Reference : Unraveling Molecular Mechanisms of THAP1 Missense Mutations in DYT6 Dystonia
Scientific journals : Article
Life sciences : Biochemistry, biophysics & molecular biology
Systems Biomedicine
http://hdl.handle.net/10993/43879
Unraveling Molecular Mechanisms of THAP1 Missense Mutations in DYT6 Dystonia
English
Krüger, Rejko mailto [University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit >]
Cheng, Fubo [Institute of Medical Genetics and Applied Genomics, University Hospital of Tuebingen]
Walter, Michael [Institute of Medical Genetics and Applied Genomics, University Hospital of Tuebingen]
Riess, Olaf [Institute of Medical Genetics and Applied Genomics, University Hospital of Tuebingen]
Wassouf, Zinah [Institute of Medical Genetics and Applied Genomics, University Hospital of Tuebingen]
Hentrich, Thomas [Institute of Medical Genetics and Applied Genomics, University Hospital of Tuebingen]
Schulze-Hentrich, Julia [Institute of Medical Genetics and Applied Genomics, University Hospital of Tuebingen]
Barbuti, Peter mailto [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > >]
Grundmann-Hauser, Kathrin [Institute of Medical Genetics and Applied Genomics, University Hospital of Tuebingen]
Ott, Thomas [Institute of Medical Genetics and Applied Genomics, University Hospital of Tuebingen]
Casadei, Nicolas [DFG NGS Competence Center Tuebingen (NCCT), University Hospital of Tuebingen]
Jan-2020
Journal of Molecular Neuroscience
Humana Press
Yes (verified by ORBilu)
International
0895-8696
1559-1166
Totowa
NJ
[en] DYT6 dystonia ; THAP1 ; Missense mutation ; Microarray analysis ; Synaptic function ; Protein stability
[en] Mutations in THAP1 (THAP domain-containing apoptosis-associated protein 1) are responsible for DYT6 dystonia. Until now, more than eighty differentmutations in THAP1 gene have been found in patientswith primary dystonia, and two third of them are missense mutations. The potential pathogeneses of these missense mutations in human are largely elusive. In the present study,
we generated stable transfected human neuronal cell lines expressing wild-type or mutated THAP1 proteins found in DYT6 patients. Transcriptional profiling using microarrays revealed a set of 28 common genes dysregulated in two mutated THAP1 (S21T and F81L) overexpression cell lines suggesting a common mechanism of these mutations. ChIP-seq showed that THAP1
can bind to the promoter of one of these genes, superoxide dismutase 2 (SOD2). Overexpression of THAP1 in SK-N-AS cells resulted in increased SOD2 protein expression, whereas fibroblasts from THAP1 patients have less SOD2 expression, which indicates that SOD2 is a direct target gene of THAP1. In addition, we show that some THAP1 mutations (C54Y and F81L) decrease the protein stability which might also be responsible for altered transcription regulation due to dosage insufficiency.
Taking together, the current study showed different potential pathogenic mechanisms of THAP1 mutations which lead to the same consequence of DYT6 dystonia.
Fortune junior grant, University of Tuebingen
http://hdl.handle.net/10993/43879
10.1007/s12031-020-01490-2
https://link.springer.com/article/10.1007/s12031-020-01490-2#Abs1
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