Molecular Basis for Synaptotagmin-1-Associated Neurodevelopmental Disorder

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 mechanistic features concerning the cooperative action, and functional specialization, of the tandem Ca2+-sensing domains of syt1. These mechanistic studies led to the discovery that a clinically approved K+ channel antagonist is able to rescue the dominant-negative heterozygous phenotype. Our results establish a molecular cause, basis for phenotypic heterogeneity, and potential treatment approach for syt1-associated neurodevelopmental disorder. •Graded, dominant-negative effects of disease-associated syt1 mutations•Clinical, physiological, and biochemical evidence for genotype-phenotype correlation•Functional segregation and positive allostery between the C2 domains of syt1•Rescue of mutant phenotypes by a clinically approved drug in cultured neurons Bradberry et al. combine clinical, physiological, and biochemical approaches to define how mutations in the Ca2+ sensor synaptotagmin-1 lead to a severe neurodevelopmental disorder. Their studies define new mechanistic aspects of synaptotagmin-1’s function and reveal that a clinically approved drug may have a role in the treatment of this disorder.