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bioRxiv · 10.64898/2026.05.22.727260

Genetic Rescue of a Lethal Wasting Mutation (Syb1lew/lew) by Neuron-Specific Expression of ECFP-Syb2

Lin, W.·Liu, Y.·Ye, Q.
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Abstract

Lethal-wasting (lew) is a spontaneous null mutation in the Syb1/Vamp1 gene encoding the vesicular SNARE protein synaptobrevin 1 (SYB1/VAMP1). Homozygous Syb1lew/lew mice exhibit profound impairment in neuromuscular transmission and die around three weeks after birth. Pathogenic variants in human SYB1 are associated with a variety of disorders such as hereditary spastic ataxia and congenital myasthenic syndrome. Although Syb1 expression is highly enriched in neurons, it has also been reported in non-neuronal tissues, raising the possibility that non-neuronal defects contribute to the lethal phenotype. Here, we tested whether neuronal dysfunction is the primary cause of death in Syb1lew/lew mice and whether the closely related isoform synaptobrevin 2 (Syb2/VAMP2) can substitute for Syb1functin in vivo. We show that neuron-specific expression of ECFP-Syb2 in Syb1lew/lew mice fully rescues lethality in Syb1lew/lewmice, restoring normal growth and motor function. Electrophysiological analyses demonstrate complete recovery of neuromuscular synaptic transmission, including spontaneous and evoked release as well as short-term plasticity. These findings establish that neuronal expression of ECFP-Syb2 is sufficient to prevent the lethal phenotype associated with Syb1 deficiency and demonstrate that Syb2 can functionally replace Syb1 at motor nerve terminals in vivo. Significance StatementNeuron-specific expression of Syb2 fully rescues survival, motor function, and neuromuscular transmission in Syb1lew/lew mice. These findings establish presynaptic Syb1 dysfunction as the primary cause of the lethal phenotype and demonstrate that Syb2 can fully substitute for Syb1 in vivo.

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Lin, W., Liu, Y., Ye, Q.. 2026-05-26. Genetic Rescue of a Lethal Wasting Mutation (Syb1lew/lew) by Neuron-Specific Expression of ECFP-Syb2. https://doi.org/10.64898/2026.05.22.727260

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