Pathogenic UNC13A variants cause a neurodevelopmental syndrome by impairing synaptic function.
Publication/Presentation Date
10-22-2025
Abstract
The UNC13A gene encodes a presynaptic protein that is crucial for setting the strength and dynamics of information transfer between neurons. Here we describe a neurodevelopmental syndrome caused by germline coding or splice-site variants in UNC13A. The syndrome presents with variable degrees of developmental delay and intellectual disability, seizures of different types, tremor and dyskinetic movements and, in some cases, death in early childhood. Using assays with expression of UNC13A variants in mouse hippocampal neurons and in Caenorhabditis elegans, we identify three mechanisms of pathogenicity, including reduction in synaptic strength caused by reduced UNC13A protein expression, increased neurotransmission caused by UNC13A gain-of-function and impaired regulation of neurotransmission by second messenger signalling. Based on a strong genotype-phenotype-functional correlation, we classify three UNC13A syndrome subtypes (types A-C). We conclude that the precise regulation of neurotransmitter release by UNC13A is critical for human nervous system function.
ISSN
1546-1718
Published In/Presented At
Asadollahi, R., Ahmad, A., Boonsawat, P., Shahanoor Hinzen, J., Lohse, M., Bouazza-Arostegui, B., Sun, S., Utesch, T., Sommer, J. D., Ilic, D., Padmanarayana, M., Fischermanns, K., Ranjan, M., Boll, M., Ka, C., Piton, A., Mattioli, F., Isidor, B., Õunap, K., Reinson, K., … Lipstein, N. (2025). Pathogenic UNC13A variants cause a neurodevelopmental syndrome by impairing synaptic function. Nature genetics, 10.1038/s41588-025-02361-5. Advance online publication. https://doi.org/10.1038/s41588-025-02361-5
Disciplines
Medicine and Health Sciences | Pediatrics
PubMedID
41125872
Department(s)
Department of Pediatrics
Document Type
Article