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Cell Mol Life Sci. 2016 Aug;73(16):3205-15. doi: 10.1007/s00018-016-2159-4. Epub 2016 Feb 15.

Evidence of TAF1 dysfunction in peripheral models of X-linked dystonia-parkinsonism.

Author information

1
Institute of Neurogenetics, University of Lübeck, Maria Goeppert Str. 1, 23562, Lübeck, Germany.
2
Graduate School Lübeck, University of Lübeck, Lübeck, Germany.
3
Edmond J. Safra Center for Bioinformatics, Tel Aviv University, Tel Aviv, Israel.
4
XDP Study Group, Philippine Children's Medical Center, Quezon City, Philippines.
5
Department of Neurology and Psychiatry, University of Santo Tomas, Manila, Philippines.
6
Department of Neurology, University Hospital Schleswig-Holstein, University of Lübeck, Lübeck, Germany.
7
Department of Neurosciences, College of Medicine, Philippine General Hospital, University of the Philippines Manila, Manila, Philippines.
8
National Institutes of Health, University of the Philippines Manila, Manila, Philippines.
9
Philippine Genome Center, University of the Philippines, Diliman, Quezon City, Philippines.
10
Albrecht-Kossel-Institute for Neuroregeneration, University of Rostock, Rostock, Germany.
11
Department of Neurology, Hannover Medical School, Hannover, Germany.
12
Department of Neurology, University of Rostock, Rostock, Germany.
13
Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
14
Institute of Neurogenetics, University of Lübeck, Maria Goeppert Str. 1, 23562, Lübeck, Germany. christine.klein@neuro.uni-luebeck.de.

Abstract

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.

KEYWORDS:

Expression profiling; Microarray; Neurodegeneration; Transcriptional dysregulation; Transcriptomics

PMID:
26879577
DOI:
10.1007/s00018-016-2159-4
[Indexed for MEDLINE]

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