Pathogenic UNC13A variants cause a neurodevelopmental syndrome by impairing synaptic function

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.

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Journal
Nature Genetics
Published
2025-10-22
DOI
https://doi.org/10.1038/s41588-025-02361-5
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1
Primary Topic
Genetics, Aging, and Longevity in Model Organisms
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article
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article

Pathogenic UNC13A variants cause a neurodevelopmental syndrome by impairing synaptic function

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1 citations
Nature Genetics
Genetics, Aging, and Longevity in Model Organisms
0.95
article

Pathogenic UNC13A variants cause a neurodevelopmental syndrome by impairing synaptic function

Jeffrey Sommer, Monica H. Wojcik, Morteza Heidari, Andrea A. Kühn, Jeremy S. Dittman, Gérald Le Gac, Caroline Maxton, Aditi I Dagli, Linda Zuurbier, Christoph Hübner, Emanuele Agolini, Konrad Platzer, Bethany Grysko, Holly Dubbs, Boris Keren, Kévin Uguen, Sarah McKeown Ruggiero, Malou Heijligers, Karit Reinson, Joy Yaplito‐Lee, Carlos E. Prada, Camerun Washington, Sylvia Redon, Caleb Bupp, Bruno de Oliveira Stephan, Siqi Sun, Antônio Edvan Camelo-Filho, Dragana Ilic, Katherine L. Helbig, Amy Margolin, Andrea Seeley, Mette Boll, Katrin Õunap, Ping Yee Billie Au, Eric M. Green, Daniel C. Koboldt, Ingrid M. Wentzensen, Gabriela E. Oprea, Jérémie Lefranc, Stéphanie Efthymiou, Henry Oppermann, Alyssa Rosen, Mrinalini Ranjan, Heather C. Mefford, Caroline Nava, Reza Asadollahi, Amélie Piton, Stephanie A. Coury, Natasha J. Brown, Robert Śmigiel, Noa Lipstein, Anita M. Rauch, Francesca Mattioli, Oliver Heath, Ronald D. Cohn, Dwight D. Koeberl, John Christodoulou, Tillmann Utesch, Shimriet Zeidler, Marta Owczarek‐Lipska, Raymond J. Louie, Bruria Ben Zeev, Anna Szuto, Sven Thoms, Christian R. Marshall, Paranchai Boonsawat, Laura G. Hendon, Balasubramaniem Ashokkumar, Axel Neu, John Neidhardt, Felix Bernhard, Mišo Mitkovski, Servi J.C. Stevens, Farrah Rajabi, Fernando Kok, Martin Delatycki, Débora Romeo Bertola, Jasmin Lisfeld, Rachel Sayuri Honjo, Olaf Jahn, Zornitza Stark, M A Lohse, Heinrich Sticht, Hunter R. Underhill, Holger Taschenberger, Lydie Bürglen, Diane Doummar, Sami J. Barmada, Nicole J. Lake, Christian Rosenmund, Boris Bouazza‐Arostegui, Kristine Bachman, Fatemeh Eghbal, Sandra Coppens, Cyril Mignot, Perumal Varalakshmi, Shila Mekhoubad, Felix Boschann, Alessandra Terracciano, Lance H. Rodan, Rami Abou Jamra, Jeffrey R. Tenney, Mark P. Fitzgerald, André Luiz Santos Pessoa, Abolfazl Rad, Ryan D. Morrie, Dennis Kraemer, Fabíola Paoli Monteiro, Nicolas Deconinck, Simone Race, Henry Houlden, Han Sun, Skadi Beblo, Reza Maroofian, Fowzan Sami Alkuraya, Perrine Charles, Naomichi Matsumoto, Bénédicte Héron, Nils Brose, Jennifer Morrison, Aaron D. Gitler, Murugesh Padmanarayana, Saadet Mercimek‐Andrews, Chong Ae Kim, Kristin G. Monaghan, Aisha Ahmad, Ehsan Ghayoor Karimiani, Noriko Miyake, Philippe M. Campeau, Ingo Helbig, Yanmin Chen, Saskia M. Maas, Bertrand Isidor, Michael J. Bamshad, Anna Lehman, Kandamurugu Manickam, Georg Christoph Korenke, Naomi L. Baker, Kacie Riley, Chandran Ka, Roman Yusupov, Parul Jayakar, Jeong Seop Rhee, Piscopo Carmelo, Annick Rein‐Rothschild, Jasmine Shahanoor Hinzen, Kati Fischermanns, Chris C. de Kruiff
article en
1 citations

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.

