title: Identification of a human synaptotagmin-1 mutation that perturbs synaptic vesicle cycling.
abstract: Synaptotagmin-1 (SYT1) is a calcium-binding synaptic vesicle protein that is required for both exocytosis and endocytosis. Here, we describe a human condition associated with a rare variant in SYT1. The individual harboring this variant presented with an early onset dyskinetic movement disorder, severe motor delay, and profound cognitive impairment. Structural MRI was normal, but EEG showed extensive neurophysiological disturbances that included the unusual features of low-frequency oscillatory bursts and enhanced paired-pulse depression of visual evoked potentials. Trio analysis of whole-exome sequence identified a de novo SYT1 missense variant (I368T). Expression of rat SYT1 containing the equivalent human variant in WT mouse primary hippocampal cultures revealed that the mutant form of SYT1 correctly localizes to nerve terminals and is expressed at levels that are approximately equal to levels of endogenous WT protein. The presence of the mutant SYT1 slowed synaptic vesicle fusion kinetics, a finding that agrees with the previously demonstrated role for I368 in calcium-dependent membrane penetration. Expression of the I368T variant also altered the kinetics of synaptic vesicle endocytosis. Together, the clinical features, electrophysiological phenotype, and in vitro neuronal phenotype associated with this dominant negative SYT1 mutation highlight presynaptic mechanisms that mediate human motor control and cognitive development.
authors.forename: Kate
authors.initials: K
authors.lastname: Baker
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Gordon
authors.forename: Detelina
authors.initials: D
authors.lastname: Grozeva
authors.forename: Margriet
authors.initials: M
authors.lastname: van Kogelenberg
authors.forename: Nicola Y
authors.initials: NY
authors.lastname: Roberts
authors.forename: Michael
authors.initials: M
authors.lastname: Pike
authors.forename: Edward
authors.initials: E
authors.lastname: Blair
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Hurles
authors.forename: W Kling
authors.initials: WK
authors.lastname: Chong
authors.forename: Torsten
authors.initials: T
authors.lastname: Baldeweg
authors.forename: Manju A
authors.initials: MA
authors.lastname: Kurian
authors.forename: Stewart G
authors.initials: SG
authors.lastname: Boyd
authors.forename: Michael A
authors.initials: MA
authors.lastname: Cousin
authors.forename: F Lucy
authors.initials: FL
authors.lastname: Raymond
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D002648:Child; D004705:Endocytosis / Q000235:genetics / Q000502:physiology; D005074:Evoked Potentials, Visual; D005089:Exocytosis / Q000235:genetics / Q000502:physiology; D005799:Genes, Dominant; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics*; D007700:Kinetics; D008297:Male; D008561:Membrane Fusion; D051379:Mice; D008969:Molecular Sequence Data; D019957:Motor Skills Disorders / Q000235:genetics*; D009069:Movement Disorders / Q000235:genetics*; D020125:Mutation, Missense; D017354:Point Mutation; D017729:Presynaptic Terminals / Q000502:physiology*; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D013572:Synaptic Vesicles / Q000502:physiology*; D050863:Synaptotagmin I / Q000235:genetics / Q000502:physiology*
chemical_list: D011993:Recombinant Fusion Proteins; C494310:SYT1 protein, human; D050863:Synaptotagmin I; D002118:Calcium