X-linked dystonia-parkinsonism (XDP) is a severe neurodegenerative disorder caused by a founder retrotransposon insertion, in which a polymorphic hexanucleotide repeat accounts for ~50% of age at onset variability. Employing a genome-wide association study to identify additional factors modifying age at onset, we establish that three independent loci are significantly associated with age at onset. The lead single nucleotide polymorphisms collectively account for 13.0% of the overall variance in age at onset in XDP with the protective alleles delaying disease onset by seven years. These regions harbor or lie adjacent to MSH3 and PMS2, the genes that were recently implicated in modifying age at onset in Huntington’s disease, likely through a common pathway influencing repeat instability. Our work indicates the existence of three modifiers of age at onset in XDP that likely affect the DNA mismatch repair pathway. From a personalized medicine point of view, our findings may help prioritize patients for clinical trials and may even serve as a basis for gene- or modifier-targeted therapeutic approaches.
Read the article here (https://www.nature.com/articles/s41467-021-23491-4).
The study was supported by the Deutsche Forschungsgemeinschaft (DFG; FOR 2488) the Collaborative
Center for XDP (CCXDP) at Massachusetts General Hospital, the Else Kröner Fresenius Foundation, intramural funds from the University of Lübeck, and a career development award from the Hermann and Lilly Schilling Foundation. We thank the XDP patients and their relatives for their participation in this study.
The study was supported by the Deutsche Forschungsgemeinschaft (DFG; FOR 2488) the Collaborative
Center for XDP (CCXDP) at Massachusetts General Hospital, the Else Kröner Fresenius Foundation, intramural funds from the University of Lübeck, and a career development award from the Hermann and Lilly Schilling Foundation. We thank the XDP patients and their relatives for their participation in this study.