Project Details
Projekt
Mechanisms of penetrance and expressivity in X-linked dystonia-parkinsonism
Subject Area
Molecular and Cellular Neurology and Neuropathology
Term
since 2016
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 287074911
X-linked dystonia-parkinsonism (XDP, DYT-TAF1) is a severe neurodegenerative disorder caused in all patients by a founder pathogenic variant on the X chromosome, i.e., a ~2,6-kb SINE-VNTR- Alu retrotransposon (SVAR) insertion in intron 32 of TAF1 (gene encoding TBP-associated factor 1). Despite this seemingly identical genetic cause and environmental and genetic isolation (all patients are Filipino and the majority of them live on an island in the Philippines), the affected individuals display wide variability in the severity and type of signs/symptoms as well as in age and site of disease onset. Therefore, the hypothesis of our initial application (P5 project – first funding period) was that the phenotypic variability seen in XDP is modified by the action of genetic factors influencing disease expression, and our overarching goal was to identify those factors. Indeed, using a genome-wide association study (GWAS) approach, in the initial three years of our project, we discovered three such candidate modifiers that likely act by regulating expression levels of the MSH3 and PMS2 genes. Additional functional characterization and the exact mode of action of the genetic factors identified in the initial P5 will be further investigated in the P9 of the second funding period together with the penetrance modifiers uncovered by other GWASs performed in the first funding period.In addition, using a hypothesis-driven approach, we have shown that the length of a polymorphic (CCCTCT)n repeat within the XDP-causing SVAR insertion seems to inversely correlate with age at onset and severity of symptoms of XDP in patients. This finding placed XDP among other neurological repeat-expansion disorders and contrived a plethora of plausible scenarios and questions regarding the mechanism of action of this hexanucleotide repeat. Therefore, we postulate that several repeat-expansion-related pathogenic mechanisms, TAF1 expression dysregulation, or other factors, acting upstream from the hexanucleotide repeats may contribute to the phenotypic variability in XDP. To address our hypothesis, we will investigate i) the role of RNA foci and repeat-associated non-ATG (RAN) translation peptides (toxic species featured in numerous repeat-expansion diseases) (Objective 1) and ii) SVAR insertion-mediated alteration of TAF1 expression (through changes in transcription-relevant regulatory elements, protein binding, or epigenetic status) (Objective 2) in neuronal overexpression and patient-derived endogenous cellular XDP models. Importantly, although this project seemingly targets a specific movement disorder occurring in a specific (and relatively small worldwide) patient population, it has a far larger global significance given that it investigates mechanisms that are fundamental for the pathogenesis, disease modification, and potential therapeutic treatment of numerous other neurological (repeat-expansion) conditions.
DFG Programme
Research Units
