Assembling the Genetic Architecture of X-Linked Dystonia-Parkinsonism

X-linked Dystonia-Parkinsonism (XDP, DYT3) is a long-standing quandary in human disease genetics. XDP is predominantly observed on Panay island in the Philippines. This study is one of the first of its kind to interrogate an unsolved Mendelian disorder by integrating genome and transcriptome assembly methods using Illumina, 10X Genomics, Pacific Biosciences, and Agilent genome targeting technologies. These data provide strong evidence for a pathogenic link between a noncoding SVA retrotransposon and XDP. We demonstrate that this Mendelian disorder is associated with a sine-VNTR-Alu (SVA) retrotransposon that inserted into the TAF1 gene and is shared by all XDP probands, yet never observed in controls from worldwide populations. Transcriptome assembly in iPSC-derived neural stem cells (NSCs) and neurons revealed that this SVA caused aberrant splicing and significant intron retention, which was negatively correlated with TAF1 expression. Remarkably, CRISPR/Cas9 excision of the SVA rescued the aberrant transcriptional signature and normalized expression of TAF1 in patient-derived NSCs. We have also interrogated iPSC-derived microglia to investigate the contribution of glial components to the cellular and molecular deficit, effect of TNF treatment on XDP transcriptional signatures. To further understand what XDP may have in common with other hereditary dystonias (such as DYT6), we are further comparing these signatures to ones associated with dystonia-specific variants in proteins that, like TAF1, are also involved in regulating transcription, i.e. THAP1. ]]>
Research subjects' phenotype data and samples were collected and shared for this work through the Dystonia Partners Research Bank (DPRB) protocol approved at Massachusetts General Hospital (PHRC protocol # 2011p-000110). People age 7 and above who have been diagnosed with dystonia or a related movement disorder and people related to (biologically or by-marriage) an individual who meets these criteria are eligible to enroll in the DPRB. For this work conducted under PHRC protocol # 2016p-000427, we required phenotype data and samples from subjects in families with a proband having a definitive diagnosis of XDP. All cases had movement disorder symptoms consistent with XDP on neurological examination and tested positive for the SVA insertion. Female carriers and female and male controls were identified among probands' family members. None of the controls had movement disorder symptoms on neurological examination and all tested negative for the SVA insertion. Samples from male subjects under age 18 with the SVA insertion and without abnormal movements consistent with XDP (pre-manifesting carriers) were excluded.]]>