Loss of symmetric cell division of apical neural progenitors drives DENND5A-related developmental and epileptic encephalopathy

作者：Emily Banks, Vincent Francis, Sheng‐Jia Lin, Fares Kharfallah, Vladimir Fonov, Maxime Lévesque, Chanshuai Han, Gopinath Kulasekaran, Marius Tuznik, Armin Bayati, Reem A. Alkhater, Fowzan S. Alkuraya, Loukas Argyriou, Meisam Babaei, Melanie Bahlo, Behnoosh Bakhshoodeh, Eileen Barr, Lauren Bartik, Mahmoud Bassiony, Miriam Bertrand, Dominique Braun, Rebecca Buchert, M Budetta, Maxime Cadieux‐Dion, Daniel G. Calame, Heidi Cope, Donna Cushing, Stéphanie Efthymiou, Marwa Abd Elmaksoud, Huda G. El Said, Tawfiq Froukh, Harinder Gill, Joseph G. Gleeson, Laura Gogoll, Elaine Goh, Vykuntaraju K. Gowda, Tobias B. Haack, Mais O. Hashem, Stefan Hauser, Trevor L. Hoffman, Jacob S. Hogue, A Hosokawa, Henry Houlden, Kevin Huang, Stephanie Huynh, Ehsan Ghayoor 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 Pehli̇van, Cassidy Petree, Lynette G. Sadleir, Carol Saunders, Ludger Schoels, Vandana Shashi, Rebecca C. Spillmann, Varunvenkat M. Srinivasan, Paria Najarzadeh Torbati, Tülay Tos, Undiagnosed Diseases Network, Heidi Cope, 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 · 发表于：Nature Communications · 年份：2024 · DOI：10.1038/s41467-024-51310-z · 被引用次数：5 · 研究领域：Microtubule and mitosis dynamics、Hippo pathway signaling and YAP/TAZ、RNA Research and Splicing

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. Developmental and epileptic encephalopathies are devastating neurological disorders. Here, the authors establish a cohort of patients with variants in the gene DENND5A and use human stem cells to discover a disease mechanism involving altered cell division.