UNC13A and the Precision Control of Synaptic Transmission
From Vesicle Priming to Human Neurodevelopmental Disease
Executive overview
Fast and reliable neurotransmission depends on the precise regulation of synaptic vesicle priming and release. Disruption of this process has long been implicated in neurodevelopmental and neurodegenerative disease, yet direct genotype–mechanism–phenotype relationships for presynaptic proteins remain rare. UNC13A, which encodes the vesicle-priming protein Munc13-1, has now emerged as a critical example of how subtle perturbations in synaptic regulation can have profound consequences for human brain function.
A comprehensive genetic and functional study published in Nature Genetics establishes UNC13A as a direct cause of a previously unrecognized neurodevelopmental syndrome (Asadollahi et al., 2025). By integrating patient genomics with electrophysiological and behavioural analyses in model systems, the study demonstrates that UNC13A variants drive disease through three distinct mechanisms: loss of synaptic protein abundance, gain-of-function hyperactivity, and impaired second-messenger regulation. Together, these findings position UNC13A as a dosage- and regulation-sensitive determinant of synaptic strength, plasticity, and neurological development.
UNC13A in synaptic vesicle priming and release
UNC13A encodes Munc13-1, a highly conserved presynaptic protein that plays an essential role in chemical synaptic transmission. Munc13-1 functions upstream of membrane fusion by converting docked synaptic vesicles into a fusion-competent, “primed” state. This priming step determines the size of the readily releasable pool of vesicles and sets the ceiling for synaptic output.
Beyond its structural role, UNC13A acts as a regulatory hub. Its activity is modulated by intracellular calcium, calmodulin, phospholipids, and diacylglycerol (DAG), allowing synapses to dynamically adapt to changes in firing frequency and signalling context. Through these mechanisms, UNC13A shapes short-term synaptic plasticity, balancing vesicle consumption with replenishment during sustained neuronal activity.
Genetic studies in rodents underscore the protein’s importance. Complete loss of Unc13a leads to neonatal lethality due to catastrophic failure of excitatory neurotransmission, while partial reductions produce graded impairments in synaptic strength. These findings predicted extreme dosage sensitivity but did not explain how partial dysfunction or dysregulation might manifest in humans.
UNC13A and human disease before 2025
Prior to 2025, evidence linking UNC13A to human neurological disease was suggestive but incomplete. Isolated case reports described children with homozygous truncating variants who exhibited profound developmental delay and early mortality. Separately, genome-wide association studies identified non-coding UNC13A variants as modifiers of disease risk and progression in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).
Subsequent work showed that TDP-43 pathology, a hallmark of ALS and FTD, induces cryptic splicing of UNC13A, resulting in reduced protein expression in affected neurons. However, whether UNC13A loss was causative, contributory, or epiphenomenal remained unresolved. Moreover, the functional consequences of altered UNC13A activity at synapses had not been systematically linked to human phenotypes.
Defining a UNC13A neurodevelopmental syndrome
The 2025 Nature Genetics study addresses these gaps by analysing dozens of individuals with rare coding and splice-site variants in UNC13A and integrating clinical data with functional assays in mouse neurons and Caenorhabditis elegans (Asadollahi et al., 2025). Crucially, pathogenic variants segregate into three mechanistically distinct classes, each associated with a characteristic clinical profile.
Type A variants: loss of function and synaptic failure
Type A variants include biallelic missense, truncating, or splice-site mutations that reduce UNC13A protein expression to approximately 20–30% of normal levels. Functional analyses demonstrate a severe depletion of synaptic UNC13A, collapse of the readily releasable vesicle pool, and markedly impaired neurotransmission. In some experimental settings, synaptic release is nearly abolished.
Clinically, individuals with Type A variants present with profound global developmental delay, hypotonia, and early-onset seizures. Many fail to achieve independent motor or language milestones, and some die in early childhood. These findings establish that even partial loss of UNC13A is sufficient to cause catastrophic synaptic dysfunction in humans, revealing a sharp threshold for functional sufficiency.
Type B variants: gain-of-function hyperactivity at the UNC13 hinge
A second group of patients harbours heterozygous de novo missense variants clustered within a short, highly conserved region linking regulatory domains to the MUN domain, referred to as the “UNC13 hinge.” Unlike loss-of-function variants, these mutations increase spontaneous and evoked neurotransmitter release without enlarging the readily releasable pool, indicating heightened vesicle fusogenicity or release probability.
These gain-of-function effects are dominant and persist even in the presence of a wild-type allele, as demonstrated in both mouse neurons and C. elegans models (Asadollahi et al., 2025). Clinically, Type B variants are associated with developmental delay accompanied by movement disorders such as tremor, ataxia, and dyskinesia. The data identify the UNC13 hinge as a regulatory hotspot where subtle structural perturbations pathologically amplify synaptic output.
Type C variants: disrupted second-messenger regulationThe third class of pathogenic variants affects the C1 domain of UNC13A, which mediates DAG-dependent regulation. These variants do not substantially alter basal synaptic transmission but abolish responsiveness to DAG signalling. As a result, synapses lose the ability to appropriately scale strength during periods of increased activity.
