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First published online 21 October 2008
doi: 10.1242/jcs.030312

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A dominant vimentin mutant upregulates Hsp70 and the activity of the ubiquitin-proteasome system, and causes posterior cataracts in transgenic mice

Roland Bornheim^1,*,, Martin Müller^1,*, Uschi Reuter¹, Harald Herrmann², Heinrich Büssow³ and Thomas M. Magin^1,

¹ Institut für Biochemie and Molekularbiologie, Abteilung für Zellbiochemie und LIMES, Universität Bonn, Nussallee 11, 53115 Bonn, Germany
² Department of Molecular Genetics, B065, German Cancer Research Center, 69120 Heidelberg, Germany
³ Anatomisches Institut der Universität Bonn, Nussallee 10, 53115 Bonn, Germany

Author for correspondence (e-mail: t.magin{at}uni-bonn.de)

Accepted 8 August 2008

Vimentin is the main intermediate filament (IF) protein of mesenchymal cells and tissues. Unlike other IF^–/– mice, vimentin^–/– mice provided no evidence of an involvement of vimentin in the development of a specific disease. Therefore, we generated two transgenic mouse lines, one with a (R113C) point mutation in the IF-consensus motif in coil1A and one with the complete deletion of coil 2B of the rod domain. In epidermal keratins and desmin, point mutations in these parts of the -helical rod domain cause keratinopathies and desminopathies, respectively. Here, we demonstrate that substoichiometric amounts of vimentin carrying the R113C point mutation disrupted the endogenous vimentin network in all tissues examined but caused a disease phenotype only in the eye lens, leading to a posterior cataract that was paralleled by the formation of extensive protein aggregates in lens fibre cells. Unexpectedly, central, postmitotic fibres became depleted of aggregates, indicating that they were actively removed. In line with an increase in misfolded proteins, the amounts of Hsp70 and ubiquitylated vimentin were increased, and proteasome activity was raised. We demonstrate here for the first time that the expression of mutated vimentin induces a protein-stress response that contributes to disease pathology in mice, and hypothesise that vimentin mutations cause cataracts in humans.

Key words: Vimentin, Intermediate filaments, Dominant-negative mutation, Cataract formation, Protein misfolding, Chaperones, Proteasomes, Transgenic mice, Mouse model systems

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This article has been cited by other articles:

				M. Muller, S. S. Bhattacharya, T. Moore, Q. Prescott, T. Wedig, H. Herrmann, and T. M. Magin Dominant cataract formation in association with a vimentin assembly disrupting mutation Hum. Mol. Genet., March 15, 2009; 18(6): 1052 - 1057. [Abstract] [Full Text] [PDF]