Overexpression of human wildtype torsinA and human ΔGAG torsinA in a transgenic mouse model causes phenotypic abnormalities

Primary torsion dystonia is an autosomal-dominant inherited movement disorder. Most cases are caused by an in-frame deletion (GAG) of the DYT1 gene encoding torsinA. Reduced penetrance and phenotypic variability suggest that alteration of torsinA amino acid sequence is necessary but not sufficient f...

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Main Authors:	K. Grundmann, B. Reischmann, G. Vanhoutte, J. Hübener, P. Teismann, T.-K. Hauser, M. Bonin, J. Wilbertz, S. Horn, H.P. Nguyen, M. Kuhn, S. Chanarat, H. Wolburg, A. Van der Linden, O. Riess
Format:	Article
Language:	English
Published:	Elsevier 2007-08-01
Series:	Neurobiology of Disease
Subjects:	Primary torsion dystonia TorsinA DYT1 Transgenic mouse model Nuclear envelope DTI-MRI
Online Access:	http://www.sciencedirect.com/science/article/pii/S0969996107000885

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spelling	doaj-cf06dd31d4e94c3cb46c3c2c05e351842021-03-20T04:54:34ZengElsevierNeurobiology of Disease1095-953X2007-08-01272190206Overexpression of human wildtype torsinA and human ΔGAG torsinA in a transgenic mouse model causes phenotypic abnormalitiesK. Grundmann0B. Reischmann1G. Vanhoutte2J. Hübener3P. Teismann4T.-K. Hauser5M. Bonin6J. Wilbertz7S. Horn8H.P. Nguyen9M. Kuhn10S. Chanarat11H. Wolburg12A. Van der Linden13O. Riess14Department of Medical Genetics, University of Tuebingen, Calwerstr. 7, 72076 Tuebingen, Germany; Corresponding author. Fax: +497071 29 5228.Department of Medical Genetics, University of Tuebingen, Calwerstr. 7, 72076 Tuebingen, GermanyBio-Imaging Laboratory, Department of Biomedical Sciences, University of Antwerp, Campus Middelheim, Groenenborgerlaan 171, 2020 Antwerp, BelgiumDepartment of Medical Genetics, University of Tuebingen, Calwerstr. 7, 72076 Tuebingen, GermanySchool of Medical Sciences College of Life Sciences and Medicine University of Aberdeen Institute of Medical Sciences Foresterhill Aberdeen AB25 2ZD, Scotland, UKDepartment of Neuroradiology, University of Tuebingen, Hoppe-Seyler-Str.3 7, 72076 Tuebingen, GermanyDepartment of Medical Genetics, University of Tuebingen, Calwerstr. 7, 72076 Tuebingen, GermanyKarolinska Institutet, Nobels väg 5, Solna, Stockholm, SwedenHertie-Institute for Clinical Brain Research, Center for Neurology, University of Tuebingen, Ottfried-Mueller-Str 27, 72076 Tuebingen, GermanyDepartment of Medical Genetics, University of Tuebingen, Calwerstr. 7, 72076 Tuebingen, GermanyDepartment of Medical Genetics, University of Tuebingen, Calwerstr. 7, 72076 Tuebingen, GermanyDepartment of Medical Genetics, University of Tuebingen, Calwerstr. 7, 72076 Tuebingen, GermanyInstitute for Pathology, University of Tubingen, Liebermeisterstrasse 8, 72076, Tuebingen, GermanyBio-Imaging Laboratory, Department of Biomedical Sciences, University of Antwerp, Campus Middelheim, Groenenborgerlaan 171, 2020 Antwerp, BelgiumDepartment of Medical Genetics, University of Tuebingen, Calwerstr. 7, 72076 Tuebingen, GermanyPrimary torsion dystonia is an autosomal-dominant inherited movement disorder. Most cases are caused by an in-frame deletion (GAG) of the DYT1 gene encoding torsinA. Reduced penetrance and phenotypic variability suggest that alteration of torsinA amino acid sequence is necessary but not sufficient for development of clinical symptoms and that additional factors must contribute to the factual manifestation of the disease. We generated 4 independent transgenic mouse lines, two overexpressing human mutant torsinA and two overexpressing human wildtype torsinA using a strong murine prion protein promoter. Our data provide for the first time in vivo evidence that not only mutant torsinA is detrimental to neuronal cells but that also wildtype torsinA can lead to neuronal dysfunction when overexpressed at high levels. This hypothesis is supported by (i) neuropathological findings, (ii) neurochemistry, (iii) behavioral abnormalities and (iv) DTI-MRI analysis.http://www.sciencedirect.com/science/article/pii/S0969996107000885Primary torsion dystoniaTorsinADYT1Transgenic mouse modelNuclear envelopeDTI-MRI
