Reduced synaptic depression in human neurons carrying homozygous disease-causing STXBP1 variant L446F
Summary
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. © The Author(s) 2024. Published by Oxford University Press.
| Authors | Öttl M, Toonen RF, Verhage M |
|---|---|
| Journal | Human molecular genetics |
| Publication Date | 2024 May 18;33(11):991-1000 |
| PubMed | 38484778 |
| PubMed Central | PMC11102591 |
| DOI | 10.1093/hmg/ddae035 |