X-linked Dystonia-Parkinsonism (XDP), is a rare Mendelian disorder predominantly observed on Panay island in the Philippines. The clinical phenotype most frequently combines features of dystonia and parkinsonism in a characteristic temporal progression. A region of the X-chromosome was linked to the disorder, yet the pathogenic mechanism has remained elusive. We demonstrate that this disorder is associated with a sine-VNTR-Alu (SVA) retrotransposon insertion into the gene TAF1, which encodes for a key protein involved in gene regulation across the human genome. This insertion causes decrease in TAF1 expression. Remarkably, excision of the SVA in patient derived cell lines using CRISPR/CAS9 genome editing tools rescues this disease associated signature and corrects the expression of TAF1.
Figure 1: XDP-Associated Genomic Region and Experimental Design
(A) Genomic segment associated with XDP on Xq13.1 with seven variants reportedly shared among probands and not observed in controls: five single nucleotide variants, annotated as disease-specific single-nucleotide changes (DSCs)—1, 2, 3, 10, and 12; a SINE-VNTR-Alu (SVA) retrotransposon inserted antisense to TAF1; and a 48-bp deletion.
(B) Experimental workflow showing the number of XDP probands (black), carrier females (mixed), and controls (red), with the number of clones for each cell line.