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

Banks, Emily; Hogue, Jacob S; Alves, Cesar; Sadleir, Lynette G; Kulasekaran, Gopinath; Braun, Dominique; Argyriou, Loukas; Bassiony, Mahmoud; Hauser, Stefan; Murphy, David; Minassian, Arakel; Petree, Cassidy; Northrup, Hope; Gan-Or, Ziv; Francis, Vincent; Tuznik, Marius; Houlden, Henry; Pehlivan, Davut; Durcan, Thomas M; Hashem, Mais O; El Said, Huda G; Zhou, Dihong; Bahlo, Melanie; Nyaga, Denis M; Schoels, Ludger; Elmaksoud, Marwa Abd; Lévesque, Maxime; Neira-Fresneda, Juanita; Han, Chanshuai; Minassian, Berge A; Oehl-Jaschkowitz, Barbara; Kritzer, Amy; Kharfallah, Fares; Haack, Tobias B; Alkuraya, Fowzan S; Zaki, Maha S; Varshney, Gaurav K; McWalter, Kirsty; Lin, Sheng-Jia; Bayati, Armin; Efthymiou, Stephanie; Kaulfuß, Silke; Bartik, Lauren; Network, Undiagnosed Diseases; Korenke, G Christoph; Tos, Tulay; Cushing, Donna; Barr, Eileen; Karimiani, Ehsan G; Gogoll, Laura; Zweier, Christiane; Person, Richard; McPherson, Peter S; Bertrand, Miriam; Osmond, Matthew; Srinivasan, Varunvenkat M; Gill, Harinder K; Trempe, Jean-François; Saunders, Carol; Froukh, Tawfiq; Rudko, David A; Calame, Daniel G; Cadieux-Dion, Maxime; Maroofian, Reza; Gleeson, Joseph G; Cope, Heidi; Budetta, Mauro; Hoffman, Trevor L; Huang, Kevin; Bakhshoodeh, Behnoosh; Spillmann, Rebecca C; Buchert, Rebecca; Huynh, Stephanie; Torbati, Paria N; Shashi, Vandana; Marco, Elysa J; Lupski, James R; Avoli, Massimo; Goh, Elaine S-Y; Lee, Hane; Babaei, Meisam; Fonov, Vladimir; Hosokawa, Akimoto; Gowda, Vykuntaraju K; Al-Khater, Reem

doi:10.1038/s41467-024-51310-z

TY  - JOUR
AU  - Banks, Emily
AU  - Francis, Vincent
AU  - Lin, Sheng-Jia
AU  - Kharfallah, Fares
AU  - Fonov, Vladimir
AU  - Lévesque, Maxime
AU  - Han, Chanshuai
AU  - Kulasekaran, Gopinath
AU  - Tuznik, Marius
AU  - Bayati, Armin
AU  - Al-Khater, Reem
AU  - Alkuraya, Fowzan S
AU  - Argyriou, Loukas
AU  - Babaei, Meisam
AU  - Bahlo, Melanie
AU  - Bakhshoodeh, Behnoosh
AU  - Barr, Eileen
AU  - Bartik, Lauren
AU  - Bassiony, Mahmoud
AU  - Bertrand, Miriam
AU  - Braun, Dominique
AU  - Buchert, Rebecca
AU  - Budetta, Mauro
AU  - Cadieux-Dion, Maxime
AU  - Calame, Daniel G
AU  - Cope, Heidi
AU  - Cushing, Donna
AU  - Efthymiou, Stephanie
AU  - Elmaksoud, Marwa Abd
AU  - El Said, Huda G
AU  - Froukh, Tawfiq
AU  - Gill, Harinder K
AU  - Gleeson, Joseph G
AU  - Gogoll, Laura
AU  - Goh, Elaine S-Y
AU  - Gowda, Vykuntaraju K
AU  - Haack, Tobias B
AU  - Hashem, Mais O
AU  - Hauser, Stefan
AU  - Hoffman, Trevor L
AU  - Hogue, Jacob S
AU  - Hosokawa, Akimoto
AU  - Houlden, Henry
AU  - Huang, Kevin
AU  - Huynh, Stephanie
AU  - Karimiani, Ehsan G
AU  - Kaulfuß, Silke
AU  - Korenke, G Christoph
AU  - Kritzer, Amy
AU  - Lee, Hane
AU  - Lupski, James R
AU  - Marco, Elysa J
AU  - McWalter, Kirsty
AU  - Minassian, Arakel
AU  - Minassian, Berge A
AU  - Murphy, David
AU  - Neira-Fresneda, Juanita
AU  - Northrup, Hope
AU  - Nyaga, Denis M
AU  - Oehl-Jaschkowitz, Barbara
AU  - Osmond, Matthew
AU  - Person, Richard
AU  - Pehlivan, Davut
AU  - Petree, Cassidy
AU  - Sadleir, Lynette G
AU  - Saunders, Carol
AU  - Schoels, Ludger
AU  - Shashi, Vandana
AU  - Spillmann, Rebecca C
AU  - Srinivasan, Varunvenkat M
AU  - Torbati, Paria N
AU  - Tos, Tulay
AU  - Zaki, Maha S
AU  - Zhou, Dihong
AU  - Zweier, Christiane
AU  - Trempe, Jean-François
AU  - Durcan, Thomas M
AU  - Gan-Or, Ziv
AU  - Avoli, Massimo
AU  - Alves, Cesar
AU  - Varshney, Gaurav K
AU  - Maroofian, Reza
AU  - Rudko, David A
AU  - McPherson, Peter S
TI  - Loss of symmetric cell division of apical neural progenitors drives DENND5A-related developmental and epileptic encephalopathy.
JO  - Nature Communications
VL  - 15
IS  - 1
SN  - 2041-1723
CY  - [London]
PB  - Nature Publishing Group UK
M1  - DZNE-2024-01073
SP  - 7239
PY  - 2024
AB  - 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.
KW  - Neural Stem Cells: metabolism
KW  - Neural Stem Cells: cytology
KW  - Humans
KW  - Animals
KW  - Cell Division
KW  - Induced Pluripotent Stem Cells: metabolism
KW  - Induced Pluripotent Stem Cells: cytology
KW  - Mice
KW  - Neurogenesis: genetics
KW  - Male
KW  - Female
KW  - Membrane Proteins: metabolism
KW  - Membrane Proteins: genetics
KW  - Guanine Nucleotide Exchange Factors: metabolism
KW  - Guanine Nucleotide Exchange Factors: genetics
KW  - Disease Models, Animal
KW  - Cell Polarity
KW  - Membrane Proteins (NLM Chemicals)
KW  - Guanine Nucleotide Exchange Factors (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:39174524
C2  - pmc:PMC11341845
DO  - DOI:10.1038/s41467-024-51310-z
UR  - https://pub.dzne.de/record/271721
ER  -

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