5月13日担当のNeuroclubでは以下の論文を紹介いたします。

Asadollahi et al.
Nature Genetics 57, 2691–2704 (2025)
https://doi.org/10.1038/s41588-025-02361-5

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 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.

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