Desminopathy

Lev G Goldfarb, National Institutes of Health, Bethesda, Maryland, USA
Montse Olivé, Institut de Neuropatologia, Barcelona, Spain
Patrick Vicart, Université Paris Diderot, Paris, France
Hans H Goebel, Mainz University Medical Center, Mainz, Germany

Published online: December 2010

DOI: 10.1002/9780470015902.a0006173.pub2

Desminopathy is one of the newly identified myopathies caused by mutations in desmin (DES), an intermediate filament, or B-crystallin (CRYAB), a chaperone for DES. The condition is defined as skeletal and cardiac myopathy characterised by the presence of chimeric aggregates in muscle fibre areas that consist of DES, CRYAB and other proteins. Identification of pathogenic mutations, analysis of underlying disease phenotypes and successful modelling of these conditions in cell cultures and transgenic mice specified critical pathogenic events. As the range of desminopathy clinical manifestations is extremely wide and myopathology not specific, diagnostic criteria need to be reliably outlined and molecular testing readily available to ensure prevention of sudden death from cardiac arrhythmias and other complications.

Key Concepts:

  • Desminopathy is associated with mutations in desmin (DES) and B-crystallin (CRYAB) genes.
  • DES is a muscle-specific type III intermediate filament; most of the known disease-associated DES mutations affect domains that are crucial for filament assembly.
  • CRYAB serves as a chaperone for DES and, if mutated, causes a disease identical to desminopathy.
  • In humans and transgenic mice, DES and CRYAB mutants invoke accumulation of chimeric intracellular aggregates containing DES, CRYAB and other cytoskeletal proteins.
  • DES mutations show diverse pathogenic effects depending on the structural relationships these mutations disrupt and the type of inheritance.
  • Desminopathy is a skeletal and cardiac myopathy. Muscle imaging (CT and MRI) is helpful in identifying characteristic patterns of skeletal muscle involvement.
  • Atrioventricular conduction abnormalities and arrhythmias are regularly present in desminopathy patients; they require urgent implantation of a permanent pacemaker or an implantable cardioverter defibrillator (ICD).
  • Respiratory insufficiency can be a major cause of disability and death and may require continuous positive airway pressure (CPAP).
  • Molecular testing of patients for DES and CRYAB mutations is available and should be used to ensure prevention of sudden death from cardiac arrhythmias and other complications.

Keywords: myopathy; desmin; B-crystallin; desmin-related myopathy; desminopathy; B-crystallinopathy; myofibrillar myopathy; cardiomyopathy; intermediate filament; chaperone

Figure 1. Schematic representation of the secondary structure of human DES and the location of DES mutations associated with desminopathy. Boxes indicate conserved helical subdomains 1A, 1B, 2A and 2B, separated by nonhelical linkers. The helical rod is flanked by N-terminal head and C-terminal tail domains. Most of the identified point mutations are located in the 2B subdomain. The 2B segment contains the highly conserved stutter and YR motif. Reproduced with permission from the American Society for Clinical Investigation, Goldfarb and Dalakas (2009).
Figure 2. Muscle pathology in a patient with a heterozygous Ile367Phe DES mutation. (a) Abnormal fibre areas containing myofibrillar inclusions visualised on trichrome-stained section (×400). (b) The inclusions display strong DES immunoreactivity (×400). (c) and (d) On electron microscopy, disrupted Z-lines, abnormal aggregates composed of dense granulofilamentous material (scale bar=1 m).
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 Further Reading
    Ferrer I and Olivé M (2008) Molecular pathology of myofibrillar myopathies. Expert Reviews in Molecular Medicine 10: e25.
    Goldfarb LG, Olivé M, Vicart P and Goebel HH (2008) Intermediate filament diseases: desminopathy. Advances in Experimental Medicine and Biology 642: 131–164.
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Related Sub-Topics:

Specific Genetic Disorders | Mutational Mechanisms of Genetic Disease | Proteins: Structure, Function, Metabolism
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Article Title: Desminopathy
 
How to Cite close
Goldfarb, Lev G, Olivé, Montse, Vicart, Patrick, and Goebel, Hans H(Dec 2010) Desminopathy. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0006173.pub2]