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

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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.

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Abbreviations

ACRC :

Acid repeat-containing gene

ATP6V0E2 :

ATPase, H+ transporting, lysosomal, 9-kD, V0 subunit E2

BHLHE40 :

Basic helix-loop-helix family, member E40

CXCR3 :

Chemokine, CXC motif, receptor 3

DBN1 :

Drebrin E

DUSP1 :

Dual-specificity phosphatase 1

EFNB1 :

Ephrin B1

ETV3 :

ETS variant gene 3

GRIN2D :

Glutamate receptor, ionotropic, N-methyl-d-aspartate, subunit 2D

GZF1 :

GDNF-inducible zinc finger protein 1

KCND2 :

Potassium voltage-gated channel, Shal-related subfamily, member 2

MRPS6 :

Mitochondrial ribosomal protein S6

OGT :

O-linked N-acetylglucosamine transferase

PRDM1 :

PR-domain containing protein 1

SLC5A3 :

Solute carrier family 5 (inositol transporter), member 3

SRF :

Serum response factor

SYTL2 :

Synaptotagmin-like 2

TAF1 :

TATA-box binding protein-associated factor 1

TBP :

TATA-box binding protein

ZADH2 :

Zinc alcohol dehydrogenase

ZC3H12A :

Zinc finger CCCH domain-containing protein 12A

DEG:

Differentially expressed gene

DSC:

Disease-specific single-nucleotide change

GO:

Gene ontology

HD:

Huntington’s disease

MTS:

Multiple transcript system

SAM:

Significance analysis of microarrays

XDP:

X-linked dystonia-parkinsonism

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Acknowledgments

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.

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18_2016_2159_MOESM1_ESM.pdf

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)

18_2016_2159_MOESM2_ESM.pdf

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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Domingo, A., Amar, D., Grütz, K. et al. Evidence of TAF1 dysfunction in peripheral models of X-linked dystonia-parkinsonism. Cell. Mol. Life Sci. 73, 3205–3215 (2016). https://doi.org/10.1007/s00018-016-2159-4

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