Title | Synaptic UNC13A protein variant causes increased neurotransmission and dyskinetic movement disorder. |
Publication Type | Journal Article |
Year of Publication | 2017 |
Authors | 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 AMV, Vorstman JA, Thoms S, Jahn O, Duran KJ, Monroe GR, Ryan TA, Taschenberger H, Dittman JS, Rhee J-S, Visser G, Jans JJ, Brose N |
Journal | J Clin Invest |
Volume | 127 |
Issue | 3 |
Pagination | 1005-1018 |
Date Published | 2017 Mar 01 |
ISSN | 1558-8238 |
Keywords | Amino Acid Substitution, Animals, Caenorhabditis elegans, Caenorhabditis elegans Proteins, Cell Line, Female, Humans, Infant, Male, Motor Disorders, Mutation, Missense, Nerve Tissue Proteins, Neuronal Plasticity, Neurons, Synaptic Transmission, Synaptic Vesicles |
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. |
DOI | 10.1172/JCI90259 |
Alternate Journal | J. Clin. Invest. |
PubMed ID | 28192369 |
PubMed Central ID | PMC5330740 |
Grant List | R01 GM095674 / GM / NIGMS NIH HHS / United States T32 GM007739 / GM / NIGMS NIH HHS / United States |
Submitted by kej2006 on June 6, 2018 - 4:10pm