X-linked Dystonia-Parkinsonism (XDP) is a unique X-linked neurodegenerative disorder that is fully penetrant and lethal. The disorder is indigenous to the Philippines and represents a type of familial scourge, particularly on the Island of Panay. The onset of XDP occurs in males around the age 40 years and symptoms are temporally separated by dystonic and Parkinsonian phenotypes. While the causal haplotype was linked to a segment of the X-chromosome in a series of studies over 25 years ago, the causal variant and pathogenic mechanism was unknown. Talkowski Lab developed novel assembly-based functional genomics methods, integrated with induced-pluripotent stem cell (iPSC) derived neuronal models to explore the genomes and in vitro transcriptomes of XDP patients. These studies discovered the causal variant in XDP to be a novel noncoding sine-VNTR-alu (SVA) retrotransposition that inserted into intron 32 of TAF1, a critical gene involved in the TIID transcriptional complex. Transcriptome assembly revealed that this SVA resulted in aberrant splicing of exon 32-33 and anomalous intron retention (IR), with concomitant reduction of TAF1 expression. Remarkably, we were able to ameliorate this deficit by excising the SVA using CRISPR/Cas9 (Aneichyk et al., 2018, Cell). In a related study in my Co-Mentor Dr. Ozelius’s lab, we discovered that the hexameric repeat (CCCTCT)n of the SVA was unstable, and that the size of this repeat was strongly correlated with age-of-onset (AOO) of the disorder, reminiscent of the trinucleotide repeat expansion in Huntington’s disease (Bragg et al., 2017, PNAS). Thus, our collaborative team has likely solved the question of the causal variant in XDP, and is currently exploring the critical questions of functional mechanism, in vivo alterations in the XDP brain, and the potential for precision therapeutics. We expand this research endeavor to interrogate the in vivo molecular characteristics of XDP, including the hexameric repeat expansion and transcriptional changes associated with XDP using our recently established XDP post-mortem brain tissue collection in the Philippines. In collaboration with the industrial partner, we are also screening an anti-sense oligonucleotide (ASO) library to rescue the aberrant splicing observed in XDP.
Aneichyk, Hendriks, Yadav, Shin, Gao, et al. Cell 2019