Desmin myopathy with severe cardiomyopathy in a Uruguayan family due to a codon deletion in a new location within the desmin 1A rod domain
Received 27 October 2009; received in revised form 17 December 2009; accepted 5 January 2010.
Abstract
Desmin myopathy is a heterogeneous neuromuscular disorder characterized by skeletal myopathy and cardiomyopathy, inherited mostly in an autosomal dominant pattern. We report a five generation Uruguayan family with severe cardiomyopathy and skeletal myopathy. Its most striking features are: atrial dilation, arrhythmia, conduction block and sudden death due to conduction impairment. Affected skeletal muscle shows alteration of mitochondria with paracrystallin inclusions and granulofilamentous material scattered in the muscle fibres. This family carries an unusual deletion p.E114del within the 1A rod domain of desmin. Transfected cells expressing the mutated desmin show punctuated and speckled cytoplasmic aggregates. The mutation causes a local conformational change in heptads a/d residues and charge positions. These findings lead to the hypothesis that coiled-coil interactions may be impaired, resulting in severe alterations in the desmin network. This is the first time that a mutation affecting this domain in the desmin molecule is described in a desminopathy.
aClinical Unit, Department of Genetics, Faculty of Medicine, University of the Republic, Av. Gral. Flores 2125, Montevideo CP 11800, Uruguay
bUniv. Paris Diderot-Paris 7, Unit of Functional and Adaptive Biology (BFA) Affiliated with CNRS, Laboratory of Stress and Pathologies of the Cytoskeleton, Bâtiment Buffon, 4e étage, 4, rue Marie-Andrée Lagroua Weill-Hallé, 75 205 Paris Cedex 13, France
cElectron Microscopy Unit, Pathology Department, Hospital de Clínicas, University of the Republic. Av. Italia s/n, Montevideo CP 11200, Uruguay
dUniv. Paris Diderot-Paris 7, Unit of Functional and Adaptive Biology (BFA) Affiliated with CNRS, Laboratory of Molecular and Cellular Responses to Xenobiotics, Bâtiment Buffon, 3e étage, 4, rue Marie-Andrée Lagroua Weill-Hallé, 75 205 Paris Cedex 13, France
eLaboratory of Neuromuscular Pathology, Hospital de Clínicas, University of the Republic, Av. Italia s/n, CP 11200 Montevideo, Uruguay
fAP-HP, Groupe Hospitalier Pitié-Salpêtrière, UF Cardiogénétique et myogénétique, Service de Biochimie Métabolique, INSERM, UMR_956, 75 013 Paris, France
ABSTRACT