Molecular Basis for Synaptotagmin-1-Associated Neurodevelopmental Disorder.

ABSTRACT: At neuronal synapses, synaptotagmin-1 (syt1) acts as a Ca²⁺ sensor that synchronizes neurotransmitter release with Ca²⁺ influx during action potential firing. Heterozygous missense mutations in syt1 have recently been associated with a severe but heterogeneous developmental syndrome, termed syt1-associated neurodevelopmental disorder. Well-defined pathogenic mechanisms, and the basis for phenotypic heterogeneity in this disorder, remain unknown. Here, we report the clinical, physiological, and biophysical characterization of three syt1 mutations from human patients. Synaptic transmission was impaired in neurons expressing mutant variants, which demonstrated potent, graded dominant-negative effects. Biophysical interrogation of the mutant variants revealed novel mechan

SUBMITTER: Bradberry MM 

PROVIDER: S-EPMC7539681 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature