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Transcriptional Alterations in X-Linked Dystonia–Parkinsonism Caused by the SVA Retrotransposon

Institute of Neurogenetics, University of Lübeck, 23538 Lübeck, Germany
Institute of Human Genetics, University of Lübeck, 23538 Lübeck, Germany
Department of Neurology, University Hospital Schleswig Holstein, 23538 Lübeck, Germany
The Hospital Neuroscience Institute, Department of Neurology and Psychiatry and The FMS-Research Center for Health Sciences, University of Santo Tomas, Manila 1008, Philippines
Department of Neurosciences, College of Medicine-Philippine General Hospital, University of the Philippines Manila, Manila 1000, Philippines
Department of Neurosciences, Movement Disorders Clinic, Makati Medical Center, Makati City 1229, Philippines
Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
Human Molecular Genomics Group, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany
DZHK (German Centre for Cardiovascular Research), Partner Site Hamburg/Lübeck/Kiel, 23538 Lübeck, Germany
Institut für Humangenetik, Universitätsklinikum Essen, Universität Duisburg-Essen, 45147 Essen, Germany
Essener Zentrum für Seltene Erkrankungen, Universitätsmedizin Essen, 45147 Essen, Germany
Authors to whom correspondence should be addressed.
Academic Editors: Amelia Casamassimi, Alfredo Ciccodicola and Monica Rienzo
Int. J. Mol. Sci. 2022, 23(4), 2231;
Received: 15 December 2021 / Revised: 9 February 2022 / Accepted: 14 February 2022 / Published: 17 February 2022
(This article belongs to the Special Issue Transcriptional Regulation and Its Misregulation in Human Diseases)
X-linked dystonia–parkinsonism (XDP) is a severe neurodegenerative disorder that manifests as adult-onset dystonia combined with parkinsonism. A SINE-VNTR-Alu (SVA) retrotransposon inserted in an intron of the TAF1 gene reduces its expression and alters splicing in XDP patient-derived cells. As a consequence, increased levels of the TAF1 intron retention transcript TAF1-32i can be found in XDP cells as compared to healthy controls. Here, we investigate the sequence of the deep intronic region included in this transcript and show that it is also present in cells from healthy individuals, albeit in lower amounts than in XDP cells, and that it undergoes degradation by nonsense-mediated mRNA decay. Furthermore, we investigate epigenetic marks (e.g., DNA methylation and histone modifications) present in this intronic region and the spanning sequence. Finally, we show that the SVA evinces regulatory potential, as demonstrated by its ability to repress the TAF1 promoter in vitro. Our results enable a better understanding of the disease mechanisms underlying XDP and transcriptional alterations caused by SVA retrotransposons. View Full-Text
Keywords: XDP; retrotransposon; SVA; splicing; epigenetics; transcription XDP; retrotransposon; SVA; splicing; epigenetics; transcription
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MDPI and ACS Style

Pozojevic, J.; Algodon, S.M.; Cruz, J.N.; Trinh, J.; Brüggemann, N.; Laß, J.; Grütz, K.; Schaake, S.; Tse, R.; Yumiceba, V.; Kruse, N.; Schulz, K.; Sreenivasan, V.K.A.; Rosales, R.L.; Jamora, R.D.G.; Diesta, C.C.E.; Matschke, J.; Glatzel, M.; Seibler, P.; Händler, K.; Rakovic, A.; Kirchner, H.; Spielmann, M.; Kaiser, F.J.; Klein, C.; Westenberger, A. Transcriptional Alterations in X-Linked Dystonia–Parkinsonism Caused by the SVA Retrotransposon. Int. J. Mol. Sci. 2022, 23, 2231.

AMA Style

Pozojevic J, Algodon SM, Cruz JN, Trinh J, Brüggemann N, Laß J, Grütz K, Schaake S, Tse R, Yumiceba V, Kruse N, Schulz K, Sreenivasan VKA, Rosales RL, Jamora RDG, Diesta CCE, Matschke J, Glatzel M, Seibler P, Händler K, Rakovic A, Kirchner H, Spielmann M, Kaiser FJ, Klein C, Westenberger A. Transcriptional Alterations in X-Linked Dystonia–Parkinsonism Caused by the SVA Retrotransposon. International Journal of Molecular Sciences. 2022; 23(4):2231.

Chicago/Turabian Style

Pozojevic, Jelena, Shela Marie Algodon, Joseph Neos Cruz, Joanne Trinh, Norbert Brüggemann, Joshua Laß, Karen Grütz, Susen Schaake, Ronnie Tse, Veronica Yumiceba, Nathalie Kruse, Kristin Schulz, Varun K. A. Sreenivasan, Raymond L. Rosales, Roland Dominic G. Jamora, Cid Czarina E. Diesta, Jakob Matschke, Markus Glatzel, Philip Seibler, Kristian Händler, Aleksandar Rakovic, Henriette Kirchner, Malte Spielmann, Frank J. Kaiser, Christine Klein, and Ana Westenberger. 2022. "Transcriptional Alterations in X-Linked Dystonia–Parkinsonism Caused by the SVA Retrotransposon" International Journal of Molecular Sciences 23, no. 4: 2231.

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