Details

Autor(en) / Beteiligte

• Lipstein, Noa
• Verhoeven-Duif, Nanda M
• Michelassi, Francesco E
• Calloway, Nathaniel
• van Hasselt, Peter M
• Pienkowska, Katarzyna
• van Haaften, Gijs
• van Haelst, Mieke M
• van Empelen, Ron
• Cuppen, Inge
• van Teeseling, Heleen C
• Evelein, Annemieke M V
• Vorstman, Jacob A
• Thoms, Sven
• Jahn, Olaf
• Duran, Karen J
• Monroe, Glen R
• Ryan, Timothy A
• Taschenberger, Holger
• Dittman, Jeremy S
• Rhee, Jeong-Seop
• Visser, Gepke
• Jans, Judith J
• Brose, Nils

Titel

Synaptic UNC13A protein variant causes increased neurotransmission and dyskinetic movement disorder

Ist Teil von

• The Journal of clinical investigation, 2017-03, Vol.127 (3), p.1005-1018

Ort / Verlag

United States: American Society for Clinical Investigation

Erscheinungsjahr

2017

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.