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Human Molecular Genetics, 2003, Vol. 12, No. 6 657-669
© 2003 Oxford University Press

On noxious desmin: functional effects of a novel heterozygous desmin insertion mutation on the extrasarcomeric desmin cytoskeleton and mitochondria

Rolf Schröder1,*,{dagger}, Bertrand Goudeau2,{dagger}, Monique Casteras Simon2, Dirk Fischer1, Thomas Eggermann3, Christoph S. Clemen4, Zhenlin Li5, Jens Reimann1, Zhigang Xue5, Sabine Rudnik-Schöneborn3, Klaus Zerres3, Peter F. M. van der Ven6, Dieter O. Fürst6, Wolfram S. Kunz7 and Patrick Vicart2

1Department of Neurology, University Hospital Bonn, Sigmund-Freud-Str. 25, 53105 Bonn, Germany, 2Laboratoire Cytosquelette et Développement, Faculté de Médecine Pitié-Salpêtrière, Paris, France, 3Institute of Human Genetics, RWTH Aachen, 52057 Aachen, Germany, 4Center for Biochemistry I, Medical Faculty, University of Cologne, 50931 Cologne, Germany, 5Biologie Moléculaire de la Différenciation, Université Paris 7, France, 6Department of Cell Biology, University of Potsdam, 14471 Potsdam, Germany and 7Department of Epileptology, University Hospital Bonn, 53105 Bonn, Germany

Received November 15, 2002; Revised December 20, 2002; Accepted January 9, 2003

Recent studies in desmin (-/-) mice have shown that the targeted ablation of desmin leads to pathological changes of the extrasarcomeric intermediate filament cytoskeleton, as well as structural and functional abnormalities of mitochondria in striated muscle. Here, we report on a novel heterozygous single adenine insertion mutation (c.5141_5143insA) in a 40-year-old patient with a distal myopathy. The insertion mutation leads to a frameshift and a truncated desmin (K239fs242). Using transfection studies in SW13 and BHK21 cells, we show that the K239fsX242 desmin mutant is incapable of forming a desmin intermediate filament network. Furthermore, it induces the collapse of a pre-existing desmin cytoskeleton, alters the subcellular distribution of mitochondria and leads to abnormal cytoplasmic protein aggregates reminiscent of desmin-immunoreactive granulofilamentous material seen in the ultrastructural analysis of the patient's muscle. Analysis of mitochondrial function in isolated saponin-permeablized skeletal muscle fibres from our patient showed decreased maximal rates of respiration with the NAD-dependent substrate combination glutamate and malate, as well as a higher amytal sensitivity of respiration, indicating an in vivo inhibition of complex I activity. Our findings suggest that the heterozygous K239fsX242 desmin insertion mutation has a dominant negative effect on the polymerization process of desmin intermediate filaments and affects not only the subcellular distribution, but also biochemical properties of mitochondria in diseased human skeletal muscle. As a consequence, the intermediate filament pathology-induced mitochondrial dysfunction may contribute to the degeneration/regeneration process leading to progressive muscle dysfunction in human desminopathies.

* To whom correspondence should be addressed. Tel: +49 2282875964; Fax: +49 2282875964; Email: rolf.schroeder{at}ukb.uni-bonn.de

{dagger} The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.


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