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Pathogenic UNC13A variants cause a neurodevelopmental syndrome by impairing synaptic function.

Publication ,  Journal Article
Asadollahi, R; Ahmad, A; Boonsawat, P; Shahanoor Hinzen, J; Lohse, M; Bouazza-Arostegui, B; Sun, S; Utesch, T; Sommer, JD; Ilic, D; Ranjan, M ...
Published in: Nat Genet
November 2025

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.

Duke Scholars

Published In

Nat Genet

DOI

EISSN

1546-1718

Publication Date

November 2025

Volume

57

Issue

11

Start / End Page

2691 / 2704

Location

United States

Related Subject Headings

  • Syndrome
  • Synaptic Transmission
  • Synapses
  • Neurons
  • Neurodevelopmental Disorders
  • Nerve Tissue Proteins
  • Mice
  • Male
  • Intellectual Disability
  • Humans
 

Citation

APA
Chicago
ICMJE
MLA
NLM
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. Nat Genet, 57(11), 2691–2704. https://doi.org/10.1038/s41588-025-02361-5
Asadollahi, Reza, Aisha Ahmad, Paranchai Boonsawat, Jasmine Shahanoor Hinzen, Mareike Lohse, Boris Bouazza-Arostegui, Siqi Sun, et al. “Pathogenic UNC13A variants cause a neurodevelopmental syndrome by impairing synaptic function.Nat Genet 57, no. 11 (November 2025): 2691–2704. https://doi.org/10.1038/s41588-025-02361-5.
Asadollahi R, Ahmad A, Boonsawat P, Shahanoor Hinzen J, Lohse M, Bouazza-Arostegui B, et al. Pathogenic UNC13A variants cause a neurodevelopmental syndrome by impairing synaptic function. Nat Genet. 2025 Nov;57(11):2691–704.
Asadollahi, Reza, et al. “Pathogenic UNC13A variants cause a neurodevelopmental syndrome by impairing synaptic function.Nat Genet, vol. 57, no. 11, Nov. 2025, pp. 2691–704. Pubmed, doi:10.1038/s41588-025-02361-5.
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 SM, 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 SJC, 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. Pathogenic UNC13A variants cause a neurodevelopmental syndrome by impairing synaptic function. Nat Genet. 2025 Nov;57(11):2691–2704.

Published In

Nat Genet

DOI

EISSN

1546-1718

Publication Date

November 2025

Volume

57

Issue

11

Start / End Page

2691 / 2704

Location

United States

Related Subject Headings

  • Syndrome
  • Synaptic Transmission
  • Synapses
  • Neurons
  • Neurodevelopmental Disorders
  • Nerve Tissue Proteins
  • Mice
  • Male
  • Intellectual Disability
  • Humans