The molecular dysfunction in X-linked dystonia-parkinsonism is not completely understood. Thus far, only noncoding alterations have been found in genetic analyses, located in or nearby the TATA-box binding protein-associated factor 1 (TAF1) gene. Given that this gene is ubiquitously expressed and is a critical component of the cellular transcription machinery, we sought to study differential gene expression in peripheral models by performing microarray-based expression profiling in blood and fibroblasts, and comparing gene expression in affected individuals vs. ethnically matched controls. Validation was performed via quantitative polymerase chain reaction in discovery and independent replication sets. We observed consistent downregulation of common TAF1 transcripts in samples from affected individuals in gene-level and high-throughput experiments. This signal was accompanied by a downstream effect in the microarray, reflected by the dysregulation of 307 genes in the disease group. Gene Ontology and network analyses revealed enrichment of genes involved in RNA polymerase II-dependent transcription, a pathway relevant to TAF1 function. Thus, the results converge on TAF1 dysfunction in peripheral models of X-linked dystonia-parkinsonism, and provide evidence of altered expression of a canonical gene in this disease. Furthermore, our study illustrates a link between the previously described genetic alterations and TAF1 dysfunction at the transcriptome level.
Potassium voltage-gated channel, Shal-related subfamily, member 2
Mitochondrial ribosomal protein S6
O-linked N-acetylglucosamine transferase
PR-domain containing protein 1
Solute carrier family 5 (inositol transporter), member 3
Serum response factor
TATA-box binding protein-associated factor 1
TATA-box binding protein
Zinc alcohol dehydrogenase
Zinc finger CCCH domain-containing protein 12A
Differentially expressed gene
Disease-specific single-nucleotide change
Multiple transcript system
Significance analysis of microarrays
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This research was funded by a Thyssen Foundation research grant, and by a Jake’s Ride for Dystonia research grant (through the Bachmann-Strauss Dystonia and Parkinson Foundation) to Ana Westenberger. Aloysius Domingo is supported by the German Academic Exchange Service (DAAD). David Amar is supported by the Azrieli Foundation and the Edmond J. Safra Center for Bioinformatics at Tel Aviv University. Ron Shamir is supported by the Raymond and Beverly Sackler Chair in Bioinformatics. Christine Klein is supported by the Hermann and Lilly Schilling Foundation.
Compliance with ethical standards
Conflict of interest
Authors report no potential conflicts of interest.
Supplementary Fig. 1. Study workflow showing the high-throughput (microarray-based, left-side) and gene-level (qPCR-based, right-side) experiments and analyses. One lane on the microarray had a defect that was undetected during hybridization but was later made obvious by quality control assessments. The blood-derived sample from an affected individual was not included in further analyses. (PDF 98 kb)
Supplementary Fig. 2. Expression in various parts of the brain of the different genes chosen for follow-up. Data is derived from the UK Brain Expression Consortium (http://www.braineac.org/). From top left, clockwise: transcript-level expression of SYTL2, SLC5A3, EFNB1, MRPS6, BHLHE40, KCND2, ATP6V0E2, TAF1. (PDF 296 kb)
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