Relevance to Autism

A de novo missense variant in the UNC13A gene (p.Pro814Leu) was identified in a 6-year-old diagnosed with ASD and comorbid ADHD and presenting with developmental delay and a dyskinetic movement disorder in Lipstein et al., 2017. Functional analysis in murine neuronal cultures and C. elegans demonstrated that this variant resulted in a gain-of-function effect characterized by increased fusion propensity of synaptic vesicles, leading to increased initial synaptic vesicle release probability and abnormal short-term synaptic plasticity. Additional de novo variants in this gene, including a mosaic loss-of-function variant and several missense variants, have been reported in ASD probands from the Simons Simplex Collection, the Autism Sequencing Consortium, and the SPARK cohort (De Rubeis et al., 2014; Krupp et al., 2017; Zhou et al., 2022). Genotype-phenotype-functional correlation analysis of an cohort of individuals with monoallelic or biallelic variants in the UNC13A gene in Asadollahi et al., 2025 led the authors to classify three UNC13A neurodevelopmental syndrome subtypes: subtype A was an autosomal recessive disorder caused by biallelic likely gene-disruptive, splice-site, or missense variants that were experimentally shown to result in decreased UNC13A expression, lower synaptic strength, a smaller readily releasable synaptic vesicle pool (RRP), and increased potentiation by synaptic activity and the membrane-permeable diacylglycerol analog Phorbol 12,13-dibutyrate (PDBu) and characterized by profound global developmental delay/intellectual disability, largely controllable epilepsy, and death in early childhood in some cases; subtype B was an autosomal dominant disorder caused by de novo missense variants in the UNC13A hinge that were experimentally shown to result in increased synaptic strength, increased freqeuency of spontaneous activity, and decreased potentiation by synaptic activity and PDBu and characterized by moderate-to-severe global developmental delay/intellectual disability, largely refractory epilepsy, and ataxia and tremor or dyskinetic movements; and subtype C was an autosomal dominant disorder caused by an inherited missense variant that was experimentally shown to result in a block of potentiation by synaptic activity and PDBu and an increased tendency towards synaptic depression during high frequency activity and characterized by mild developmental delay/intellectual disability and controllable epilepsy. Notably, three of the six individuals with the pathogenic gain-of-function Pro814Leu missense variant described in Asadollahi et al., 2025 were reported to have either autism (n=2) or autistic features (n=1).

Molecular Function

Plays a role in vesicle maturation during exocytosis as a target of the diacylglycerol second messenger pathway. Involved in neurotransmitter release by acting in synaptic vesicle priming prior to vesicle fusion and participates in the activity-dependent refilling of readily releasable vesicle pool (RRP). Essential for synaptic vesicle maturation in most excitatory/glutamatergic but not inhibitory/GABA-mediated synapses. Also involved in secretory granule priming in insulin secretion.

External Links

References