Department of Neurology, the University of Pennsylvania, Philadelphia, PA, USA; Raymond G. Perelman Center for Cellular and Molecular Therapy, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Neurobiol Dis. 2019 Jul;127:233-241. doi: 10.1016/j.nbd.2019.03.007. Epub 2019 Mar 12.
During the last two decades, our knowledge on the genetic bases of Mendelian forms of dystonia has expanded significantly. This has translated into the generation of multiple cell and animal models to explore the neurobiological bases of this hyperkinetic movement disorder. A majority of these studies have focused on DYT1 dystonia, caused by dominant mutations in the gene encoding for the protein torsinA. Since its discovery, work in multiple laboratories helped identify the subcellular localization of torsinA, key structural features, functionally important physical interactions and biological pathways and physiological events influenced by torsinA. Moreover, recent experimental work indicates potential shared pathogenic pathways between different genetic forms of dystonia. This review will summarize our current knowledge on the molecular and basic biological features of torsinA and its dysfunction when carrying disease-causing mutation, identifying future research priorities and proposing a model of dystonia pathogenesis that might extend beyond DYT1.
在过去的二十年中，我们对孟德尔形式的肌张力障碍的遗传基础的了解有了显著的扩展。这转化为多种细胞和动物模型的产生，以探索这种运动障碍的神经生物学基础。这些研究中的大多数都集中在 DYT1 型肌张力障碍上，其由编码蛋白 torsinA 的基因中的显性突变引起。自发现以来，多个实验室的工作帮助确定了 torsinA 的亚细胞定位、关键结构特征、功能上重要的物理相互作用以及受 torsinA 影响的生物学途径和生理事件。此外，最近的实验工作表明，不同遗传形式的肌张力障碍之间存在潜在的共同致病途径。这篇综述将总结我们目前对 torsinA 的分子和基本生物学特征及其携带致病突变时功能障碍的了解，确定未来的研究重点，并提出一种可能超越 DYT1 的肌张力障碍发病机制模型。