Individuals with Type C variants exhibit milder phenotypes, including learning difficulties, controlled seizures, and mild to moderate intellectual disability. These findings demonstrate that disruption of regulatory flexibility alone, even in the absence of baseline synaptic failure, can impair neurodevelopment.
UNC13A and short-term synaptic plasticity
Beyond basal neurotransmission, UNC13A variants exert profound effects on short-term synaptic plasticity. Loss-of-function variants favour facilitation and exaggerated post-train augmentation, reflecting slow vesicle replenishment. In contrast, gain-of-function hinge variants drive rapid synaptic depression during high-frequency activity and blunt post-train augmentation.
These opposing effects highlight UNC13A’s central role in balancing vesicle consumption and resupply. Disruption of this balance likely contributes to network-level instability, abnormal excitability, and seizure susceptibility observed across the UNC13A clinical spectrum.
UNC13A within the SNAREopathy landscape
The UNC13A syndrome joins a growing class of disorders caused by mutations in presynaptic release machinery, often referred to as SNAREopathies. Disorders linked to STXBP1, SNAP25, and VAMP2 similarly exhibit extreme dosage sensitivity and overlapping phenotypes, including developmental delay and epilepsy.
UNC13A is distinctive, however, in that pathogenic variants selectively perturb vesicle priming efficiency, release probability, or regulatory responsiveness rather than abolishing SNARE complex formation outright. This mechanistic diversity likely underlies the unusually broad phenotypic range associated with UNC13A mutations.
Implications for ALS and FTD
One of the most consequential findings of the study is the demonstration that reducing UNC13A expression to 20–30% of normal levels is sufficient to cause severe synaptic dysfunction (Asadollahi et al., 2025). This observation has direct relevance for ALS and FTD, where TDP-43–mediated mis-splicing leads to partial UNC13A loss.
Although ALS and FTD are neurodegenerative rather than neurodevelopmental, chronic synaptic vulnerability caused by reduced UNC13A may lower the threshold for neuronal failure under stress. These data support a model in which UNC13A acts as a disease modifier by weakening synaptic resilience rather than directly initiating degeneration.
Therapeutic and translational considerations
The mechanistic stratification of UNC13A variants has important therapeutic implications. Strategies aimed at increasing UNC13A expression or activity may benefit loss-of-function contexts but could exacerbate symptoms in gain-of-function cases. Similarly, indiscriminate enhancement of synaptic release risks worsening excitotoxicity or seizure burden.
These findings argue strongly for precision approaches that account for variant-specific mechanisms. More broadly, UNC13A represents a compelling example of how finely tuned synaptic regulation must be maintained within a narrow functional window to support healthy brain development and long-term neuronal survival.
Conclusion
The identification of a UNC13A-associated neurodevelopmental syndrome represents a major advance in synaptic biology and human genetics. By linking specific genetic variants to precise alterations in synaptic transmission and plasticity, the work of Asadollahi et al. (2025) provides a rare and complete genotype–mechanism–phenotype framework.
More broadly, the study underscores a fundamental principle of neuroscience: human brain development depends not only on the presence of synaptic machinery, but on its precise regulation. UNC13A sits at the centre of this balance, where too little, too much, or improperly regulated activity can each derail normal neurological function.\
References
Asadollahi, R., Lipstein, N., et al. (2025). Pathogenic UNC13A variants cause a neurodevelopmental syndrome by impairing synaptic function. Nature Genetics, 57, 2691–2704.
https://doi.org/10.1038/s41588-025-02361-5
Augustin, I., Rosenmund, C., Südhof, T. C., & Brose, N. (1999). Munc13-1 is essential for fusion competence of glutamatergic synaptic vesicles. Nature, 400(6743), 457–461.
https://doi.org/10.1038/22768
Brown, A. L., Wilkins, O. G., Keuss, M. J., et al. (2022). TDP-43 loss and ALS-risk variants drive mis-splicing of UNC13A. Nature Neuroscience, 25, 1506–1517.
https://doi.org/10.1038/s41593-022-01178-0
Ling, J. P., Pletnikova, O., Troncoso, J. C., & Wong, P. C. (2015). TDP-43 repression of nonconserved cryptic exons is compromised in ALS-FTD. Science, 349(6248), 650–655.
https://doi.org/10.1126/science.aab0983
Rizo, J., & Südhof, T. C. (2012). The membrane fusion machinery of neurotransmitter release. Annual Review of Cell and Developmental Biology, 28, 279–308.
https://doi.org/10.1146/annurev-cellbio-101011-155824
Südhof, T. C. (2013). Neurotransmitter release: The last millisecond in the life of a synaptic vesicle. Neuron, 80(3), 675–690.
https://doi.org/10.1016/j.neuron.2013.10.022
van Es, M. A., Veldink, J. H., Saris, C. G. J., et al. (2009). Genome-wide association study identifies UNC13A as a susceptibility locus for amyotrophic lateral sclerosis. Nature Genetics, 41(10), 1083–1087.
https://doi.org/10.1038/ng.442