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Human Molecular Genetics Advance Access published online on April 5, 2007
Human Molecular Genetics, doi:10.1093/hmg/ddm085
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© The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

The pathomechanism of filaminopathy: altered biochemical properties explain the cellular phenotype of a protein aggregation myopathy

Thomas Löwe1,{dagger}, Rudolf A. Kley2, Peter F.M. van der Ven1,3, Mirko Himmel1,{ddagger}, Angela Huebner4, Matthias Vorgerd2 and Dieter O. Fürst1,3,*

1 Department of Cell Biology, University of Potsdam, 14476 Potsdam-Golm, Germany 2 Department of Neurology, Neuromuscular Center Ruhrgebiet, Ruhr-University Bochum, 44789 Bochum, Germany 3 Department of Molecular Cell Biology, University of Bonn, 53121 Bonn, Germany 4 Children's Hospital, Technical University Dresden, 01307 Dresden, Germany

* Correspondence should be addressed to: Dieter O. Fürst, Department of Molecular Cell Biology, University of Bonn, Ulrich-Haberland-Str. 61a, 53121 Bonn, Germany. Phone: int+ 49228735301; Fax: int+ 49228735302; Email: zellbiologie{at}uni-bonn.de

Received December 19, 2006; Revised March 19, 2007; Accepted March 28, 2007

Myofibrillar myopathy (MFM) is a pathologically defined group of hereditary human muscle diseases, characterized by focal myofibrillar destruction and cytoplasmic aggregates that contain several Z-disk-related proteins. The previously reported MFM-associated mutation (8130G->A; W2710X) in the filamin C gene (FLNC) leads to a partial disturbance of the secondary structure of the dimerization domain of filamin C, resulting in massive protein aggregation in skeletal muscle fibers of the patients. Here we provide a thorough characterization of the biochemical, biophysical and cellular properties of the mutated filamin C polypeptide. Our experiments revealed that the mutant dimerization domain is less stable and more susceptible to proteolysis. As a consequence, it does not dimerize properly and forms aggregates in vitro. Furthermore, the expression of mutant filamin in cultured cells results in the formation of protein aggregates. The mutant filamin does not associate with wild type filamin. These findings are of great importance to explain the pathomechanism of this disease.

{dagger} Present address: Centre for Molecular Neurobiology (ZMNH), University of Hamburg, 20251 Hamburg, Germany

{ddagger} Present address: Interdisciplinary Centre for Clinical Research (IZKF), Cell Migration Group, 04103 Leipzig, Germany


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