Pathogenic UNC13A variants cause a neurodevelopmental syndrome by impairing synaptic function

Asadollahi R, Ahmad A, Boonsawat P, Shahanoor Hinzen J, Lohse M, Bouazza-Arostegui B, Sun S, Utesch T, Sommer JD, Ilic D, Padmanarayana M, Fischermanns K, Ranjan M, Boll M, Ka C, Piton A, Mattioli F, Isidor B, Õunap K, Reinson K, Wojcik MH, Marshall CR, Mercimek-Andrews S, Matsumoto N, Miyake N, Stephan BdO, Honjo RS, Bertola DR, Kim CA, Yusupov R, Mefford HC, Christodoulou J, Lee J, Heath O, Brown NJ, Baker N, Stark Z, Delatycki M, Lake NJ, Zeidler S, Zuurbier L, Maas SM, de Kruiff CC, Rajabi F, Rodan LH, Coury SA, Platzer K, Oppermann H, Abou Jamra R, Beblo S, Maxton C, Śmigiel R, Underhill H, Dubbs H, Rosen A, Helbig KL, Helbig I, Ruggiero SMK, Fitzgerald MP, Kraemer D, Prada CE, Tenney J, Jayakar P, Redon S, Lefranc J, Uguen K, Race S, Efthymiou S, Maroofian R, Houlden H, Coppens S, Deconinck N, Ashokkumar B, Varalakshmi P, Gowda K VR, Eghbal F, Ghayoor Karimiani E, Heidari M, Neidhardt J, Owczarek-Lipska M, Korenke GC, Bamshad MJ, Campeau PM, Lehman A, Hendon LG, Wentzensen IM, Monaghan KG, Chen Y, Szuto A, Cohn RD, Au PYB, Hübner C, Boschann F, Manickam K, Koboldt DC, Rad A, Oprea G, Bachman KK, Seeley AH, Agolini E, Terracciano A, Carmelo P, Bupp C, Grysko B, Rein-Rothschild A, Ben Zeev B, Margolin A, Morrison J, Dagli A, Stolerman E, Louie RJ, Washington C, Stevens SJ, Heijligers M, Alkuraya FS, Lisfeld J, Neu A, Paoli Monteiro F, Santos Pessoa AL, Camelo-Filho AE, Kok F, Koeberl D, Riley K, Burglen L, Doummar D, Héron B, Mignot C, Keren B, Charles P, Nava C, Bernhard FP, Kühn AA, Thoms S, Morrie RD, Mekhoubad S, Green EM, Barmada SJ, Gitler AD, Jahn O, Rhee JS, Rosenmund C, Mitkovski M, Sticht H, Sun H, Le Gac G, Taschenberger H, Brose N, Dittman JS, Rauch A, Lipstein N (2025)

Publication Type: Journal article

Publication year: 2025

Journal

Book Volume: 57

Pages Range: 2691-2704

Journal Issue: 11

DOI: 10.1038/s41588-025-02361-5

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.

