labor-Saar-Practice of Human Genetics, Homburg (Saar), Germany.
Matthew OsmondChildren's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Canada.
Richard PersonGeneDx, Gaithersburg, MD, USA.
Davut PehlivanDepartment of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
Cassidy PetreeGenes & Human Disease Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA.
Lynette G SadleirDepartment of Paediatrics and Child Health, University of Otago, Wellington, New Zealand.
Carol SaundersUniversity of Missouri-Kansas City, School of Medicine, Kansas City, MO, USA.ORCID 0000-0002-7407-7735
Ludger SchoelsGerman Center of Neurodegenerative Diseases (DZNE), Tübingen, Germany.
Vandana ShashiDivision of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, NC, USA.
Rebecca C SpillmannDivision of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, NC, USA.
Varunvenkat M SrinivasanDepartment of Pediatric Neurology, Indira Gandhi Institute of Child Health, Bangalore, India.
Paria N TorbatiDepartment of Medical Genetics, Next Generation Genetic Polyclinic, Mashhad, Iran.
Tulay TosDepartment of Medical Genetics, University of Health Sciences, Zubeyde Hanim Research and Training Hospital of Women's Health and Diseases, Ankara, Turkey.
Undiagnosed Diseases Network
Maha S ZakiHuman Genetics and Genome Research Institute, Clinical Genetics Department, National Research Centre, Cairo, Egypt.ORCID 0000-0001-7840-0002
Dihong ZhouUniversity of Missouri-Kansas City, School of Medicine, Kansas City, MO, USA.
Christiane ZweierDepartment of Human Genetics, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.ORCID 0000-0001-8002-2020
Jean-François TrempeDepartment of Pharmacology & Therapeutics and Centre de Recherche en Biologie Structurale, McGill University, Montréal, QC, Canada.ORCID 0000-0002-6543-3371
Thomas M DurcanDepartment of Neurology and Neurosurgery, the Neuro, McGill University, Montréal, QC, Canada.
Ziv Gan-OrDepartment of Neurology and Neurosurgery, the Neuro, McGill University, Montréal, QC, Canada.ORCID 0000-0003-0332-234X
Massimo AvoliDepartment of Neurology and Neurosurgery, the Neuro, McGill University, Montréal, QC, Canada.
Cesar AlvesDivision of Neuroradiology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
Gaurav K VarshneyGenes & Human Disease Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA.ORCID 0000-0002-0429-1904
Reza MaroofianDepartment of Neuromuscular Diseases, University College London (UCL) Queen Square Institute of Neurology, London, UK.ORCID 0000-0001-6763-1542
David A RudkoDepartment of Neurology and Neurosurgery, the Neuro, McGill University, Montréal, QC, Canada.
Peter S McPhersonDepartment of Neurology and Neurosurgery, the Neuro, McGill University, Montréal, QC, Canada. peter.mcpherson@mcgill.ca.ORCID 0000-0001-7806-5662
Funding
Baylor-Johns Hopkins Center for Mendelian GeneticsUM1HG006542 · NHGRI · JOHNS HOPKINS UNIVERSITY · PI VALLE, DAVID · 2016 to 2020
$14.5MFrequency of variants of unknown significance by ancestry groups in the All of Us Research Program cohortU01HG011758 · NHGRI · BAYLOR COLLEGE OF MEDICINE · PI RICHARD A GIBBS, JAMES R. LUPSKI · 2021 to 2026
$13.8MAn integrated and diverse genomic medicine program for undiagnosed diseasesU01HG007672 · NHGRI · DUKE UNIVERSITY · PI SHASHI, VANDANA · 2014 to 2022
$13.4MSTRUCTURAL VARIATION IN NEUROLOGICAL DISEASER35NS105078 · NINDS · BAYLOR COLLEGE OF MEDICINE · PI LUPSKI, JAMES R. · 2018 to 2025
$6.0MClinical Genome Wide Sequencing Core for the Undiagnosed Disease NetworkU01HG007943 · NHGRI · MEDICAL COLLEGE OF WISCONSIN · PI WORTHEY, ELIZABETH A · 2014 to 2017
$4.1MAn integrated and diverse genomic medicine program for undiagnosed diseasesU01NS134350 · NINDS · DUKE UNIVERSITY · PI VANDANA SHASHI · 2023 to 2026
$3.6MDeutscher Akademischer Austauschdienst (German Academic Exchange Service) 57166498NHGRI NIH HHS U01 HG007672NHGRI NIH HHS U01 HG007943NHGRI NIH HHS U01 HG011758NHGRI NIH HHS UM1 HG006542NINDS NIH HHS R35 NS105078NINDS NIH HHS U01 NS134350Ontario Genomics Institute (OGI) OGI-147U.S. Department of Health & Human Services | NIH | National Human Genome Research Institute (NHGRI) HG011758U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS) NS105078U.S. Department of Health & Human Services | NIH | Office of Strategic Coordination (OSC) U01HG007943
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.
Indexed as
Cell DivisionInduced Pluripotent Stem CellsNeural Stem CellsAnimalsCell PolarityDisease Models, AnimalFemaleGuanine Nucleotide Exchange FactorsHumansMaleMembrane ProteinsMiceNeurogenesisDENND5A protein, humanGuanine Nucleotide Exchange FactorsMembrane Proteins
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