Nature GeneticsVol. 57(11)
Broad Institute (US), Northwestern University (US), Brigham and Women's Hospital (US), Cincinnati Children's Hospital Medical Center (US), Boston Children's Hospital (US), Geisinger Medical Center (US), Carl von Ossietzky Universität Oldenburg (DE), St. Jude Children's Research Hospital (US), Nationwide Children's Hospital (US), Université Libre de Bruxelles (BE), Royal Children's Hospital (AU), Madurai Kamaraj University (IN), Children's Hospital of Philadelphia (US), Alfaisal University (SA), University of British Columbia (CA), University of Alberta (CA), Inserm (FR), Universität Hamburg (DE), Philipps University of Marburg (DE), Université de Bretagne Occidentale (FR), Tel Aviv University (IL), The University of Melbourne (AU), University of Calgary (CA), Duke University (US), Universidade de São Paulo (BR), École nationale d'ingénieurs de Brest (FR), Friedrich-Alexander-Universität Erlangen-Nürnberg (DE), Bielefeld University (DE), University of Washington (US), University of Zurich (CH), Hochschule Bielefeld (DE), Cornell University (US), University of Utah (US), Medical University of Warsaw (PL), University of Michigan (US), Sheba Medical Center (IL), Arnold Palmer Hospital for Children (US), King Faisal Specialist Hospital & Research Centre (SA), Hospital for Sick Children (CA), Erasmus MC (NL), Alberta Children's Hospital (CA), Tartu University Hospital (EE), Centre Hospitalier Universitaire Sainte-Justine (CA), Jackson Memorial Hospital (US), University of Mississippi Medical Center (US), Centre Hospitalier Universitaire de Nantes (FR), Yale University (US), Maastricht University (NL), Humboldt-Universität zu Berlin (DE), Sorbonne Université (FR), Hôpital Armand-Trousseau (FR), Ospedale Antonio Cardarelli (IT), National Center for Global Health and Medicine (JP), Emma Kinderziekenhuis (NL), Assistance Publique – Hôpitaux de Paris (FR), Leibniz-Forschungsinstitut für Molekulare Pharmakologie (DE), Queen Fabiola Children's University Hospital (BE), University Medical Center Hamburg-Eppendorf (DE), Kinderkrebs-Zentrum Hamburg (DE), Klinikum Oldenburg (DE), Victorian Clinical Genetics Services (AU), Children's Medical Center (IR), Pitié-Salpêtrière Hospital (FR), Bambino Gesù Children's Hospital (IT), Lurie Children's Hospital (US), University Hospital Leipzig (DE), Bangalore Diabetes Centre (IN), University Children's Hospital Zurich (CH), Helen DeVos Children's Hospital (US), Centre Hospitalier Régional Universitaire de Brest (FR), Max Planck Institute of Experimental Medicine (DE), Mendelics (BR), Berlin Institute of Health at Charité - Universitätsmedizin Berlin (DE), Hospital Infantil Albert Sabin (BR), Edmond and Lily Safra Children's Hospital (IL), Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (BR), Miami Children's Hospital (US), Greenwood Genetic Center (US), Murdoch Children's Research Institute (AU), Broad Center (US), National Hospital for Neurology and Neurosurgery (GB), BC Children's Hospital (CA), Génétique Médicale & Génomique Fonctionelle (FR), Joe DiMaggio Children's Hospital (US), Institut de Biologie Moléculaire et Cellulaire (FR), Indira Gandhi Institute of Child Health (IN), Posit Science (United States) (US), Geisinger Neuroscience Institute (US), University Hospital Carl Gustav Carus (DE), Weill Cornell Medicine (US), Max Planck Institute for Multidisciplinary Sciences (DE), University College London (GB), University of Colorado Anschutz Medical Campus (US), The Ohio State University (US), University of Greenwich (GB), Amsterdam University of Applied Sciences (NL), University of Tartu (EE), Tehran University of Medical Sciences (IR), Université de Montréal (CA), University of Göttingen (DE), Charité - Universitätsmedizin Berlin (DE), University of Pennsylvania (US), University of Amsterdam (NL), Yokohama City University (JP), Erasmus University Rotterdam (NL), University of Cincinnati Medical Center (US), Leipzig University (DE), Stanford University (US), Nantes Université (FR)
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