<i>Drosophila</i> studies support a role for a presynaptic synaptotagmin mutation in a human congenital myasthenic syndrome

<div><p>During chemical transmission, the function of synaptic proteins must be coordinated to efficiently release neurotransmitter. Synaptotagmin 2, the Ca²⁺ sensor for fast, synchronized neurotransmitter release at the human neuromuscular junction, has recently been implicated in a dominantly inherited congenital myasthenic syndrome associated with a non-progressive motor neuropathy. In one family, a proline residue within the C₂B Ca²⁺-binding pocket of synaptotagmin is replaced by a leucine. The functional significance of this residue has not been investigated previously. Here we show that <i>in silico</i> modeling predicts disruption of the C₂B Ca²⁺-binding pocket, and we examine the <i>in vivo</i> effects of the homologous mutation in <i>Drosophila</i>. 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 carrying one copy of the wild type <i>synaptotagmin</i> gene. We now show that <i>Drosophila</i> carrying this mutation developed neurological and behavioral manifestations similar to those of human patients and provide insight into the mechanisms underlying these deficits. Our <i>Drosophila</i> studies support a role for this synaptotagmin point mutation in disease etiology.</p>