Reduced synaptic depression in human neurons carrying homozygous disease-causing STXBP1 variant L446F.
Hum Mol Genet
; 33(11): 991-1000, 2024 May 18.
Article
in En
| MEDLINE
| ID: mdl-38484778
ABSTRACT
MUNC18-1 is an essential protein of the regulated secretion machinery. De novo, heterozygous mutations in STXBP1, the human gene encoding this protein, lead to a severe neurodevelopmental disorder. Here, we describe the electrophysiological characteristics of a unique case of STXBP1-related disorder caused by a homozygous mutation (L446F). We engineered this mutation in induced pluripotent stem cells from a healthy donor (STXBP1LF/LF) to establish isogenic cell models. We performed morphological and electrophysiological analyses on single neurons grown on glial micro-islands. Human STXBP1LF/LF neurons displayed normal morphology and normal basal synaptic transmission but increased paired-pulse ratios and charge released, and reduced synaptic depression compared to control neurons. Immunostainings revealed normal expression levels but impaired recognition by a mutation-specific MUNC18-1 antibody. The electrophysiological gain-of-function phenotype is in line with earlier overexpression studies in Stxbp1 null mouse neurons, with some potentially human-specific features. Therefore, the present study highlights important differences between mouse and human neurons critical for the translatability of pre-clinical studies.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Synaptic Transmission
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Munc18 Proteins
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Induced Pluripotent Stem Cells
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Homozygote
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Neurons
Limits:
Animals
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Humans
Language:
En
Journal:
Hum Mol Genet
Journal subject:
BIOLOGIA MOLECULAR
/
GENETICA MEDICA
Year:
2024
Type:
Article
Affiliation country:
Netherlands