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

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

SUBMITTER: Asadollahi R 

PROVIDER: S-EPMC12597829 | biostudies-literature | 2025 Nov

REPOSITORIES: biostudies-literature