Dataset Information

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

ABSTRACT: Developmental 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 in DENND5A and 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 lacking DENND5A fail to undergo symmetric cell division during neural induction and have an inherent propensity to differentiate into neurons, and transgenic DENND5A mice, with phenotypes like the human syndrome, have an increased number of neurons in the adult subventricular zone. Disruption of symmetric cell division following loss of DENND5A results 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 behind DENND5A-related DEE that may be generalizable to other developmental conditions and provides variant-specific clinical information for physicians and families.

SUBMITTER: Banks E

PROVIDER: S-EPMC10863025 | biostudies-literature | 2024 Jan

REPOSITORIES: biostudies-literature

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

Banks Emily E Francis Vincent V Lin Sheng-Jia SJ Kharfallah Fares F Fonov Vladimir V Levesque Maxime M Han Chanshuai C Kulasekaran Gopinath G Tuznik Marius M Bayati Armin A Al-Khater Reem R Alkuraya Fowzan S FS Argyriou Loukas L Babaei Meisam M Bahlo Melanie M Bakhshoodeh Behnoosh B Barr Eileen E Bartik Lauren L Bassiony Mahmoud M Bertrand Miriam M Braun Dominique D Buchert Rebecca R Budetta Mauro M Cadieux-Dion Maxime M Calame Daniel D Cope Heidi H Cushing Donna D Efthymiou Stephanie S Elmaksoud Marwa A MA El Said Huda G HG Froukh Tawfiq T Gill Harinder K HK Gleeson Joseph G JG Gogoll Laura L Goh Elaine S-Y ES Gowda Vykuntaraju K VK Haack Tobias B TB Hashem Mais O MO Hauser Stefan S Hoffman Trevor L TL Hogue Jacob S JS Hosokawa Akimoto A Houlden Henry H Huang Kevin K Huynh Stephanie S Karimiani Ehsan G EG Kaulfuß Silke S Korenke G Christoph GC Kritzer Amy A Lee Hane H Lupski James R JR Marco Elysa J EJ McWalter Kirsty K Minassian Arakel A Minassian Berge A BA Murphy David D Neira-Fresneda Juanita J Northrup Hope H Nyaga Denis D Oehl-Jaschkowitz Barbara B Osmond Matthew M Person Richard R Pehlivan Davut D Petree Cassidy C Sadleir Lynette G LG Saunders Carol C Schoels Ludger L Shashi Vandana V Spillman Rebecca C RC Srinivasan Varunvenkat M VM Torbati Paria N PN Tos Tulay T Zaki Maha S MS Zhou Dihong D Zweier Christiane C Trempe Jean-François JF Durcan Thomas M TM Gan-Or Ziv Z Avoli Massimo M Alves Cesar C Varshney Guarav K GK Maroofian Reza R Rudko David A DA McPherson Peter S PS

medRxiv : the preprint server for health sciences 20240131

Developmental 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 in <i>DENND5A</i> and determine that variant type is correlated with disease severity. We demonst ...[more]

PMID: 38352438

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Project description:BackgroundDevelopmental and epileptic encephalopathies (DEEs) signify a group of heterogeneous neurodevelopmental disorder associated with early-onset seizures accompanied by developmental delay, hypotonia, mild to severe intellectual disability, and developmental regression. Variants in the DNM1 gene have been associated with autosomal dominant DEE type 31A and autosomal recessive DEE type 31B.MethodsIn the current study, a consanguineous Pakistani family consisting of a proband (IV-2) was clinically evaluated and genetically analyzed manifesting in severe neurodevelopmental phenotypes. WES followed by Sanger sequencing was performed to identify the disease-causing variant. Furthermore, 3D protein modeling and dynamic simulation of wild-type and mutant proteins along with reverse transcriptase (RT)-based mRNA expression were checked using standard methods.ResultsData analysis of WES revealed a novel homozygous non-sense variant (c.1402G>T; p. Glu468*) in exon 11 of the DNM1 gene that was predicted as pathogenic class I. Variants in the DNM1 gene have been associated with DEE types 31A and B. Different bioinformatics prediction tools and American College of Medical Genetics guidelines were used to verify the identified variant. Sanger sequencing was used to validate the disease-causing variant. Our approach validated the pathogenesis of the variant as a cause of heterogeneous neurodevelopmental disorders. In addition, 3D protein modeling showed that the mutant protein would lose most of the amino acids and might not perform the proper function if the surveillance non-sense-mediated decay mechanism was skipped. Molecular dynamics analysis showed varied trajectories of wild-type and mutant DNM1 proteins in terms of root mean square deviation, root mean square fluctuation and radius of gyration. Similarly, RT-qPCR revealed a substantial reduction of the DNM1 gene in the index patient.ConclusionOur finding further confirms the association of homozygous, loss-of-function variants in DNM1 associated with DEE type 31B. The study expands the genotypic and phenotypic spectrum of pathogenic DNM1 variants related to DNM1-associated pathogenesis.

Dataset Information

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

Publications

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

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