De novo missense variants in BAIAP2 are associated with developmental and epileptic encephalopathies
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Le résumé fourni par la source
OBJECTIVE: Brain-specific angiogenesis inhibitor 1-associated protein 2 (BAIAP2) plays a crucial role in dendritic spine morphogenesis and excitatory synapse formation. We establish de novo variants in BAIAP2 as a novel genetic cause for developmental and epileptic encephalopathies (DEEs). METHODS: Using whole exome/genome sequencing, we identified de novo missense variants in BAIAP2 in six patients with DEEs. Molecular docking was utilized to predict the effect of these variants on the protein structures. Functional assays were conducted by overexpressing wild-type and mutant BAIAP2 in cultured cells, primary hippocampal neurons, and zebrafish. RESULTS: All six patients exhibited severe infantile or early childhood onset epilepsy, with refractory seizures in four individuals. Language and motor development delays were prevalent, with varying degrees of intellectual disability observed. The missense variants were clustered within the multiple phosphorylation site region that is critical for the autoinhibited conformation of BAIAP2 through 14-3-3 binding. In silico modeling and HeLa cell spreading assays demonstrated that BAIAP2 mutants potentially disrupted its autoinhibited state and induced hybrid filopodia-lamellipodia protrusions in cells, phenocopying the effects of Rac1/Cdc42 overexpression. Electrophysiological recordings revealed that neurons expressing BAIAP2 variants exhibited increased excitability, due to enhanced excitatory synaptogenesis. Additionally, transgenic overexpression of mutant BAIAP2 mRNA in zebrafish embryos led to developmental defects, abnormal neurite growth, and enhanced sensitivity to pentylenetetrazole-induced locomotor hyperactivity. SIGNIFICANCE: De novo variants in BAIAP2 represent a novel cause of DEEs. The functional consequences of these variants suggest that the gain of function of BAIAP2 can affect filopodia-lamellipodia formation, dendritic spine development, and synaptic transmission.
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Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé, mais le titre doit être comparé manuellement.
- Titre Crossref
- De novo missense variants in <scp> <i>BAIAP2</i> </scp> are associated with developmental and epileptic encephalopathies
- Date Crossref
- 24/10/2025
- Éditeur
- Wiley
- Type
- journal-article
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Où se fait cette recherche
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Second Affiliated Hospital of Nanjing Medical University State Key Laboratory of Reproductive Medicine and Offspring Health pays non établi dans la noticeÉtablissement de santé
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Nanjing Medical University Department of Neurology pays non établi dans la noticeUniversité ou école supérieure
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Children's Hospital of Chongqing Medical University Department of Neurology pays non établi dans la noticeÉtablissement de santé
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Chongqing Medical University pays non établi dans la noticeUniversité ou école supérieure
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University of Zurich Institute of Medical Genetics pays non établi dans la noticeUniversité ou école supérieure
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Institutul National Victor Babes pays non établi dans la noticeStructure de recherche
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University Children's Hospital Zurich pays non établi dans la noticeÉtablissement de santé
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Salzburger Landeskliniken pays non établi dans la noticeÉtablissement de santé
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University of London St George's pays non établi dans la noticeUniversité ou école supérieure
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Leipzig University pays non établi dans la noticeUniversité ou école supérieure
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Düsseldorf University Hospital pays non établi dans la noticeÉtablissement de santé
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Heinrich Heine University Düsseldorf pays non établi dans la noticeUniversité ou école supérieure
State Key Laboratory of Reproductive Medicine and Offspring Health — Second Affiliated Hospital of Nanjing Medical University, Department of Neurology — Nanjing Medical University et Department of Neurology — Children's Hospital of Chongqing Medical University, avec 9 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.