School of Physiology, Pharmacology and Neuroscience, University of Bristol, University Walk, Bristol, BS8 1TD, UK.
Department of Pathology and Cell Biology, College of Physicians and Surgeons, Columbia University, New York, NY, 10032, USA.
Sci Rep. 2018 May 16;8(1):7664. doi: 10.1038/s41598-018-25949-w.
Essential Tremor (ET) is one of the most common neurological diseases, with an estimated 7 million affected individuals in the US; the pathophysiology of the disorder is poorly understood. Recently, we identified a mutation (KCNS2 (Kv9.2), c.1137 T > A, p.(D379E) in an electrically silent voltage-gated K channel α-subunit, Kv9.2, in a family with ET, that modulates the activity of Kv2 channels. We have produced transgenic Drosophila lines that express either the human wild type Kv9.2 (hKv9.2) or the ET causing mutant Kv9.2 (hKv9.2-D379E) subunit in all neurons. We show that the hKv9.2 subunit modulates activity of endogenous Drosophila K channel Shab. The mutant hKv9.2-D379E subunit showed significantly higher levels of Shab inactivation and a higher frequency of spontaneous firing rate consistent with neuronal hyperexcitibility. We also observed behavioral manifestations of nervous system dysfunction including effects on night time activity and sleep. This functional data further supports the pathogenicity of the KCNS2 (p.D379E) mutation, consistent with our prior observations including co-segregation with ET in a family, a likely pathogenic change in the channel pore domain and absence from population databases. The Drosophila hKv9.2 transgenic model recapitulates several features of ET and may be employed to advance our understanding of ET disease pathogenesis.
特发性震颤（ET）是最常见的神经系统疾病之一，据估计，美国有 700 万人受到影响；该疾病的病理生理学尚未完全了解。最近，我们在一个 ET 家族中发现了一种突变（KCNS2（Kv9.2），c.1137T> A，p.（D379E），位于一个电静默电压门控 K 通道α亚基 Kv9.2 中，该突变可调节 Kv2 通道的活性。我们已经制备了表达人野生型 Kv9.2（hKv9.2）或引起 ET 的突变型 Kv9.2（hKv9.2-D379E）亚基的转基因果蝇系，在所有神经元中表达。我们表明，hKv9.2 亚基调节内源性果蝇 K 通道 Shab 的活性。突变型 hKv9.2-D379E 亚基显示出显着更高水平的 Shab 失活和更高的自发发射率频率，与神经元过度兴奋一致。我们还观察到神经系统功能障碍的行为表现，包括对夜间活动和睡眠的影响。这些功能数据进一步支持 KCNS2（p.D379E）突变的致病性，与我们之前的观察结果一致，包括在一个家族中与 ET 共分离，通道孔域中的可能致病性改变以及不存在于人群数据库中。果蝇 hKv9.2 转基因模型再现了 ET 的几个特征，并且可能用于推进我们对 ET 疾病发病机制的理解。
