Banks, Emily; Francis, Vincent; Lin, Sheng-Jia; Kharfallah, Fares; Fonov, Vladimir; Lévesque, 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; ... (2024). Loss of symmetric cell division of apical neural progenitors drives DENND5A-related developmental and epileptic encephalopathy. Nature communications, 15(7239) Nature Publishing Group 10.1038/s41467-024-51310-z
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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.
Item Type: |
Journal Article (Original Article) |
|---|---|
Division/Institute: |
04 Faculty of Medicine > Department of Gynaecology, Paediatrics and Endocrinology (DFKE) > Clinic of Human Genetics |
UniBE Contributor: |
Braun, Dominique |
Subjects: |
600 Technology > 610 Medicine & health |
ISSN: |
2041-1723 |
Publisher: |
Nature Publishing Group |
Language: |
English |
Submitter: |
Pubmed Import |
Date Deposited: |
23 Aug 2024 10:02 |
Last Modified: |
23 Aug 2024 10:11 |
Publisher DOI: |
10.1038/s41467-024-51310-z |
PubMed ID: |
39174524 |
BORIS DOI: |
10.48350/199939 |
URI: |
https://boris.unibe.ch/id/eprint/199939 |
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