原发性肌张力障碍相关基因变异调控细胞周期致病的作用及机制研究

肌张力障碍(DYT)是肌肉不自主收缩导致扭转、重复运动或姿势异常的综合征，遗传因素起重要作用。研究提示DYT多个基因可能存在共同致病通路。多个DYT基因均与细胞周期G1/S监测点相关，提示细胞周期异常可能参与DYT的共同致病通路。但目前对这些和肌张力障碍的共同发病机制的系统性研究尚不完善。因此，本研究小组拟对中国原发性肌张力障碍患者开展深入系统研究，对累及颈段的原发性肌张力障碍样本群开展候选基因的检测；探讨变异在发病机制中的作用及疾病易感性。并采用实时定量PCR、Western-blot、流式细胞检测等方法进行系统功能研究，深入探讨基因变异是否调控细胞周期。该项研究有望为多个基因存在共同致病通路提供实验依据，提升对肌张力障碍发病机制的认识水平。

Primary dystonia (DYT) is a syndrome characterized by sustained involuntary twisting, repetitive movements and abnormal postures. The exact aetiology of primary dystonia remains obscure, however, genetic factors are believed to play an important role in the pathogenesis of dystonia. To date, the mutations in 4 dystonia-associated genes have been linked to cervical onset or cervical involved primary dystonia: DYT1(TOR1A)，DYT6(THAP1)，DYT23(CIZ1)，and DYT25（GNAL）. The increasing findings of many proteins whose mutant forms cause dystonia have implicated a large number of neurobiological pathways that lead to dystonia movement. It is worth to seek common pathways in the mechanisms of primary dystonia. It was reported that the above-mentioned dystonia- associated genes are involved in G1-S cell-cycle regulation, which indicated that the G1-S cell-circle checkpoint has been implicated in the common molecular pathology of primary dystonia. However, the association study of these themes is far from perfect in China. To systematically investigate the G1-S cell-circle regulated by the genetic variations in Chinese population, we plan to perform mutation screening of 4 candidate genes in a cohort of 400 Chinese patients of cervical onset or cervical involved primary dystonia and 200 normal controls. Furthermore, a series of functional studies will be conducted by immunohistochemistry, Real-Time quantitative PCR, Western blot and so on to explore the relation of the gene variations and G1-S cell-cycle regulation. This study will not only advance our understanding of the genetic basis of primary dystonia but also provide new insights into the common pathways in the mechanisms of primary dystonia..