Genetic modifiers of disease expression in X-linked dystonia-parkinsonism

• Applicants: Professor Dr. Lars Bertram; Dr. Ana Westenberger
• Subject Area: Molecular and Cellular Neurology and Neuropathology ; Molecular Biology and Physiology of Neurons and Glial Cells
• Term: from 2016 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 289285036

An important unresolved issue in inherited forms of dystonia, as in other neurogenetic disorders, is the difficulty to predict the disease course in individual patients. Elucidating the underlying factors of the variability in disease expression has a high imperative and translational potential. However, such studies are currently rare and generally hampered by small sample sizes, private mutations with different potential effects, and variable genetic and environmental background. Moreover, these studies are usually performed in a multicenter setting, thereby increasing variability in assessing phenotypes. The present proposal aims to elucidate the mechanisms explaining clinical variability in a genetic form of dystonia, i.e. X-linked dystonia-parkinsonism (XDP, DYT3). XDP is inherited in an X-linked recessive fashion with the causative genetic change being highly penetrant and, due to a founder mutation, specific to the Filipino population. The clinical presentation of XDP, characterized by the presence of two overlapping phenotypes (dystonia and parkinsonism), shows an extraordinary additional variability in the severity of signs as well as in age and site of disease onset. Interestingly, due to the fact that all of the patients carry exactly the same disease-causing change and most live in a similar environment on a genetically and geographically isolated island, they represent "one extended family", thereby providing a unique model system for studying genetic modifiers of disease expression. The goal of the present proposal is to identify genetic factors that modify the age of XDP onset, symptoms at onset, initial region affected by dystonia, initial parkinsonian symptom, and the time until dystonia generalizes. Within the framework of a German-Filipino collaboration, the applicants collected/will collect DNA samples from ~800 carefully phenotyped patients with a confirmed molecular diagnosis of XDP who will be included in a genome-wide association study (GWAS) (Objective 1). As natural extension of the first objective, in Objective 2, the applicants will perform in-depth and multipronged in-silico and in-vitro functional follow-up analyses of the most compelling results. These subsequent analyses will include: i) selecting and ranking the SNPs showing the highest association, ii) fine-mapping of confirmed XDP modifying variants iii) in-silico modeling for potential effects on gene / protein expression or protein function of noncoding or nonsynonymous candidate variants, respectively, and iv) experimental validation of predicted functional effects emerging from the in-silico modeling. With this approach, important clues on modifiers of gene expression will likely be derived from XDP, possibly impacting also on other forms of dystonia and parkinsonism.

• DFG Programme: Research Grants