Authors with CRIS profile

Involved external institutions

Freie Universität Berlin Germany (DE) Wrocław Medical University / Uniwersytet Medyczny we Wrocławiu Poland (PL) University of Zurich / Universität Zürich (UZH) Switzerland (CH) Max-Planck-Institut für Multidisziplinäre Naturwissenschaften / Max Planck Institute for Multidisciplinary Sciences Germany (DE) Weill Cornell Medicine United States (USA) (US) Leibniz-Forschungsinstitut für Molekulare Pharmakologie im Forschungsverbund Berlin e.V. (FMP) Germany (DE) Murdoch Childrens Research Institute Australia (AU) Erasmus University Medical Center (MC) Netherlands (NL) University of Amsterdam Netherlands (NL) Academic Medical Centre / Academisch Medisch Centrum (AMC) Netherlands (NL) Boston Children's Hospital United States (USA) (US) Universität Leipzig Germany (DE) Universitätsklinikum Leipzig Germany (DE) University of Utah United States (USA) (US) Children's Hospital of Philadelphia United States (USA) (US) University of Cincinnati United States (USA) (US) Université de Bretagne Occidentale France (FR) Institute of Genetics and Molecular and Cellular Biology / Institut de génétique et de biologie moléculaire et cellulaire (IGBMC) France (FR) Nantes University Hospital / Centre hospitalier universitaire de Nantes (CHU) France (FR) Tartu University Hospital Estonia (EE) Harvard University United States (USA) (US) The Hospital for Sick Children (SickKids) Canada (CA) University of Alberta Canada (CA) Yokohama City University Japan (JP) University of São Paulo / Universidade de São Paulo (USP) Brazil (BR) Joe DiMaggio Children's Hospital United States (USA) (US) St. Jude Children’s Research Hospital United States (USA) (US) The Royal Children's Hospital Melbourne Australia (AU) Tehran University of Medical Sciences (TUMS) / دانشگاه علوم پزشکی تهران Iran, Islamic Republic of (IR) Carl von Ossietzky Universität Oldenburg Germany (DE) University of Washington United States (USA) (US) Centre Hospitalier Universitaire Sainte-Justine, CHU Sainte-Justine Canada (CA) University of British Columbia Canada (CA) University of Mississippi Medical Center United States (USA) (US) GeneDX United States (USA) (US) Alberta Children's Hospital Research Institute (ACHRI) Canada (CA) Universitätsklinikum Carl Gustav Carus Dresden Germany (DE) Nationwide Children's Hospital United States (USA) (US) Ohio State University United States (USA) (US) Arcensus GmbH Germany (DE) Geisinger Medical Center United States (USA) (US) Chaim Sheba Medical Center at Tel HaShomer / המרכז הרפואי עש חיים שיבא – תל השומר‎‎ Israel (IL) Tel Aviv University Israel (IL) Orlando Health Arnold Palmer Hospital for Children United States (USA) (US) Greenwood Genetic Center United States (USA) (US) Maastricht University Netherlands (NL) King Faisal Specialist Hospital & Research Centre Saudi Arabia (SA) Universitätsklinikum Hamburg-Eppendorf (UKE) Germany (DE) Mendelics Brazil (BR) Universidade Federal do Ceará (UCF) Brazil (BR) Nicklaus Children's Hospital United States (USA) (US) Centre hospitalier universitaire de Brest (CHRU Brest) France (FR) British Columbia Children's Hospital (BC Children's Hospital) Canada (CA) University College London (UCL) United Kingdom (GB) Brussels University Hospital (H.U.B) / Hôpital Universitaire de Bruxelles Belgium (BE) Queen Fabiola Childrens Hospital / L'Hôpital universitaire des enfants Reine Fabiola Belgium (BE) Madurai Kamaraj University / மதுரை காமராசர் பல்கலைக்கழகம் India (IN) Indira Gandhi Institute of Child Health India (IN) Ospedale Pediatrico Bambino Gesu Italy (IT) Helen DeVos Children's Hospital United States (USA) (US) Hôpital Armand-Trousseau (AP-HP) France (FR) Pitié-Salpêtrière University Hospital / Hôpital universitaire Pitié-Salpêtrière France (FR) Duke University United States (USA) (US) Philipps-Universität Marburg Germany (DE) Charité - Universitätsmedizin Berlin Germany (DE) Universität Bielefeld Germany (DE) Trace Neuroscience United States (USA) (US) University of Michigan United States (USA) (US) Stanford University United States (USA) (US)

How to cite

APA:

Asadollahi, R., Ahmad, A., Boonsawat, P., Shahanoor Hinzen, J., Lohse, M., Bouazza-Arostegui, B.,... Lipstein, N. (2025). Pathogenic UNC13A variants cause a neurodevelopmental syndrome by impairing synaptic function. Nature Genetics, 57(11), 2691-2704. https://doi.org/10.1038/s41588-025-02361-5

MLA:

Asadollahi, Reza, et al. "Pathogenic UNC13A variants cause a neurodevelopmental syndrome by impairing synaptic function." Nature Genetics 57.11 (2025): 2691-2704.

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