Cellular and Molecular Life Sciences

, Volume 73, Issue 16, pp 3205–3215 | Cite as

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

  • Aloysius Domingo
  • David Amar
  • Karen Grütz
  • Lillian V. Lee
  • Raymond Rosales
  • Norbert Brüggemann
  • Roland Dominic Jamora
  • Eva Cutiongco-dela Paz
  • Arndt Rolfs
  • Dirk Dressler
  • Uwe Walter
  • Dimitri Krainc
  • Katja Lohmann
  • Ron Shamir
  • Christine KleinEmail author
  • Ana Westenberger
Original Article


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.


Microarray Expression profiling Transcriptomics Transcriptional dysregulation Neurodegeneration 


Gene names


Acid repeat-containing gene


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


Basic helix-loop-helix family, member E40


Chemokine, CXC motif, receptor 3


Drebrin E


Dual-specificity phosphatase 1


Ephrin B1


ETS variant gene 3


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


GDNF-inducible zinc finger protein 1


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


Synaptotagmin-like 2


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


Gene ontology


Huntington’s disease


Multiple transcript system


Significance analysis of microarrays


X-linked dystonia-parkinsonism



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 material

18_2016_2159_MOESM1_ESM.pdf (99 kb)
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 (296 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 ( From top left, clockwise: transcript-level expression of SYTL2, SLC5A3, EFNB1, MRPS6, BHLHE40, KCND2, ATP6V0E2, TAF1. (PDF 296 kb)
18_2016_2159_MOESM3_ESM.xlsx (55 kb)
Supplementary material 3 (XLSX 55 kb)


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Copyright information

© Springer International Publishing 2016

Authors and Affiliations

  • Aloysius Domingo
    • 1
    • 2
  • David Amar
    • 3
  • Karen Grütz
    • 1
  • Lillian V. Lee
    • 4
  • Raymond Rosales
    • 5
  • Norbert Brüggemann
    • 1
    • 6
  • Roland Dominic Jamora
    • 7
  • Eva Cutiongco-dela Paz
    • 8
    • 9
  • Arndt Rolfs
    • 10
  • Dirk Dressler
    • 11
  • Uwe Walter
    • 12
  • Dimitri Krainc
    • 13
  • Katja Lohmann
    • 1
  • Ron Shamir
    • 3
  • Christine Klein
    • 1
    Email author
  • Ana Westenberger
    • 1
  1. 1.Institute of NeurogeneticsUniversity of LübeckLübeckGermany
  2. 2.Graduate School LübeckUniversity of LübeckLübeckGermany
  3. 3.Edmond J. Safra Center for BioinformaticsTel Aviv UniversityTel AvivIsrael
  4. 4.XDP Study GroupPhilippine Children’s Medical CenterQuezon CityPhilippines
  5. 5.Department of Neurology and PsychiatryUniversity of Santo TomasManilaPhilippines
  6. 6.Department of NeurologyUniversity Hospital Schleswig–Holstein, University of LübeckLübeckGermany
  7. 7.Department of Neurosciences, College of Medicine, Philippine General HospitalUniversity of the Philippines ManilaManilaPhilippines
  8. 8.National Institutes of HealthUniversity of the Philippines ManilaManilaPhilippines
  9. 9.Philippine Genome CenterUniversity of the PhilippinesQuezon CityPhilippines
  10. 10.Albrecht-Kossel-Institute for NeuroregenerationUniversity of RostockRostockGermany
  11. 11.Department of NeurologyHannover Medical SchoolHannoverGermany
  12. 12.Department of NeurologyUniversity of RostockRostockGermany
  13. 13.Northwestern University Feinberg School of MedicineChicagoUSA

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