Desmin myopathy with severe cardiomyopathy in a Uruguayan family due to a codon deletion in a new location within the desmin 1A rod domain.
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.
Department of Genetics, Faculty of Medicine, University of the Republic, Montevideo, Uruguay.
Luis
L
Vernengo
Oussama
O
Chourbagi
Ana
A
Panuncio
Alain
A
Lilienbaum
Sabrina
S
Batonnet-Pichon
Francine
F
Bruston
Fernando
F
Rodrigues-Lima
Rosario
R
Mesa
Carlos
C
Pizzarossa
Laurence
L
Demay
Pascale
P
Richard
Patrick
P
Vicart
Maria-Mirta
MM
Rodriguez
D000328:Adult; D000368:Aged; D000818:Animals; D009202:Cardiomyopathies / Q000209:etiology* / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002461:Cell Line, Transformed; D004252:DNA Mutational Analysis / Q000379:methods; D003893:Desmin / Q000235:genetics* / Q000378:metabolism; D005192:Family Health; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D046529:Microscopy, Electron, Transmission / Q000379:methods; D008875:Middle Aged; D008958:Models, Molecular; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D009135:Muscular Diseases / Q000150:complications* / Q000473:pathology; D016297:Mutagenesis, Site-Directed / Q000379:methods; D017434:Protein Structure, Tertiary / Q000235:genetics; D017384:Sequence Deletion / Q000235:genetics*; D014057:Tomography, X-Ray Computed / Q000379:methods; D014162:Transfection / Q000379:methods; D014583:Uruguay
D003893:Desmin