Asadollahi, Reza ORCID: https://orcid.org/0000-0002-1497-0564, Ahmad, Aisha, Boonsawat, Paranchai, Hinzen, Jasmine Shahanoor, Lohse, Mareike, Bouazza-Arostegui, Boris, Sun, Siqi, Utesch, Tillmann, Sommer, Jonas D, Ilic, Dragana, Padmanarayana, Murugesh, Fischermanns, Kati, Ranjan, Mrinalini, Boll, Moritz, Ka, Chandran, Piton, Amélie, Mattioli, Francesca, Isidor, Bertrand, Õunap, Katrin, Reinson, Karit, Wojcik, Monica H., Marshall, Christian R., Mercimek-Andrews, Saadet, Matsumoto, Naomichi, Miyake, Noriko, de Oliveira Stephan, Bruno, Honjo, Rachel Sayuri, Bertola, Debora R., Kim, Chong Ae, Yusupov, Roman, Mefford, Heather C., Christodoulou, John, Lee, Joy, Heath, Oliver, Brown, Natasha J. and et., al. (2025) Pathogenic UNC13A variants cause a neurodevelopmental syndrome by impairing synaptic function. Nature Genetics. ISSN 1061-4036 (Print), 1546-1718 (Online) (doi:10.1038/s41588-025-02361-5)

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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.

Noriko Miyake, Bruno de Oliveira Stephan, Rachel Sayuri Honjo, Debora R. Bertola, Chong Ae Kim, Roman Yusupov, Heather C. Mefford, John Christodoulou, Joy Lee, Oliver Heath, Natasha J. Brown,

Item Type:	Article
Additional Information:	Open access funding provided by Leibniz-Forschungsinstitut für Molekulare Pharmakologie im Forschungsverbund Berlin e.V. (FMP). - MP
Uncontrolled Keywords:	Genetics, neurodevelopmental syndrome, UNC13A
Subjects:	Q Science > Q Science (General) R Medicine > R Medicine (General)
Faculty / School / Research Centre / Research Group:	Faculty of Engineering & Science Faculty of Engineering & Science > School of Science (SCI)
Last Modified:	05 Nov 2025 11:19
URI:	https://gala.gre.ac.uk/id/eprint/51383

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