title: Evidence of TAF1 dysfunction in peripheral models of X-linked dystonia-parkinsonism.
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.
authors.affiliation: Institute of Neurogenetics, University of Lübeck, Maria Goeppert Str. 1, 23562, Lübeck, Germany.|Graduate School Lübeck, University of Lübeck, Lübeck, Germany.
authors.forename: Aloysius
authors.identifier: 0000-0002-1396-3303
authors.initials: A
authors.lastname: Domingo
authors.affiliation: Edmond J. Safra Center for Bioinformatics, Tel Aviv University, Tel Aviv, Israel.
authors.forename: David
authors.initials: D
authors.lastname: Amar
authors.affiliation: Institute of Neurogenetics, University of Lübeck, Maria Goeppert Str. 1, 23562, Lübeck, Germany.
authors.forename: Karen
authors.initials: K
authors.lastname: Grütz
authors.affiliation: XDP Study Group, Philippine Children's Medical Center, Quezon City, Philippines.
authors.forename: Lillian V
authors.initials: LV
authors.lastname: Lee
authors.affiliation: Department of Neurology and Psychiatry, University of Santo Tomas, Manila, Philippines.
authors.forename: Raymond
authors.initials: R
authors.lastname: Rosales
authors.affiliation: Institute of Neurogenetics, University of Lübeck, Maria Goeppert Str. 1, 23562, Lübeck, Germany.|Department of Neurology, University Hospital Schleswig-Holstein, University of Lübeck, Lübeck, Germany.
authors.forename: Norbert
authors.initials: N
authors.lastname: Brüggemann
authors.affiliation: Department of Neurosciences, College of Medicine, Philippine General Hospital, University of the Philippines Manila, Manila, Philippines.
authors.forename: Roland Dominic
authors.initials: RD
authors.lastname: Jamora
authors.affiliation: National Institutes of Health, University of the Philippines Manila, Manila, Philippines.|Philippine Genome Center, University of the Philippines, Diliman, Quezon City, Philippines.
authors.forename: Eva
authors.initials: E
authors.lastname: Cutiongco-Dela Paz
authors.affiliation: Albrecht-Kossel-Institute for Neuroregeneration, University of Rostock, Rostock, Germany.
authors.forename: Arndt
authors.initials: A
authors.lastname: Rolfs
authors.affiliation: Department of Neurology, Hannover Medical School, Hannover, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Dressler
authors.affiliation: Department of Neurology, University of Rostock, Rostock, Germany.
authors.forename: Uwe
authors.initials: U
authors.lastname: Walter
authors.affiliation: Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: Dimitri
authors.initials: D
authors.lastname: Krainc
authors.affiliation: Institute of Neurogenetics, University of Lübeck, Maria Goeppert Str. 1, 23562, Lübeck, Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: Lohmann
authors.affiliation: Edmond J. Safra Center for Bioinformatics, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Ron
authors.initials: R
authors.lastname: Shamir
authors.affiliation: Institute of Neurogenetics, University of Lübeck, Maria Goeppert Str. 1, 23562, Lübeck, Germany. christine.klein@neuro.uni-luebeck.de.
authors.forename: Christine
authors.initials: C
authors.lastname: Klein
authors.affiliation: Institute of Neurogenetics, University of Lübeck, Maria Goeppert Str. 1, 23562, Lübeck, Germany.
authors.forename: Ana
authors.initials: A
authors.lastname: Westenberger
mesh_terms: D020821:Dystonic Disorders / Q000235:genetics*; D053263:Gene Regulatory Networks; D040181:Genetic Diseases, X-Linked / Q000235:genetics*; D051548:Histone Acetyltransferases / Q000235:genetics*; D006801:Humans; D008297:Male; D035381:TATA-Binding Protein Associated Factors / Q000235:genetics*; D035362:Transcription Factor TFIID / Q000235:genetics*; D015533:Transcriptional Activation; D059467:Transcriptome
chemical_list: D035381:TATA-Binding Protein Associated Factors; D035362:Transcription Factor TFIID; D051548:Histone Acetyltransferases; C069001:TATA-binding protein associated factor 250 kDa
keywords: Expression profiling; Microarray; Neurodegeneration; Transcriptional dysregulation; Transcriptomics