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

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 in silico modeling predicts disruption of
the C2B Ca2+-binding pocket, and we examine the in vivo effects of the
homologous mutation in Drosophila. 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 synaptotagmin gene. We now show
that Drosophila carrying this mutation developed neurological and
behavioral manifestations similar to those of human patients and provide
insight into the mechanisms underlying these deficits. Our Drosophila
studies support a role for this synaptotagmin point mutation in disease
etiology.

在化学传递过程中，突触蛋白的功能必须协同配合以高效释放神经递质。突触结合蛋白2（Synaptotagmin 2）作为人类神经肌肉接头处快速同步神经递质释放的Ca2+传感器，近期被发现与一种常染色体显性遗传的先天性肌无力综合征相关，该综合征还伴随非进展性运动神经病。在某一家系中，突触结合蛋白C2B结构域Ca2+结合口袋内的一个脯氨酸残基被亮氨酸取代，而该残基的功能意义此前尚未得到研究。本研究通过计算机模拟（in silico modeling）预测该突变会破坏C2B Ca2+结合口袋，并在果蝇中探究了该同源突变的体内效应。结果显示，当在缺乏内源性突触结合蛋白的条件下表达时，该突变具有致死性，首次证实该残基在突触结合蛋白功能中发挥关键作用。为模拟人类患者的表达模式，我们在携带一个野生型突触结合蛋白基因拷贝的果蝇中表达该突变，发现携带此突变的果蝇出现了与人类患者相似的神经及行为表现，并为这些功能缺陷的潜在机制提供了见解。我们的果蝇研究支持该突触结合蛋白点突变在疾病病因学中的作用。