Elucidating novel genetic causes of dystonia by large-scale sequencing

肌张力障碍是一种罕见的，临床和遗传高度异质性的运动障碍，其特征是持续或间歇性肌肉收缩，导致异常运动和/或姿势。这些症状对生活质量有重大影响。目前，没有治愈方法，治疗选择有限，部分原因是对分子基础知之甚少。约25%的高遗传率表明遗传因素在其病因学中有相当大的贡献。几种单基因形式，其中一些可以特异性治疗，和遗传风险因素已被确定，但在大多数患者的病因仍然难以捉摸。正如最近在一篇社论（Gan-Or et al. PMID：30580910）中指出的，需要基于合作努力的大型遗传研究来进一步阐明肌张力障碍的遗传原因。虽然一个大型的全基因组关联研究正在进行中，以确定风险因素（在吕贝克研究单位FOR 2488的框架内），在本提案中，我们将主要使用外显子组，但也对2000名肌张力障碍患者进行基因组和转录组测序，以解开这组致残疾病的其他单基因原因。经过严格的筛选程序，新的候选基因将进行功能表征，包括途径分析和使用各种细胞模型，如诱导多能干细胞（IPSC）衍生的神经元在选择的情况下。将对各突变携带者进行全面的随访表型分析，并收集家庭成员进行分离分析。这三位申请人联合收割机将肌张力障碍的临床、遗传和功能表征方面的专业知识与高通量、最新的遗传数据分析和解释相结合，将能够成功地进行拟议的项目。在两个不同的登记处/生物储存库（BMBF资助的DysTract联盟和NIH资助的肌张力障碍联盟内的德国肌张力障碍登记处）的框架内，收集了>5000名肌张力障碍患者的详细人口统计学和临床数据以及DNA样本。这些数据和样本将完全用于我们拟议的项目。在大多数样本中进行了遗传预筛选（排除已知的遗传因素）。值得注意的是，来自美国肌张力障碍联盟生物储存库的样本已经被运往吕贝克进行大规模的SNP基因分型，这强调了吕贝克作为世界领先的肌张力障碍遗传学中心的认可，该中心将成为该领域未来发现的中心。该项目将阐明肌张力障碍的新遗传原因，并为建立新的治疗策略铺平道路。

Dystonias are a rare, clinically and genetically highly heterogeneous group of movement disorder characterized by sustained or intermittent muscle contractions causing abnormal movements and/or postures. The symptoms have a major impact on quality of life. Currently, there is no cure, and treatment options are limited, in part because the molecular basis is poorly understood. The high heritability of about 25% suggests a considerable contribution of genetic factors in its etiology. Several monogenic forms, a few of which can be specifically treated, and genetic risk factors have been identified but the etiology in most patients remains elusive. As recently pointed out in an editorial (Gan-Or et al. PMID: 30580910), large genetic studies based on collaborative efforts are required to further elucidate the genetic causes of dystonia. While a large genome-wide association study is underway to identify risk factors (in the framework of the Research Unit FOR2488 in Lübeck), in the present proposal we will use mainly exome but also genome and transcriptome sequencing in 2000 dystonia patients to unravel additional monogenic causes of this disabling group of diseases. Following a stringent filtering procedure, novel candidate genes will be functionally characterized including pathway analyses and usage of various cell models such as induced pluripotent stem cell (IPSC)-derived neurons in select cases. Respective mutation carriers will undergo comprehensive, follow-up phenotyping and family members will be collected for segregation analyses. The three applicants combine expertise in clinical, genetic, and functional characterization of dystonia with high-throughput, up-to-date genetic data analyses and interpretation and will be able to successfully conduct the proposed project. Detailed demographic and clinical data as well as DNA samples have been collected for >5000 dystonia patients in the framework of two different registries/biorepositories (German Dystonia Registry within the BMBF-funded DysTract consortium and NIH-funded Dystonia Coalition). These data and samples will fully be available for our proposed project. Genetic prescreening (exclusion of known genetic factors) has been carried out in the majority of these samples. Of note, samples from the US-based Dystonia Coalition biorepository have already been shipped to Lübeck for large-scale, SNP genotyping which underscores the recognition of Lübeck as a world-leading center in the genetics of dystonia which will serve as a hub for future discoveries in the field. This project will elucidate novel genetic causes of dystonia and pave the road for the establishment of novel therapeutic strategies.