Loss of symmetric cell division of apical neural progenitors drivesDENND5A-related developmental and epileptic encephalopathy
Authors: 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 , Lupski James R. , Marco Elysa J. , McWalter Kirsty , Minassian Arakel , Minassian Berge A. , Murphy David , Neira-Fresneda Juanita , Northrup Hope , Nyaga Denis , Oehl-Jaschkowitz Barbara , Osmond Matthew , Person Richard , Pehlivan Davut , Petree Cassidy , Sadleir Lynette G. , Saunders Carol , Schoels Ludger , Shashi Vandana , Spillman Rebecca C. , Srinivasan Varunvenkat M. , Torbati Paria N. , Tos Tulay ,   Undiagnosed Diseases Network, Zaki Maha S. , Zhou Dihong , Zweier Christiane , Trempe Jean-François , Durcan Thomas M. , Gan-Or Ziv , Avoli Massimo , Alves Cesar , Varshney Guarav K. , Maroofian Reza , Rudko David A. , McPherson Peter S. 
Published: August 2022

AbstractDevelopmental 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 inDENND5Aand 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 lackingDENND5Afail to undergo symmetric cell division during neural induction and have an inherent propensity to differentiate into neurons, and transgenicDENND5Amice, with phenotypes like the human syndrome, have an increased number of neurons in the adult subventricular zone. Disruption of symmetric cell division following loss ofDENND5Aresults 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 behindDENND5A-related DEE that may be generalizable to other developmental conditions and provides variant-specific clinical information for physicians and families.