Asadollahi, Reza;
Ahmad, Aisha;
Boonsawat, Paranchai;
Shahanoor Hinzen, Jasmine;
Lohse, Mareike;
Bouazza-Arostegui, Boris;
Sun, Siqi;
... Lipstein, Noa; + view all
(2025)
Pathogenic UNC13A variants cause a neurodevelopmental syndrome by impairing synaptic function.
Nature Genetics
10.1038/s41588-025-02361-5.
(In press).
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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.
| Type: | Article |
|---|---|
| Title: | Pathogenic UNC13A variants cause a neurodevelopmental syndrome by impairing synaptic function |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1038/s41588-025-02361-5 |
| Publisher version: | https://doi.org/10.1038/s41588-025-02361-5 |
| Language: | English |
| Additional information: | This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Department of Neuromuscular Diseases |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10216199 |
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