1. Synaptic UNC13A protein variant causes increased neurotransmission and dyskinetic movement disorder.
- Author
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Lipstein N, Verhoeven-Duif NM, Michelassi FE, Calloway N, van Hasselt PM, Pienkowska K, van Haaften G, van Haelst MM, van Empelen R, Cuppen I, van Teeseling HC, Evelein AM, Vorstman JA, Thoms S, Jahn O, Duran KJ, Monroe GR, Ryan TA, Taschenberger H, Dittman JS, Rhee JS, Visser G, Jans JJ, and Brose N
- Subjects
- Amino Acid Substitution, Animals, Caenorhabditis elegans genetics, Caenorhabditis elegans Proteins genetics, Cell Line, Female, Humans, Infant, Male, Motor Disorders genetics, Nerve Tissue Proteins genetics, Neuronal Plasticity, Neurons metabolism, Synaptic Vesicles genetics, Caenorhabditis elegans metabolism, Caenorhabditis elegans Proteins metabolism, Motor Disorders metabolism, Mutation, Missense, Nerve Tissue Proteins metabolism, Synaptic Transmission, Synaptic Vesicles metabolism
- 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.
- Published
- 2017
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