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Human Molecular Genetics Advance Access originally published online on March 30, 2005
Human Molecular Genetics 2005 14(10):1251-1260; doi:10.1093/hmg/ddi136
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© The Author 2005. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oupjournals.org

Pathogenic effects of a novel heterozygous R350P desmin mutation on the assembly of desmin intermediate filaments in vivo and in vitro

Harald Bär1,2, Dirk Fischer3,4, Bertrand Goudeau3, Rudolf A. Kley5, Christoph S. Clemen4,6, Patrick Vicart3, Harald Herrmann1, Matthias Vorgerd5 and Rolf Schröder4,6,*

1Department of Cell Biology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany, 2Department of Cardiology, University of Heidelberg, 69120 Heidelberg, Germany, 3Laboratoire Cytosquelette et Développement, Faculté de Médecine Pitié-Salpêtrière, Paris, France, 4Department of Neurology, University Hospital Bonn, 53105 Bonn, Germany, 5Department of Neurology, Klinikum Bergmannsheil, 44789 Bochum, Germany and 6Center for Biochemistry I, Medical Faculty, University of Cologne, 50931 Cologne, Germany

* To whom correspondence should be addressed at: Department of Neurology, University Hospital Bonn, Sigmund-Freud-Strasse 25, 53105 Bonn, Germany. Tel: +49 2282876805; Fax: +49 2282875042; Email: rolf.schroeder{at}ukb.uni-bonn.de

Received January 19, 2005; Accepted March 21, 2005

Mutations of the human desmin gene on chromosome 2q35 cause a familial or sporadic form of skeletal myopathy frequently associated with cardiac abnormalities. Here, we report the pathogenic effects of a novel heterozygous R350P desmin missense mutation, which resides in the evolutionary highly conserved coil 2B domain of the {alpha}-helical coiled-coil desmin rod domain, on the assembly of desmin intermediate filaments (IF) in cultured cells and in vitro. By transfection experiments, we show that R350P desmin is incapable of de novo formation of a desmin IF network in vimentin-free BMGE+H, MCF7 and SW13 cells and that it disrupts the endogenous vimentin cytoskeleton in 3T3 fibroblast cells. Hence, transfected cells displayed abnormal cytoplasmic protein aggregates reminiscent of desmin-positive protein deposits seen in the immunohistochemical and ultrastructural analysis of skeletal muscle derived from the index patient of the affected family. To study the functional effects of the R350P desmin mutation at the protein level, we performed in vitro assembly studies with wild-type (WT) and mutant desmin protein. Our analysis revealed that the in vitro assembly process of R350P desmin is already disturbed at the unit length filament level and that further association reactions generate huge, tightly packed protein aggregates. On assessing the pathogenic effects of R350P desmin in various mixtures with WT desmin, we show that a ratio of 1 : 3 (R350P desmin/WT desmin) is sufficient to effectively block the normal polymerization process of desmin IFs. Our findings indicate that the heterozygous R350P desmin mutation exerts a dominant negative effect on the ordered lateral arrangement of desmin subunits. This disturbance of the lateral packing taking place in the first phase of assembly is ultimately leading to abnormal protein aggregation.


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