title: Synaptic UNC13A protein variant causes increased neurotransmission and dyskinetic movement disorder.
abstract: Munc13 proteins are essential regulators of neurotransmitter release at nerve cell synapses. They mediate the priming step that renders synaptic vesicles fusion-competent, and their genetic elimination causes a complete block of synaptic transmission. Here we have described a patient displaying a disorder characterized by a dyskinetic movement disorder, developmental delay, and autism. Using whole-exome sequencing, we have shown that this condition is associated with a rare, de novo Pro814Leu variant in the major human Munc13 paralog UNC13A (also known as Munc13-1). Electrophysiological studies in murine neuronal cultures and functional analyses in Caenorhabditis elegans revealed that the UNC13A variant causes a distinct dominant gain of function that is characterized by increased fusion propensity of synaptic vesicles, which leads to increased initial synaptic vesicle release probability and abnormal short-term synaptic plasticity. Our study underscores the critical importance of fine-tuned presynaptic control in normal brain function. Further, it adds the neuronal Munc13 proteins and the synaptic vesicle priming process that they control to the known etiological mechanisms of psychiatric and neurological synaptopathies.
authors.forename: Noa
authors.initials: N
authors.lastname: Lipstein
authors.forename: Nanda M
authors.initials: NM
authors.lastname: Verhoeven-Duif
authors.forename: Francesco E
authors.initials: FE
authors.lastname: Michelassi
authors.forename: Nathaniel
authors.initials: N
authors.lastname: Calloway
authors.forename: Peter M
authors.initials: PM
authors.lastname: van Hasselt
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Pienkowska
authors.forename: Gijs
authors.initials: G
authors.lastname: van Haaften
authors.forename: Mieke M
authors.initials: MM
authors.lastname: van Haelst
authors.forename: Ron
authors.initials: R
authors.lastname: van Empelen
authors.forename: Inge
authors.initials: I
authors.lastname: Cuppen
authors.forename: Heleen C
authors.initials: HC
authors.lastname: van Teeseling
authors.forename: Annemieke M V
authors.initials: AM
authors.lastname: Evelein
authors.forename: Jacob A
authors.initials: JA
authors.lastname: Vorstman
authors.forename: Sven
authors.initials: S
authors.lastname: Thoms
authors.forename: Olaf
authors.initials: O
authors.lastname: Jahn
authors.forename: Karen J
authors.initials: KJ
authors.lastname: Duran
authors.forename: Glen R
authors.initials: GR
authors.lastname: Monroe
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Ryan
authors.forename: Holger
authors.initials: H
authors.lastname: Taschenberger
authors.forename: Jeremy S
authors.initials: JS
authors.lastname: Dittman
authors.forename: Jeong-Seop
authors.initials: JS
authors.lastname: Rhee
authors.forename: Gepke
authors.initials: G
authors.lastname: Visser
authors.forename: Judith J
authors.initials: JJ
authors.lastname: Jans
authors.forename: Nils
authors.initials: N
authors.lastname: Brose
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D000068079:Motor Disorders / Q000235:genetics / Q000378:metabolism*; D020125:Mutation, Missense; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009473:Neuronal Plasticity; D009474:Neurons / Q000378:metabolism; D009435:Synaptic Transmission; D013572:Synaptic Vesicles / Q000235:genetics / Q000378:metabolism*
chemical_list: D029742:Caenorhabditis elegans Proteins; D009419:Nerve Tissue Proteins; C485548:UNC13B protein, human; C503321:Unc13a protein, mouse