Synaptic UNC13A protein variant causes increased neurotransmission and dyskinetic movement disorder. Academic Article uri icon

Overview

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.

publication date

  • February 13, 2017

Research

keywords

  • Caenorhabditis elegans
  • Caenorhabditis elegans Proteins
  • Motor Disorders
  • Mutation, Missense
  • Nerve Tissue Proteins
  • Synaptic Transmission
  • Synaptic Vesicles

Identity

PubMed Central ID

  • PMC5330740

Scopus Document Identifier

  • 85015969576

Digital Object Identifier (DOI)

  • 10.1074/jbc.270.42.25273

PubMed ID

  • 28192369

Additional Document Info

volume

  • 127

issue

  • 3