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Drosophila studies support a role for a presynaptic synaptotagmin mutation in a human congenital myasthenic syndrome

Lookup NU author(s): Professor Hanns Lochmuller, Professor Roger Whittaker, Professor Rita HorvathORCiD



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


During chemical transmission, the function of synaptic proteins must be coordinated to efficientlyrelease neurotransmitter. Synaptotagmin 2, the Ca2+ sensor for fast, synchronizedneurotransmitter release at the human neuromuscular junction, has recently been implicatedin a dominantly inherited congenital myasthenic syndrome associated with a non-progressivemotor neuropathy. In one family, a proline residue within the C2B Ca2+-binding pocket ofsynaptotagmin is replaced by a leucine. The functional significance of this residue has notbeen investigated previously. Here we show that in silico modeling predicts disruption of theC2B Ca2+-binding pocket, and we examine the in vivo effects of the homologous mutation inDrosophila. When expressed in the absence of native synaptotagmin, this mutation is lethal,demonstrating for the first time that this residue plays a critical role in synaptotagmin function.To achieve expression similar to human patients, the mutation is expressed in flies carryingone copy of the wild type synaptotagmin gene. We now show that Drosophila carrying thismutation developed neurological and behavioral manifestations similar to those of humanpatients and provide insight into the mechanisms underlying these deficits. Our Drosophilastudies support a role for this synaptotagmin point mutation in disease etiology.

Publication metadata

Author(s): Shields MC, Bowers MR, Fulcer MM, Bollig MK, Rock PJ, Sutton BR, Vrailas-Mortimer AD, Lochmueller H, Whittaker RG, Horvath R, Reist NE

Publication type: Article

Publication status: Published

Journal: PLOS One

Year: 2017

Pages: 1-25

Online publication date: 27/09/2017

Acceptance date: 31/08/2017

Date deposited: 28/09/2017

ISSN (electronic): 1932-6203

Publisher: Public Library of Science


DOI: 10.1371/journal.pone.0184817


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