Synaptic UNC13A protein variant causes increased neurotransmission and dyskinetic movement disorder

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

Research output: Contribution to journalArticleAcademicpeer-review

72 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)1005-1018
Number of pages14
JournalJournal of clinical investigation
Issue number3
Publication statusPublished - 1 Mar 2017

Cite this