Elucidating novel genetic causes of dystonia by large-scale sequencing

• Applicants: Professor Dr. Hauke Busch; Professorin Dr. Christine Klein; Professorin Dr. Katja Lohmann
• Subject Area: Molecular and Cellular Neurology and Neuropathology ; Human Genetics ; Molecular Biology and Physiology of Neurons and Glial Cells
• Term: from 2020 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 433112024

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.

• DFG Programme: Research Grants
• Co-Investigator: Professor Dr. Tobias Bäumer