collection	DOAJ
language	English
format	Article
sources	DOAJ
author	K. Grundmann B. Reischmann G. Vanhoutte J. Hübener P. Teismann T.-K. Hauser M. Bonin J. Wilbertz S. Horn H.P. Nguyen M. Kuhn S. Chanarat H. Wolburg A. Van der Linden O. Riess
spellingShingle	K. Grundmann B. Reischmann G. Vanhoutte J. Hübener P. Teismann T.-K. Hauser M. Bonin J. Wilbertz S. Horn H.P. Nguyen M. Kuhn S. Chanarat H. Wolburg A. Van der Linden O. Riess Overexpression of human wildtype torsinA and human ΔGAG torsinA in a transgenic mouse model causes phenotypic abnormalities Neurobiology of Disease Primary torsion dystonia TorsinA DYT1 Transgenic mouse model Nuclear envelope DTI-MRI
author_facet	K. Grundmann B. Reischmann G. Vanhoutte J. Hübener P. Teismann T.-K. Hauser M. Bonin J. Wilbertz S. Horn H.P. Nguyen M. Kuhn S. Chanarat H. Wolburg A. Van der Linden O. Riess
author_sort	K. Grundmann
title	Overexpression of human wildtype torsinA and human ΔGAG torsinA in a transgenic mouse model causes phenotypic abnormalities
title_short	Overexpression of human wildtype torsinA and human ΔGAG torsinA in a transgenic mouse model causes phenotypic abnormalities
title_full	Overexpression of human wildtype torsinA and human ΔGAG torsinA in a transgenic mouse model causes phenotypic abnormalities
title_fullStr	Overexpression of human wildtype torsinA and human ΔGAG torsinA in a transgenic mouse model causes phenotypic abnormalities
title_full_unstemmed	Overexpression of human wildtype torsinA and human ΔGAG torsinA in a transgenic mouse model causes phenotypic abnormalities
title_sort	overexpression of human wildtype torsina and human δgag torsina in a transgenic mouse model causes phenotypic abnormalities
publisher	Elsevier
series	Neurobiology of Disease
issn	1095-953X
publishDate	2007-08-01
description	Primary torsion dystonia is an autosomal-dominant inherited movement disorder. Most cases are caused by an in-frame deletion (GAG) of the DYT1 gene encoding torsinA. Reduced penetrance and phenotypic variability suggest that alteration of torsinA amino acid sequence is necessary but not sufficient for development of clinical symptoms and that additional factors must contribute to the factual manifestation of the disease. We generated 4 independent transgenic mouse lines, two overexpressing human mutant torsinA and two overexpressing human wildtype torsinA using a strong murine prion protein promoter. Our data provide for the first time in vivo evidence that not only mutant torsinA is detrimental to neuronal cells but that also wildtype torsinA can lead to neuronal dysfunction when overexpressed at high levels. This hypothesis is supported by (i) neuropathological findings, (ii) neurochemistry, (iii) behavioral abnormalities and (iv) DTI-MRI analysis.
topic	Primary torsion dystonia TorsinA DYT1 Transgenic mouse model Nuclear envelope DTI-MRI
url	http://www.sciencedirect.com/science/article/pii/S0969996107000885
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Overexpression of human wildtype torsinA and human ΔGAG torsinA in a transgenic mouse model causes phenotypic abnormalities

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