Human Molecular Genetics Advance Access originally published online on January 6, 2009
Human Molecular Genetics 2009 18(6):1052-1057; doi:10.1093/hmg/ddn440
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Dominant cataract formation in association with a vimentin assembly disrupting mutation
1 Institut für Biochemie und Molekularbiologie, Abteilung für Zellbiochemie und LIMES, Universität Bonn, Nussallee 11, 53115 Bonn, Germany 2 Department of Molecular Genetics, Institute of Ophthalmology, University College of London, London, UK 3 Department of Molecular Genetics, B065, German Cancer Research Center, 69120 Heidelberg, Germany
* To whom correspondence should be addressed. Tel: +49 228734444; Fax: +49 228734558; Email: t.magin{at}uni-bonn.de
Received November 19, 2008; Accepted December 22, 2008
Cataracts are characterized by an opacification of the eye lens, often caused by protein misfolding and aggregation. The intermediate filament protein vimentin, which is highly expressed in lens fiber cells and in mesenchymal tissues, is a main structural determinant in these cells forming a membrane-connected cytoskeleton. Additional functions of vimentin remain to be identified. Here, we demonstrate that a mutation in VIM causes a dominant, pulverulent cataract. We sequenced the complete human VIM gene in 90 individuals suffering from congenital cataract and found a G596A change in exon 1 in a single individual, causing the missense mutation E151K in coil 1B of vimentin. The mutant vimentin formed an aberrant vimentin cytoskeleton and increased the proteasome activity in transfected cells. Furthermore, this mutation causes a severe kinetic defect in vimentin assembly both in vitro and in vivo. Hence, in conjunction with available mouse and cell culture models, our results reveal for the first time an important functional role for vimentin in the maintenance of lens integrity. Finally, this invites novel therapy approaches for cataracts.