Biochemical and Cellular Analysis of Human Variants of the DYT1 Dystonia Protein,TorsinA/TOR1A |
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| Authors: | Osmar Norberto de Souza Luís Fernando Saraiva Macedo Timmers Shelun Tsai Nadia A. Atai Cintia C. da Hora Xuan Zhang Rashmi Kothary Erik Snapp Maria Ericsson Kathrin Grundmann Xandra O. Breakefield Flávia C. Nery |
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| Affiliation: | 1. Laboratory of Bioinformatics, Modeling and Simulation of Biosystems‐LABIO, Pontifical Catholic University of Rio Grande do Sul, Porto Alegre, Brazil;2. Molecular Neurogenetics Unit, Department of Neurology and Center for Molecular Imaging Research, Department of Radiology, Massachusetts General Hospital and Program in Neuroscience, Harvard Medical School, Boston, Massachusetts;3. Department of Cell Biology and Histology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands;4. Ottawa Hospital Research Institute and the University of Ottawa, Ottawa, Ontario, Canada;5. Department of Anatomy and Structural Biology, Albert Einstein College of Medicine of Yeshiva University, New York, New York;6. Department of Cell Biology, Harvard Medical School, Boston, Massachusetts;7. Department of Medical Genetics and Applied Genomics, University of Tuebingen, Tübingen, Germany |
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| Abstract: | Early‐onset dystonia is associated with the deletion of one of a pair of glutamic acid residues (c.904_906delGAG/c.907_909delGAG; p.Glu302del/Glu303del; ΔE 302/303) near the carboxyl‐terminus of torsinA, a member of the AAA+ protein family that localizes to the endoplasmic reticulum lumen and nuclear envelope. This deletion commonly underlies early‐onset DYT1 dystonia. While the role of the disease‐causing mutation, torsinAΔE, has been established through genetic association studies, it is much less clear whether other rare human variants of torsinA are pathogenic. Two missense variations have been described in single patients: R288Q (c.863G>A; p.Arg288Gln; R288Q) identified in a patient with onset of severe generalized dystonia and myoclonus since infancy and F205I (c.613T>A, p.Phe205Ile; F205I) in a psychiatric patient with late‐onset focal dystonia. In this study, we have undertaken a series of analyses comparing the biochemical and cellular effects of these rare variants to torsinAΔE and wild‐type (wt) torsinA to reveal whether there are common dysfunctional features. The results revealed that the variants, R288Q and F205I, are more similar in their properties to torsinAΔE protein than to torsinAwt. These findings provide functional evidence for the potential pathogenic nature of these rare sequence variants in the TOR1A gene, thus implicating these pathologies in the development of dystonia. |
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| Keywords: | torsinA TOR1A dystonia DYT1 endoplasmic reticulum protein secretion ER stress |
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